**Human Immunodeficiency Virus Testing Algorithm in Resource Limiting Settings**

Teddy Charles Adias and Osaro Erhabor

Additional information is available at the end of the chapter

http://dx.doi.org/10.5772/53675

### **1. Introduction**

Testing and counseling for human immunodeficiency virus (HIV) is now recognized as a priority in national HIV programs because it is the gateway to HIV/AIDS prevention, care, treatment, and support interventions. In order to ensure access to HIV testing for large pop‐ ulations and to facilitate access to antiretroviral treatment in the context of the World Health Organization's universal access strategy, radical scaling up of HIV testing and counseling services is being advocated globally.

The use of HIV rapid tests will facilitate this in many settings, particularly in services in which the people most likely to benefit from knowing their HIV status can be reached. These Settings include diagnostic and treatment services for tuberculosis and sexually trans‐ mitted infections; services linked to the prevention of mother-to-child transmission of HIV; the management of occupational and non-occupational exposures to HIV; at voluntary counseling and testing (VCT) sites; in remote areas where the creation and maintenance of a laboratory infrastructure is not possible; and where hard-to-reach populations have access to HIV testing (PAHO, 2008).

To date, HIV testing strategies has clear objective for diagnosis, surveillance and transfusion safety. The need for appropriate selection of testing platforms and protocol had also varied from setting to setting. In general, four criteria had underpinned the choice of most appro‐ priate test or combination of tests for any given setting and depend on: General goal for test‐ ing, Diagnostic indices of sensitivity and specificity, Prevalence of HIV infection in the general population and Cost of testing (WHO, 2004).

© 2013 Adias and Erhabor; licensee InTech. This is an open access article distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/3.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited. © 2013 The Author(s). Licensee InTech. This chapter is distributed under the terms of the Creative Commons Attribution License http://creativecommons.org/licenses/by/3.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.

HIV testing is the entry point for both care and prevention. In resource limiting settings, this declaration seems more valid than ever given the increase prevalence and incidence of HIV infection in these settings and current efforts at universal access for care and prevention. The aim of this chapter is to provide trend in HIV testing Algorithm- a combination and se‐ quence of specific testing employed in given strategy for the confirmation of HIV status of an individual or sample.

initially reactive on conventional EIAs. Alternatively, repetitive testing incorporating EIAs or rapid tests selected for their specificity may be used to confirm whether specimens found to be reactive for HIV antibodies with a particular screening test are specific to HIV. For practical purposes, resource-poor settings depend heavily on EIA and rapid tests for screen‐

Human Immunodeficiency Virus Testing Algorithm in Resource Limiting Settings

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97

EIAs are the most widely used screening tests because of their suitability for analyzing large numbers of specimens, particularly in blood screening centers. Since 1985, EIAs have pro‐ gressed considerably from first to fourth generation assays: first generation assays were based on purified HIV whole viral lysates, however, sensitivity and specificity of these as‐ says were poor; second generation assays used HIV-recombinant proteins and/or synthetic peptides, which enabled the production of assays capable of detecting HIV-1 and HIV-2. The assays had improved specificity, although their overall sensitivity was similar to that of first-generation assays. Third-generation assays used the solid phase coated with recombi‐ nant antigens and /or peptides and similar recombinant antigens and peptides conjugated to a detection enzyme or hapten that could detect HIV-specific antibodies bound to a solid phase. These assays could detect immunoglobulin M, early antibodies to HIV, in addition to IgG, thus resulting in a reduction of the seroconversion window. Fourth generation assays are very similar to third-generations tests but have the ability to detect simultaneously HIV antibodies and antigens. Typical fourth-generation EIAs incorporate cocktails of HIV-1 group M (HIV-1 p24, HIV-1 gp160), HIV-1 group O, and HIV-2 antigens (HIV-2 env pep‐

Furthermore, third and fourth-generation assays are able to detect IgM and IgG antibodies to both HIV-1 and HIV-2. These assays may reduce the 2-4 week time period, "window peri‐

Simple, instrument-free assays are also available and are now widely used in Africa. They include agglutination, immunofiltration, and immunochromatographic assays. The appear‐ ance of a colored dot or line, or an agglutination pattern indicates a positive result. Most of these tests can be performed in less than 20 minutes, and are therefore called simple/rapid assays. Some simple tests, such as agglutination assays, are less rapid and may require about 30 minutes to 2 hours to be completed. In general, these rapid/simple tests are most suitable for use in settings that have limited facilities and process fewer than 100 samples

Although EIA–based serodiagnostic algorithms are highly cost effective, their application in resource-poor settings is limited by several factors. They require well-trained personnel, need a consistent supply of electricity, and maintenance and cost of most equipment. Rapid

ing and confirmation (WHO, 2004).

**2.2. Enzyme immunsorbent assays**

tide) (WHO, 2009a/b and 2004).

**2.3. Rapid/simple assays**

per day (WHO, 2009b and 2004).

*2.3.1. Importance of rapid/simple assays*

od" of detecting HIV antibodies (WHO, 2009b).

In the evolving Chapter, we shall transit with set-out for HIV testing algorithms (with ap‐ propriate sub-themes) from HIV testing evolution and forms of testing to HIV testing strat‐ egies and algorithm platforms.

### **2. HIV testing**

### **2.1. Evolution of HIV testing**

HIV screening and diagnostic tests have been developed, and a variety of testing algorithms have come into use. HIV antibody tests have evolved from first generation HIV-1(clade B) viral lysate-based, indirect antibody enzyme immunoassays (EIAs) to third generation anti‐ gen-sandwich immunoassays that use synthetic peptide and recombinant DNA derived an‐ tigens that represent the immunodominant epitopes from diverse HIV-1 and HIV-2 strains. These third generation enzyme immunoassays have substantially enhanced sensitivity to di‐ vergent viral variants and have shortened the infection-to-seroconversion window period by more than 3 weeks compared with first generation tests. Assays have also been devel‐ oped that detect and quantitate viral antigen (p24) and nucleic acids (HIV RNA or DNA) in blood, and in body fluids and tissues (Branson, 2010; WHO, 2009a).

These assays have seen increasing application in blood and organ donor screening, as well as in clinical diagnosis, prognosis, and therapeutic monitoring; and clinicians now have ac‐ cess to a broad and potentially confusing array of test options, each with its own advantages and limitations. Developing testing algorithms and interpretive criteria appropriate to a par‐ ticular group of patients—high-risk adults; blood, plasma and organ donors; recently ex‐ posed healthcare workers; paediatric patients, and especially in resource limiting settings poses a challenge, especially as new tests appear with tantalizing claims of enhanced per‐ formance (WHO, 2009a/b).

The laboratory diagnosis of the HIV infection is based on a two-stage strategy: a screening analysis followed by a confirmation analysis. A positive screening analysis must always be supplemented by a confirmation analysis on the same sample. An HIV infection can only be confirmed when the result of the confirmation analysis is positive and consistent results are obtained for two separate samples (PAHO, 2008).

Screening tests provide presumptive identification of specimens that contain antibody to HIV. These enzyme immunosorbent assays (EIAs) or simple/rapid immuno-diagnostics are selected for their high sensitivity of detecting antibodies to HIV. Supplemental or confirma‐ tory tests, such as Western blot (WB), can be used to confirm infection in samples that are initially reactive on conventional EIAs. Alternatively, repetitive testing incorporating EIAs or rapid tests selected for their specificity may be used to confirm whether specimens found to be reactive for HIV antibodies with a particular screening test are specific to HIV. For practical purposes, resource-poor settings depend heavily on EIA and rapid tests for screen‐ ing and confirmation (WHO, 2004).

#### **2.2. Enzyme immunsorbent assays**

HIV testing is the entry point for both care and prevention. In resource limiting settings, this declaration seems more valid than ever given the increase prevalence and incidence of HIV infection in these settings and current efforts at universal access for care and prevention. The aim of this chapter is to provide trend in HIV testing Algorithm- a combination and se‐ quence of specific testing employed in given strategy for the confirmation of HIV status of

In the evolving Chapter, we shall transit with set-out for HIV testing algorithms (with ap‐ propriate sub-themes) from HIV testing evolution and forms of testing to HIV testing strat‐

HIV screening and diagnostic tests have been developed, and a variety of testing algorithms have come into use. HIV antibody tests have evolved from first generation HIV-1(clade B) viral lysate-based, indirect antibody enzyme immunoassays (EIAs) to third generation anti‐ gen-sandwich immunoassays that use synthetic peptide and recombinant DNA derived an‐ tigens that represent the immunodominant epitopes from diverse HIV-1 and HIV-2 strains. These third generation enzyme immunoassays have substantially enhanced sensitivity to di‐ vergent viral variants and have shortened the infection-to-seroconversion window period by more than 3 weeks compared with first generation tests. Assays have also been devel‐ oped that detect and quantitate viral antigen (p24) and nucleic acids (HIV RNA or DNA) in

These assays have seen increasing application in blood and organ donor screening, as well as in clinical diagnosis, prognosis, and therapeutic monitoring; and clinicians now have ac‐ cess to a broad and potentially confusing array of test options, each with its own advantages and limitations. Developing testing algorithms and interpretive criteria appropriate to a par‐ ticular group of patients—high-risk adults; blood, plasma and organ donors; recently ex‐ posed healthcare workers; paediatric patients, and especially in resource limiting settings poses a challenge, especially as new tests appear with tantalizing claims of enhanced per‐

The laboratory diagnosis of the HIV infection is based on a two-stage strategy: a screening analysis followed by a confirmation analysis. A positive screening analysis must always be supplemented by a confirmation analysis on the same sample. An HIV infection can only be confirmed when the result of the confirmation analysis is positive and consistent results are

Screening tests provide presumptive identification of specimens that contain antibody to HIV. These enzyme immunosorbent assays (EIAs) or simple/rapid immuno-diagnostics are selected for their high sensitivity of detecting antibodies to HIV. Supplemental or confirma‐ tory tests, such as Western blot (WB), can be used to confirm infection in samples that are

blood, and in body fluids and tissues (Branson, 2010; WHO, 2009a).

an individual or sample.

96 Current Perspectives in HIV Infection

**2. HIV testing**

egies and algorithm platforms.

**2.1. Evolution of HIV testing**

formance (WHO, 2009a/b).

obtained for two separate samples (PAHO, 2008).

EIAs are the most widely used screening tests because of their suitability for analyzing large numbers of specimens, particularly in blood screening centers. Since 1985, EIAs have pro‐ gressed considerably from first to fourth generation assays: first generation assays were based on purified HIV whole viral lysates, however, sensitivity and specificity of these as‐ says were poor; second generation assays used HIV-recombinant proteins and/or synthetic peptides, which enabled the production of assays capable of detecting HIV-1 and HIV-2. The assays had improved specificity, although their overall sensitivity was similar to that of first-generation assays. Third-generation assays used the solid phase coated with recombi‐ nant antigens and /or peptides and similar recombinant antigens and peptides conjugated to a detection enzyme or hapten that could detect HIV-specific antibodies bound to a solid phase. These assays could detect immunoglobulin M, early antibodies to HIV, in addition to IgG, thus resulting in a reduction of the seroconversion window. Fourth generation assays are very similar to third-generations tests but have the ability to detect simultaneously HIV antibodies and antigens. Typical fourth-generation EIAs incorporate cocktails of HIV-1 group M (HIV-1 p24, HIV-1 gp160), HIV-1 group O, and HIV-2 antigens (HIV-2 env pep‐ tide) (WHO, 2009a/b and 2004).

Furthermore, third and fourth-generation assays are able to detect IgM and IgG antibodies to both HIV-1 and HIV-2. These assays may reduce the 2-4 week time period, "window peri‐ od" of detecting HIV antibodies (WHO, 2009b).

#### **2.3. Rapid/simple assays**

Simple, instrument-free assays are also available and are now widely used in Africa. They include agglutination, immunofiltration, and immunochromatographic assays. The appear‐ ance of a colored dot or line, or an agglutination pattern indicates a positive result. Most of these tests can be performed in less than 20 minutes, and are therefore called simple/rapid assays. Some simple tests, such as agglutination assays, are less rapid and may require about 30 minutes to 2 hours to be completed. In general, these rapid/simple tests are most suitable for use in settings that have limited facilities and process fewer than 100 samples per day (WHO, 2009b and 2004).

#### *2.3.1. Importance of rapid/simple assays*

Although EIA–based serodiagnostic algorithms are highly cost effective, their application in resource-poor settings is limited by several factors. They require well-trained personnel, need a consistent supply of electricity, and maintenance and cost of most equipment. Rapid assays have high sensitivity and specificity and perform as well as EIAs on specimens from persons seroconverting for non-B HIV-1 subtypes (Koblavi-Dème *et al*, 2001). Rapid enzyme assays circumvent the issue of low rates of return for serologic results associated with EIAbased testing algorithms because results can be delivered on the same day (Puro *et al*, 2004). In addition, their performance has improved considerably, and some do not require recon‐ stitution of reagents or refrigeration; thus, making them very suitable for use in resource limited settings and hard to reach populations (Koblavi-Dème *et al*, 2001). Practical applica‐ tions for the use of simple/rapid assays are in settings such as Voluntary Counseling and Testing (VCT) and Prevention of Mother to Child Transmission (PMTCT) programs. Studies have shown that using rapid assay testing algorithms result in remarkable increase in the number of HIV-positive women identified as eligible to receive the short-course therapy that reduces mother-to-child transmission of HIV (Sibailly *et al*, 2000).

### **3. HIV testing strategies and algorithm**

#### **3.1. Nature of algorithm/testing strategy**

A testing algorithm for serologic diagnosis of HIV-infection is the sequence in which assays are performed to detect HIV antibody in a body fluid. The most common referenced testing algorithm employs an EIA to screen specimens with those found to be positive then con‐ firmed by WB testing. This so-called conventional algorithm has several limitations (PAHO, 2008):


Various combinations of tests can be used: combinations of HIV EIAs; combinations of rapid tests; or an EIA in conjunction with rapid tests. The choice of strategy and of HIV tests should be determined by the quality of the tests and by the practicality of their implementa‐ tion, logistics, and the cost-benefit analysis. Figure 1, depicts the WHO/UNAIDS testing strategies which can be adopted in diverse settings

In the WHO/UNAIDS testing strategies I – III, as applicable relative to testing objective (sur‐ veillance, blood screening, or diagnosis) or diagnostic indices (sero-prevalence in a given population and the duo of sensitivity and specificity of the test being used. The three HIV testing strategies recommended by WHO and UNAIDS are described below (Figure 1) (WHO, 2009a; UNAID/WHO, 1998).

**Figure 1.** Schematic Representation of the WHO/UNAIDS HIV Testing Strategy(Adapted from WHO, 2009a/b and UN‐

Human Immunodeficiency Virus Testing Algorithm in Resource Limiting Settings

http://dx.doi.org/10.5772/53675

99

AID/WHO,1998)

assays have high sensitivity and specificity and perform as well as EIAs on specimens from persons seroconverting for non-B HIV-1 subtypes (Koblavi-Dème *et al*, 2001). Rapid enzyme assays circumvent the issue of low rates of return for serologic results associated with EIAbased testing algorithms because results can be delivered on the same day (Puro *et al*, 2004). In addition, their performance has improved considerably, and some do not require recon‐ stitution of reagents or refrigeration; thus, making them very suitable for use in resource limited settings and hard to reach populations (Koblavi-Dème *et al*, 2001). Practical applica‐ tions for the use of simple/rapid assays are in settings such as Voluntary Counseling and Testing (VCT) and Prevention of Mother to Child Transmission (PMTCT) programs. Studies have shown that using rapid assay testing algorithms result in remarkable increase in the number of HIV-positive women identified as eligible to receive the short-course therapy

A testing algorithm for serologic diagnosis of HIV-infection is the sequence in which assays are performed to detect HIV antibody in a body fluid. The most common referenced testing algorithm employs an EIA to screen specimens with those found to be positive then con‐ firmed by WB testing. This so-called conventional algorithm has several limitations (PAHO,

**•** WB often yields indeterminate results with certain types of specimens with uncertain di‐

**•** Both ELISA and WB are time consuming and require a well-equipped laboratory infra‐

Various combinations of tests can be used: combinations of HIV EIAs; combinations of rapid tests; or an EIA in conjunction with rapid tests. The choice of strategy and of HIV tests should be determined by the quality of the tests and by the practicality of their implementa‐ tion, logistics, and the cost-benefit analysis. Figure 1, depicts the WHO/UNAIDS testing

In the WHO/UNAIDS testing strategies I – III, as applicable relative to testing objective (sur‐ veillance, blood screening, or diagnosis) or diagnostic indices (sero-prevalence in a given population and the duo of sensitivity and specificity of the test being used. The three HIV testing strategies recommended by WHO and UNAIDS are described below (Figure 1)

that reduces mother-to-child transmission of HIV (Sibailly *et al*, 2000).

agnostic significance, e.g., hyperimmunoglobulinemia specimens.

**3. HIV testing strategies and algorithm**

**•** WB is expensive and requires technical expertise.

strategies which can be adopted in diverse settings

(WHO, 2009a; UNAID/WHO, 1998).

**3.1. Nature of algorithm/testing strategy**

98 Current Perspectives in HIV Infection

2008):

structure.

**Figure 1.** Schematic Representation of the WHO/UNAIDS HIV Testing Strategy(Adapted from WHO, 2009a/b and UN‐ AID/WHO,1998)

### **Strategy I:**


prenatal clinics where blood specimens are taken for other testing purposes, the set-up may allow for HIV EIA-based algorithms or algorithms combining EIA and rapid tests (Owusu-

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101

Another factor determining the most cost-efficient approach is the volume of specimens to be processed daily or weekly. An EIA test is half the price of a rapid test, so if a particular setting processes 40 specimens a day and the laboratory has the required equipment, it is more cost effective to use EIAs than rapid tests. It is important that the HIV tests and algo‐ rithms be chosen carefully and with the aim of optimal integration into the existing health care facilities, minimizing the potential to disrupt their operations or unnecessarily overbur‐

There are many strategies for HIV testing (Parekh *et al*, 2010; WHO, 2009a/b; P*aul et al, 2004*). WHO, CDC, and the Association of Public Health Laboratories have jointly developed one of the most useful references for HIV testing algorithms. These strategies can be divided into

In a Serial or sequential testing strategy, samples are initially tested with only one, highly sensitive assay. Samples that are reactive in the first assay are then re-tested using a second, highly specific assay. A third test may be performed, depending on the result of the second assay and the objective of the testing. Both the selection of and the order in which the assays are used are of the utmost importance for the final outcome of the tests. If test combinations are not carefully selected, individuals may be incorrectly diagnosed. WHO recommends se‐ quential testing (Figure 2) in most settings because it is more economical, as the second test is required only when the initial test result is positive (Gershy=Damet *et al*, 2010; WHO,

In a parallel testing strategy (Figure 3), samples are tested using two different assays simul‐ taneously. This approach is rather expensive, as it virtually doubles the cost of testing in low- prevalence settings by requiring two tests at the outset. As with sequential testing, a third test may be performed preferably at the secondary level, where laboratory facilities and experienced staff are available, depending on the result of the assays and the objective

Therefore, the parallel testing strategy is recommended only in situations in which it can add value. Prenatal clinics provide one such example: A woman's first visit to the clinic may be to deliver her child, thus requiring a rapid decision whether an intervention to prevent mother-to-child transmission of HIV is needed. Other emergency situations, such as work accidents, sexual violence, and discordant couples also would benefit from this strategy. In these cases, two rapid tests using whole-blood finger-stick specimens in parallel will pro‐

two approaches: serial (or sequential) testing and parallel testing.

Ofori et al, 2005; Routet et al, 2004).

den staff.

**3.2. Algorithm platforms**

2009a/b; Ferreira *et al*, 2005).

*3.2.2. Parallel testing strategy*

of the testing (WHO, 2009a/b).

*3.2.1. Serial/sequential testing strategy*


#### **Strategy II:**


#### **Strategy III:**


Sensitivity and specificity are two important factors that determine a test's accuracy in dis‐ tinguishing between HIV-infected and uninfected individuals. It is crucial that the HIV tests used in the algorithms all have a sensitivity of at least 99% and a specificity of at least 98% (WHO, 2009a and 1997). There are commercially available HIV EIAs and HIV rapid tests that meet these criteria. When selecting HIV tests to be used in combination, it is important to select tests that do not share the same false positive and same false negative results. This information can be obtained from comparative evaluation studies of HIV test kits, such as those published in international scientific publications and in WHO reports (WHO, 2009a/b). It is recommended that such comparative evaluations of a select number of HIV test kits be conducted at the national and/or regional level prior to the establishment of the national HIV test algorithms. These principles apply to both conventional HIV EIA and HIV rapid tests. The national reference laboratory should validate a select number of test kits for use in the national HIV testing algorithms.

Specific implementation requirements must be considered when selecting tests kits and al‐ gorithms. For example, will testing be performed in a laboratory setting, or in a VCT or clini‐ cal setting without extensive laboratory facilities? In settings without extensive laboratory facilities or where clients do not return for follow-up visits, algorithms using only rapid tests are preferred. In situations in which patients return at regular intervals (e.g., TB clinics) or in prenatal clinics where blood specimens are taken for other testing purposes, the set-up may allow for HIV EIA-based algorithms or algorithms combining EIA and rapid tests (Owusu-Ofori et al, 2005; Routet et al, 2004).

Another factor determining the most cost-efficient approach is the volume of specimens to be processed daily or weekly. An EIA test is half the price of a rapid test, so if a particular setting processes 40 specimens a day and the laboratory has the required equipment, it is more cost effective to use EIAs than rapid tests. It is important that the HIV tests and algo‐ rithms be chosen carefully and with the aim of optimal integration into the existing health care facilities, minimizing the potential to disrupt their operations or unnecessarily overbur‐ den staff.

There are many strategies for HIV testing (Parekh *et al*, 2010; WHO, 2009a/b; P*aul et al, 2004*). WHO, CDC, and the Association of Public Health Laboratories have jointly developed one of the most useful references for HIV testing algorithms. These strategies can be divided into two approaches: serial (or sequential) testing and parallel testing.

### **3.2. Algorithm platforms**

**Strategy I:**

**Strategy II:**

**Strategy III:**

**•** Requires one test.

100 Current Perspectives in HIV Infection

No results are provided.

**•** Requires up to two tests.

**•** Requires up to three tests.

use in the national HIV testing algorithms.

tomatic persons.

with clinical signs or symptoms of HIV infection.

**•** For use in blood screening, for all prevalence rates.

transmitted infection clinics). No results are provided.

**•** For use in diagnostic testing in populations with an HIV prevalence >30% among persons

**•** For use in surveillance testing in populations with an HIV prevalence >10% (example: un‐ linked anonymous testing for surveillance among pregnant women at antenatal clinics).

**•** For use in diagnostic testing in populations with an HIV prevalence ≤30% among persons with clinical signs or symptoms of HIV infection or >10% among asymptomatic persons.

**•** For use in surveillance testing in populations with an HIV prevalence ≤10% (example: un‐ linked anonymous testing for surveillance among patients at antenatal clinics or sexually

**•** For use in diagnostic testing in populations with an HIV prevalence ≤10% among asymp‐

Sensitivity and specificity are two important factors that determine a test's accuracy in dis‐ tinguishing between HIV-infected and uninfected individuals. It is crucial that the HIV tests used in the algorithms all have a sensitivity of at least 99% and a specificity of at least 98% (WHO, 2009a and 1997). There are commercially available HIV EIAs and HIV rapid tests that meet these criteria. When selecting HIV tests to be used in combination, it is important to select tests that do not share the same false positive and same false negative results. This information can be obtained from comparative evaluation studies of HIV test kits, such as those published in international scientific publications and in WHO reports (WHO, 2009a/b). It is recommended that such comparative evaluations of a select number of HIV test kits be conducted at the national and/or regional level prior to the establishment of the national HIV test algorithms. These principles apply to both conventional HIV EIA and HIV rapid tests. The national reference laboratory should validate a select number of test kits for

Specific implementation requirements must be considered when selecting tests kits and al‐ gorithms. For example, will testing be performed in a laboratory setting, or in a VCT or clini‐ cal setting without extensive laboratory facilities? In settings without extensive laboratory facilities or where clients do not return for follow-up visits, algorithms using only rapid tests are preferred. In situations in which patients return at regular intervals (e.g., TB clinics) or in

#### *3.2.1. Serial/sequential testing strategy*

In a Serial or sequential testing strategy, samples are initially tested with only one, highly sensitive assay. Samples that are reactive in the first assay are then re-tested using a second, highly specific assay. A third test may be performed, depending on the result of the second assay and the objective of the testing. Both the selection of and the order in which the assays are used are of the utmost importance for the final outcome of the tests. If test combinations are not carefully selected, individuals may be incorrectly diagnosed. WHO recommends se‐ quential testing (Figure 2) in most settings because it is more economical, as the second test is required only when the initial test result is positive (Gershy=Damet *et al*, 2010; WHO, 2009a/b; Ferreira *et al*, 2005).

#### *3.2.2. Parallel testing strategy*

In a parallel testing strategy (Figure 3), samples are tested using two different assays simul‐ taneously. This approach is rather expensive, as it virtually doubles the cost of testing in low- prevalence settings by requiring two tests at the outset. As with sequential testing, a third test may be performed preferably at the secondary level, where laboratory facilities and experienced staff are available, depending on the result of the assays and the objective of the testing (WHO, 2009a/b).

Therefore, the parallel testing strategy is recommended only in situations in which it can add value. Prenatal clinics provide one such example: A woman's first visit to the clinic may be to deliver her child, thus requiring a rapid decision whether an intervention to prevent mother-to-child transmission of HIV is needed. Other emergency situations, such as work accidents, sexual violence, and discordant couples also would benefit from this strategy. In these cases, two rapid tests using whole-blood finger-stick specimens in parallel will pro‐ vide the answer in just 10–15 minutes. HIV rapid tests using wholeblood finger-stick speci‐ mens have great potential in situations where results need to be known quickly, or where taking a conventional venous sample is difficult (Gershy-Damet *et al*, 2010; WHO, 2009a/b; Ferreira *et al*, 2005).

**Figure 3.** Parallel Testing Algorithm (Adapted from WHO, 2009a/b)

HIV testing is the essential entry point for both treatment and prevention. As in all societies, especially in Africa, high degree of genetic diversity exist. One implication for this is the need for each country to have an in-house evaluation of its country –specific testing strat‐ egy. The selection of a national algorithm is the responsibility of the country's Ministry of Health. The choice of sequential or parallel testing should be made after a thorough analysis of the scientific evidence, logistics, test performance requirements, and cost/affordability of

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103

**4. Conclusion**

the various algorithms.

**Figure 2.** Serial/ Sequential Testing Algorithm (Adapted from WHO, 2009a/b)

**Figure 3.** Parallel Testing Algorithm (Adapted from WHO, 2009a/b)

#### **4. Conclusion**

vide the answer in just 10–15 minutes. HIV rapid tests using wholeblood finger-stick speci‐ mens have great potential in situations where results need to be known quickly, or where taking a conventional venous sample is difficult (Gershy-Damet *et al*, 2010; WHO, 2009a/b;

**Figure 2.** Serial/ Sequential Testing Algorithm (Adapted from WHO, 2009a/b)

Ferreira *et al*, 2005).

102 Current Perspectives in HIV Infection

HIV testing is the essential entry point for both treatment and prevention. As in all societies, especially in Africa, high degree of genetic diversity exist. One implication for this is the need for each country to have an in-house evaluation of its country –specific testing strat‐ egy. The selection of a national algorithm is the responsibility of the country's Ministry of Health. The choice of sequential or parallel testing should be made after a thorough analysis of the scientific evidence, logistics, test performance requirements, and cost/affordability of the various algorithms.

### **Author details**

Teddy Charles Adias1\* and Osaro Erhabor2

\*Address all correspondence to: teddyadias@yahoo.com

1 Bayelsa State College of Health Technology, Ogbia Town, Yenagoa, Nigeria

2 Department of Blood Sciences, Royal Bolton Hospital NHS Trust UK, Bolton, United King‐ dom

algorithm for diagnosis and differentiation of HIV type 1 (HIV-1), HIV-2, and dual HIV-1–HIV-2 infections in West African pregnant women. *J Clin Microbiol.* 42(9):

Human Immunodeficiency Virus Testing Algorithm in Resource Limiting Settings

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105

[11] Sibailly TS, Ekpini ER, Kamelan-Tanoh A, *et al* (2000). Impact of on-site HIV rapid testing with same-day post-test counseling on acceptance of short-course zidovudine for the prevention of mother-to-child transmission of HIV in Abidjan, Côte d'Ivoire.

[12] UNAIDS/WHO (1998). UNAIDS/WHO Recommendations. The importance of sim‐ ple/rapid assays in HIV testing. Weekly Epidemiological Record. 73:321-28.

[13] World Health Organisation ( WHO) (2009a). *HIV assays. Operational characteristics.* Re‐

[14] World Health Organisation (WHO) (2009b). Guidelines for using HIV testing tech‐ nologies in surveillance: Selection, Evaluation and Implementation 2009 Update

[15] World Health Organisation (WHO) (2004). Rapid HIV tests: guidelines for use in

[16] WHO/UNAIDS (1997). Revised Recommendations for the selection and use of HIV

HIV testing and counseling services in resource-constrained settings.

4147–4153.

*The XIII International AIDS 2000 Conference*.

antibody tests. WHO Weekly Epidemiol*. 72:* 81-7.

port 16. *Rapid assay*. Geneva.

### **References**


algorithm for diagnosis and differentiation of HIV type 1 (HIV-1), HIV-2, and dual HIV-1–HIV-2 infections in West African pregnant women. *J Clin Microbiol.* 42(9): 4147–4153.

**Author details**

104 Current Perspectives in HIV Infection

dom

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Teddy Charles Adias1\* and Osaro Erhabor2

\*Address all correspondence to: teddyadias@yahoo.com

1 Bayelsa State College of Health Technology, Ogbia Town, Yenagoa, Nigeria

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[3] Gershy-Damet G, Rotz P, Cross, D, *et al* (2010). The World Health Organization Afri‐ can region laboratory accreditation process: Improving the quality of laboratory sys‐

[4] Koblavi-Dème S, Maurice C, Yavo D, *et al* (2001). Sensitivity and specificity of HIV rapid serologic assays and testing algorithms in an antenatal clinic in Abidjan, Côte

[5] Owusu-Ofori S, Temple J, Sarkodie F, Anokwa M, Candotti D, Allain JP (2005). Pre‐ donation screening of blood donors with rapid tests: Implementation and efficacy of a novel approach to blood safety in resource-poor settings. *Transfusion*. 45(2):133–140.

[6] Pan American Health Organisation (PAHO) (2008). Guidelines for the implementa‐ tion of Reliable and Efficient Diagnostic HIV Testing, Region of the Americas.

[7] Parekh B, Kalou M, Alemnji G, Ou C, *et al* (2010). Scaling up HIV rapid testing in de‐ veloping countries: comprehensive approach for implementing quality assurance.

[8] Paul SM, Grimes-Dennis J, Burr CK, DiFerdinando GT (2003). Rapid diagnostic test‐

[9] Puro V, Francisci D, Sighinolfi L, Civljak R, Belfiori B, Deparis P, et al (2004) Benefits of a rapid HIV test for evaluation of the source patient after occupational exposure of

[10] Rouet F, Ekouevi DK, Inwoley A, Chaix ML, Burgard M, Bequet L, et al (2004). Field evaluation of a rapid human immunodeficiency virus (HIV) serial serologic testing


**Section 3**

**HIV and NeuroAIDS**

**Section 3**

**HIV and NeuroAIDS**

**Chapter 6**

**NeuroAIDS: Mechanisms, Causes,**

Shailendra K. Saxena, Sneham Tiwari and

Additional information is available at the end of the chapter

Madhavan P.N. Nair

**1. Introduction**

http://dx.doi.org/10.5772/55100

**Prevalence, Diagnostics and Social Issues**

Human immunodeficiency virus-1 (HIV-1) engulfs 33 millions of life as per the latest UN AIDS report [Saxena, Tiwari., *et al.,* 2012] and the effect worsens up when it causes dementia with alarming occurrence worldwide but the mechanism through which it happens is still not well understood, and is in the embryonic stages. The estimated overall prevalence of nervous system disorders among patients receiving highly active antiretrovi‐ ral therapy but also requiring neurological care is over 25% (Singh *et al.,* 2011). Accord‐ ing to WHO there are ~ 34 million people in the world infected with HIV. Out of that 95 percent of these cases as well as deaths from AIDS occur in the developing world. Dementia (HIV-associated dementia) is becoming common in HIV infected adults having prevalence up to 40% in western countries where clade B prevails (Sacktor *et al.,* 2007). Dementia cannot be considered as a disease by itself but it is the term used to describe a set of symptoms resulting from damages and disorders affecting the brain. These symp‐ toms can be caused by a multitude of diseases and depend upon the specific brain regions affected. These symptoms appear as a variety of cognitive, behavioural, affective, motor, and psychiatric disorders. Dementia can be caused by a variety of diseases, known as neurodegenerative diseases resulting from protein aggregation in the brain. Many studies related to this area are been carried out in respect to this, to provide new insights (Saxena *et al.,* 2012). HIV-1 infects macrophages and microglia, and there is an indirect pathway to neuronal injury which happens due to release of macrophage, microglial and astrocytes toxins and viral proteins. The toxins which are released over stimulate neurons, form free radicals, finally leading to neurodegenerative diseases. The cognitive and motor dysfunc‐ tion which is observed in HIV patients is termed as HIV associated dementia (HAD). The

> © 2013 Saxena et al.; licensee InTech. This is an open access article distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/3.0), which permits unrestricted use,

© 2013 The Author(s). Licensee InTech. This chapter is distributed under the terms of the Creative Commons Attribution License http://creativecommons.org/licenses/by/3.0), which permits unrestricted use, distribution,

distribution, and reproduction in any medium, provided the original work is properly cited.

and reproduction in any medium, provided the original work is properly cited.

**Chapter 6**

### **NeuroAIDS: Mechanisms, Causes, Prevalence, Diagnostics and Social Issues**

Shailendra K. Saxena, Sneham Tiwari and Madhavan P.N. Nair

Additional information is available at the end of the chapter

http://dx.doi.org/10.5772/55100

### **1. Introduction**

Human immunodeficiency virus-1 (HIV-1) engulfs 33 millions of life as per the latest UN AIDS report [Saxena, Tiwari., *et al.,* 2012] and the effect worsens up when it causes dementia with alarming occurrence worldwide but the mechanism through which it happens is still not well understood, and is in the embryonic stages. The estimated overall prevalence of nervous system disorders among patients receiving highly active antiretrovi‐ ral therapy but also requiring neurological care is over 25% (Singh *et al.,* 2011). Accord‐ ing to WHO there are ~ 34 million people in the world infected with HIV. Out of that 95 percent of these cases as well as deaths from AIDS occur in the developing world. Dementia (HIV-associated dementia) is becoming common in HIV infected adults having prevalence up to 40% in western countries where clade B prevails (Sacktor *et al.,* 2007). Dementia cannot be considered as a disease by itself but it is the term used to describe a set of symptoms resulting from damages and disorders affecting the brain. These symp‐ toms can be caused by a multitude of diseases and depend upon the specific brain regions affected. These symptoms appear as a variety of cognitive, behavioural, affective, motor, and psychiatric disorders. Dementia can be caused by a variety of diseases, known as neurodegenerative diseases resulting from protein aggregation in the brain. Many studies related to this area are been carried out in respect to this, to provide new insights (Saxena *et al.,* 2012). HIV-1 infects macrophages and microglia, and there is an indirect pathway to neuronal injury which happens due to release of macrophage, microglial and astrocytes toxins and viral proteins. The toxins which are released over stimulate neurons, form free radicals, finally leading to neurodegenerative diseases. The cognitive and motor dysfunc‐ tion which is observed in HIV patients is termed as HIV associated dementia (HAD). The

© 2013 Saxena et al.; licensee InTech. This is an open access article distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/3.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited. © 2013 The Author(s). Licensee InTech. This chapter is distributed under the terms of the Creative Commons Attribution License http://creativecommons.org/licenses/by/3.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.

prevalence of the dementia is eventually increasing as AIDS patients are now surviving more. HIV-1 replicates in monocyte and macrophage but not as severe as in infected T cells and blood mononuclear cells (Sundaravaradan *et al.,* 2006). These cells differentiate and travel to several organs, henceforth acting as a source of infectious virus and secret‐ ed viral proteins to cause pathological issues and alternating several signalling pathways and distorting many cellular transcription factors, ultimately resulting in HIV-1 pathogen‐ esis. Increased transcription leads to the upregulation of virus production, and hence increased production of viral proteins (gp120, Tat, Nef, and Vpr) (Gandhi et al., 2020; Samikkannu et al., 2010; Saiyed et al., 2011; Saxena et al., 2012; Saxena et al., 2012). The high concentration of these toxic proteins lead to distorted cellular functions, and in‐ creased production of toxic metabolites, finally leading to organ-specific like neuroAIDS, in case of viral entry inside the brain (Kilareski et al., 2009). Antiretroviral therapy has increased the lifespan of HIV patients, but CNS function often remains diminished sometimes developing into HIV-associated dementia and the severity and progression of dementia is studied to be increased with the effect of drug abuse [Reddy *et al.,* 2012; Ferris *et al.,* 2008].

enters the central nervous system through infected monocytes and leads to pathogenesis involving activation of macrophages and microglia and further toxin release, that activates several pathways leading to neuronal dysfunction. There are several extracellular and intracellular signalling pathways, which when activated lead to macrophage or microglial activation, and induction in neurons and astrocytes. These pathways are of potential thera‐

NeuroAIDS: Mechanisms, Causes, Prevalence, Diagnostics and Social Issues

http://dx.doi.org/10.5772/55100

111

peutic importance as targets for the prevention or treatment of neuropathogenesis.

**Figure 1.** HIV virus can enter the CNS by altering the integrity of blood brain barrier.

HIV-1 is capable of causing a multi-system disorder including the CNS. HIV-1 enters the CNS at the early phase of infection, it persists and induces several motor and cognitive disorders leading to behavioural changes. Major clinical symptoms include impaired short termmemory, reduced mental concentration, weakness, slowness of hand and leg movement and depression accompanied by behavioural issues like personality disorders, lethargy and social withdrawal. These neurological and psychiatric symptoms caused by HIV-1 infection, constitute together as neuropathogenesis. A more subtle form of CNS dysfunction, known as minor cognitive motor disorder (MCMD), is also seen common in HIV patients. HAD cannot be controlled by HAART, HIV-1 infection becomes chronic and even rise in disease has been reported. The HIV-1 associated neuropathology is characterized by the infiltration of macro‐

**4. Neuropathology of AIDS**

### **2. Prevalence**

The prevalence of HAD is estimated to be more than 30% of HIV infected patients, and it is still reported to be increasing (Dean *et al*., 2012). Improvements in control of peripheral viral replication and the treatment of opportunistic infections, helps in extending life expectancy, resulting in an increase in neuropathogenesis. We are seeing a linear increase in prevalence in rich countries, but an exponential increase in low-income countries. Just under half of people with dementia live in high-income countries, 39% live in middle-income countries, and only 14% live in low-income countries. Increasing living standards, in low income countries such as India (Shankar *et al*., 2005), may lead to increased life expectancy, which may increase the frequency of dementia cases. As biggest risk factor for dementia is age, a longer-living global population means there will be more people with dementia. The report predicts that the numbers of people with dementia will double every 20 years, to 65.7 million in 2030 and 115.4 million in 2050. Most of this increase will be in developing countries (Prince *et al.,* 2012). A more complete understanding of the pathogenesis of HAD will help in identifying therapeutic targets for its prevention and treatment. The global age standardized death rate for dementia is ~ 6.7 per 100,000 for males and 7.7 per 100,000 for females. According to the World Health Organization, dementia mortality rate for India is 13.5 per 100,000 males and 11.1 for 100,000 females, which is quite alarming (Prince *et al.,* 2012).

### **3. HIV- Mechanism of neuronal injury**

Presently, neuropathogenesis is winning, because there is an incomplete knowledge about the mechanism of HIV infection causing neuronal injury and apoptosis in the host (Fig. 1). HIV enters the central nervous system through infected monocytes and leads to pathogenesis involving activation of macrophages and microglia and further toxin release, that activates several pathways leading to neuronal dysfunction. There are several extracellular and intracellular signalling pathways, which when activated lead to macrophage or microglial activation, and induction in neurons and astrocytes. These pathways are of potential thera‐ peutic importance as targets for the prevention or treatment of neuropathogenesis.

**Figure 1.** HIV virus can enter the CNS by altering the integrity of blood brain barrier.

### **4. Neuropathology of AIDS**

prevalence of the dementia is eventually increasing as AIDS patients are now surviving more. HIV-1 replicates in monocyte and macrophage but not as severe as in infected T cells and blood mononuclear cells (Sundaravaradan *et al.,* 2006). These cells differentiate and travel to several organs, henceforth acting as a source of infectious virus and secret‐ ed viral proteins to cause pathological issues and alternating several signalling pathways and distorting many cellular transcription factors, ultimately resulting in HIV-1 pathogen‐ esis. Increased transcription leads to the upregulation of virus production, and hence increased production of viral proteins (gp120, Tat, Nef, and Vpr) (Gandhi et al., 2020; Samikkannu et al., 2010; Saiyed et al., 2011; Saxena et al., 2012; Saxena et al., 2012). The high concentration of these toxic proteins lead to distorted cellular functions, and in‐ creased production of toxic metabolites, finally leading to organ-specific like neuroAIDS, in case of viral entry inside the brain (Kilareski et al., 2009). Antiretroviral therapy has increased the lifespan of HIV patients, but CNS function often remains diminished sometimes developing into HIV-associated dementia and the severity and progression of dementia is studied to be increased with the effect of drug abuse [Reddy *et al.,* 2012; Ferris

The prevalence of HAD is estimated to be more than 30% of HIV infected patients, and it is still reported to be increasing (Dean *et al*., 2012). Improvements in control of peripheral viral replication and the treatment of opportunistic infections, helps in extending life expectancy, resulting in an increase in neuropathogenesis. We are seeing a linear increase in prevalence in rich countries, but an exponential increase in low-income countries. Just under half of people with dementia live in high-income countries, 39% live in middle-income countries, and only 14% live in low-income countries. Increasing living standards, in low income countries such as India (Shankar *et al*., 2005), may lead to increased life expectancy, which may increase the frequency of dementia cases. As biggest risk factor for dementia is age, a longer-living global population means there will be more people with dementia. The report predicts that the numbers of people with dementia will double every 20 years, to 65.7 million in 2030 and 115.4 million in 2050. Most of this increase will be in developing countries (Prince *et al.,* 2012). A more complete understanding of the pathogenesis of HAD will help in identifying therapeutic targets for its prevention and treatment. The global age standardized death rate for dementia is ~ 6.7 per 100,000 for males and 7.7 per 100,000 for females. According to the World Health Organization, dementia mortality rate for India is 13.5 per 100,000 males and 11.1 for 100,000

Presently, neuropathogenesis is winning, because there is an incomplete knowledge about the mechanism of HIV infection causing neuronal injury and apoptosis in the host (Fig. 1). HIV

*et al.,* 2008].

**2. Prevalence**

110 Current Perspectives in HIV Infection

females, which is quite alarming (Prince *et al.,* 2012).

**3. HIV- Mechanism of neuronal injury**

HIV-1 is capable of causing a multi-system disorder including the CNS. HIV-1 enters the CNS at the early phase of infection, it persists and induces several motor and cognitive disorders leading to behavioural changes. Major clinical symptoms include impaired short termmemory, reduced mental concentration, weakness, slowness of hand and leg movement and depression accompanied by behavioural issues like personality disorders, lethargy and social withdrawal. These neurological and psychiatric symptoms caused by HIV-1 infection, constitute together as neuropathogenesis. A more subtle form of CNS dysfunction, known as minor cognitive motor disorder (MCMD), is also seen common in HIV patients. HAD cannot be controlled by HAART, HIV-1 infection becomes chronic and even rise in disease has been reported. The HIV-1 associated neuropathology is characterized by the infiltration of macro‐ phages into the CNS, the formation of microglial nodules and multinucleated giant cells, astrocyte activation and damage; neuronal loss in ganglions and hippocampus, myelin damage, axonal damage and presence of HIV-1 in the CSF. MRI reports say that HIV infection is associated with progressive cortical atrophy which might be caused by neuronal loss and demyelination worsening in certain cognitive functions (Ghafouri *et al.,* 2006).

dysregulation by letting sufficient entry of infected or activated immune cells into the brain

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http://dx.doi.org/10.5772/55100

113

BBB is selectively permeable, made up of firmly concurrent brain microvascular endothelial cells, and its major role is to separate the CNS from the periphery. It manages the trafficking of cells and molecules across it into the brain parenchyma. For the purpose of brain entry, HIV-1 has to cross the BBB using several mechanisms which are still poorly understood and are unclear. Numerous *in vitro* experimentations have been done to understand the mecha‐ nisms of HIV-1 introduction into the CNS via BBB. It is reported that the severity of HIV-1 associated neuropathogenesis is dependent on amount of HIV DNA circulating in PBMCs (Shiramizu *et al*., 2009). It is hypothesized that HIV-1 enters the CNS, in disguise as a commuter in cells trafficking till the brain (Verma *et al.,* 2010). CD4+ cells, like T cells and monocytes are infected by HIV-1, which circulate in blood and have the ability to cross the BBB and introduce the infection into CNS. Though presence of CD4 receptors in human brain microvascular endothelial cells is still a matter of debate whereas its presence is studied along with expression of HIV-1 co-receptors have also being reported on primary human brain's microvascular endothelial cells. Other proposed hypothesis for the entry of HIV-1 is the migration between/ transcytosis of endothelial cells. All types of the CNS cells like astrocytes (Wang *et al.,* 2009), oligodendrocytes, neurons, macrophage and microglia, are easily infected by HIV-1 as they have receptors and co-receptors for HIV-1 entry, but only macrophage and microglia get infected most commonly which are the resident immunocompetent cells of the brain (Gen‐ dleman *et al*., 1985). Expression of CCL2/MCP-1 in astrocytes is enhanced by nef via calmodulin dependent pathway. Consequently, increased CCL2/MCP-1 functions as a chemoattractant for monocytes, thereby facilitating entry of monocytes into the brain (Lehmann *et al.,* 2006). Peripheral macrophage population is necessary to be refilled, which is compensated by the migration of monocytes into the CNS, resulting in major drawback of facilitating the entry of intracellular virus. Microglia and monocyte-derived macrophages are the main culprits of HIV-1 CNS infection. Immunostaining experiments have shown HIV-1 infection in parenchy‐ mal microglia, but it is still unclear that whether the HIV-1 immunopositive microglia receives influx of infected cells from blood or directly results from prolonged infection in the CNS. *Invitro* experiments demonstrate that HIV-1 replication takes place in primary microglia isolated from adults and infants leading to cytopathology. Microglial cells are the major targets as they express CD4/CCR5 major receptors/co-receptors which is a necessity for HIV-1 infection. On the other hand astrocytes express CXCR4 and other HIV-1 coreceptors like CCR5, but do not express CD4 receptors and are still reported to be infected by HIV-1 mechanisms to which are still unclear. Also i*n vivo*, oligodendrocytes infection by HIV-1 remains unclear and less understood as they do not have CD4 receptors. Mostly there is absence of *in vivo* infection in neurons, however sometimes presence of HIV-1 DNA and proteins in neurons have been reported too, leading to need of further studies. Various pathways for the entry of virus into the brain have been studied like (i) direct entry, (ii) transcytosis, (iii) Trojan horse hypothesis

causing neuronal injury.

**6. Types of CNS cells invaded by HIV-1**

### **5. HIV entry into the brain and initiation of HAD**

HIV-1 infects cells having major HIV-1 receptors, CD4 and CD8, and several chemokine receptors which are known to be as HIV-1 co-receptors which help in the attachment of the virus to the cell and membrane fusion leading to viral entry. Infected CD4+ T cells and monocytes circulating in the blood are the potential source of CNS infection. HIV-1 infected cells can be either highly active producers or low/non producers of viruses. Both types of infections occur in the CNS. Studies of different astrocytes cell lines, demonstrated the presence of large quantities of Rev in the cytoplasm. Changes in cell environment, like the elevation in the level of cytokines such as TNF-α and IL-1β, might reactivate virus production (Ghafouri *et al.,* 2006). During early infection, HIV enters the CNS (Bertin *et al.,* 2012) and attacks cells macrophages and microglial cells (Foley *et al.,* 2008). But along with this infection, periphery factors (non-CNS) are also important for initiating neurodegener‐ ation and triggering dementia, which are like for example; increased number of circulat‐ ing monocytes that express CD16 and CD69. The cells which get activated by viral entry, progressively adhere to the endothelium membrane of the brain microvasculature, and further transmigrate, triggering a spontaneous array of harmful processes which might finally lead to the loss of Blood Brain Barrier (BBB) integrity making it easy for virus to enter and replicate inside the brain. The BBB is crucial in HIV infection of the CNS. BBB is composed of specialized Human brain microvascular endothelial cells (HBMECs), which do not have any opening and are connected by intercellular junctions in an impermeable single layer. BBB plays a central role in neuropathogenesis as it serves as the channel through which free virus and infected immune cells enter the brain. The BBB loses its integrity and permeability due to progressive HIV infection and immune compromisa‐ tion, which leads to easy entry of toxins, free virus, infected and activated monocytes into the brain. It has been reported that HIV-1 gp120 protein and also Tat protein are behind BBB disregulation. PKC signaling pathways and receptor-mediated Ca2+ release are the involved pathways resulting into cytotoxicity of the brain endothelial cells (Kanmogne *et al.,* 2005) leading to downregulation and rupture of tight junction proteins (TJPs) of HBMECs, by the induction of proteasome by HIV-1. It has been studied that circulating virus or envelope proteins may also cause BBB dysfunction during primary infection. CNS infection of HIV is detected by viral RNA load in CSF (Woods *et al.,* 2009; Morgan *et al.,* 2011). Chemokines like monocyte chemoattractant protein (MCP)-1 control PBMCs relocation through BBB. Cellular migration engages adhesion molecules and differential regulation of inflammatory cytokines, leading to BBB disintegration and finally immune dysregulation by letting sufficient entry of infected or activated immune cells into the brain causing neuronal injury.

### **6. Types of CNS cells invaded by HIV-1**

phages into the CNS, the formation of microglial nodules and multinucleated giant cells, astrocyte activation and damage; neuronal loss in ganglions and hippocampus, myelin damage, axonal damage and presence of HIV-1 in the CSF. MRI reports say that HIV infection is associated with progressive cortical atrophy which might be caused by neuronal loss and

HIV-1 infects cells having major HIV-1 receptors, CD4 and CD8, and several chemokine receptors which are known to be as HIV-1 co-receptors which help in the attachment of the virus to the cell and membrane fusion leading to viral entry. Infected CD4+ T cells and monocytes circulating in the blood are the potential source of CNS infection. HIV-1 infected cells can be either highly active producers or low/non producers of viruses. Both types of infections occur in the CNS. Studies of different astrocytes cell lines, demonstrated the presence of large quantities of Rev in the cytoplasm. Changes in cell environment, like the elevation in the level of cytokines such as TNF-α and IL-1β, might reactivate virus production (Ghafouri *et al.,* 2006). During early infection, HIV enters the CNS (Bertin *et al.,* 2012) and attacks cells macrophages and microglial cells (Foley *et al.,* 2008). But along with this infection, periphery factors (non-CNS) are also important for initiating neurodegener‐ ation and triggering dementia, which are like for example; increased number of circulat‐ ing monocytes that express CD16 and CD69. The cells which get activated by viral entry, progressively adhere to the endothelium membrane of the brain microvasculature, and further transmigrate, triggering a spontaneous array of harmful processes which might finally lead to the loss of Blood Brain Barrier (BBB) integrity making it easy for virus to enter and replicate inside the brain. The BBB is crucial in HIV infection of the CNS. BBB is composed of specialized Human brain microvascular endothelial cells (HBMECs), which do not have any opening and are connected by intercellular junctions in an impermeable single layer. BBB plays a central role in neuropathogenesis as it serves as the channel through which free virus and infected immune cells enter the brain. The BBB loses its integrity and permeability due to progressive HIV infection and immune compromisa‐ tion, which leads to easy entry of toxins, free virus, infected and activated monocytes into the brain. It has been reported that HIV-1 gp120 protein and also Tat protein are behind BBB disregulation. PKC signaling pathways and receptor-mediated Ca2+ release are the involved pathways resulting into cytotoxicity of the brain endothelial cells (Kanmogne *et al.,* 2005) leading to downregulation and rupture of tight junction proteins (TJPs) of HBMECs, by the induction of proteasome by HIV-1. It has been studied that circulating virus or envelope proteins may also cause BBB dysfunction during primary infection. CNS infection of HIV is detected by viral RNA load in CSF (Woods *et al.,* 2009; Morgan *et al.,* 2011). Chemokines like monocyte chemoattractant protein (MCP)-1 control PBMCs relocation through BBB. Cellular migration engages adhesion molecules and differential regulation of inflammatory cytokines, leading to BBB disintegration and finally immune

demyelination worsening in certain cognitive functions (Ghafouri *et al.,* 2006).

**5. HIV entry into the brain and initiation of HAD**

112 Current Perspectives in HIV Infection

BBB is selectively permeable, made up of firmly concurrent brain microvascular endothelial cells, and its major role is to separate the CNS from the periphery. It manages the trafficking of cells and molecules across it into the brain parenchyma. For the purpose of brain entry, HIV-1 has to cross the BBB using several mechanisms which are still poorly understood and are unclear. Numerous *in vitro* experimentations have been done to understand the mecha‐ nisms of HIV-1 introduction into the CNS via BBB. It is reported that the severity of HIV-1 associated neuropathogenesis is dependent on amount of HIV DNA circulating in PBMCs (Shiramizu *et al*., 2009). It is hypothesized that HIV-1 enters the CNS, in disguise as a commuter in cells trafficking till the brain (Verma *et al.,* 2010). CD4+ cells, like T cells and monocytes are infected by HIV-1, which circulate in blood and have the ability to cross the BBB and introduce the infection into CNS. Though presence of CD4 receptors in human brain microvascular endothelial cells is still a matter of debate whereas its presence is studied along with expression of HIV-1 co-receptors have also being reported on primary human brain's microvascular endothelial cells. Other proposed hypothesis for the entry of HIV-1 is the migration between/ transcytosis of endothelial cells. All types of the CNS cells like astrocytes (Wang *et al.,* 2009), oligodendrocytes, neurons, macrophage and microglia, are easily infected by HIV-1 as they have receptors and co-receptors for HIV-1 entry, but only macrophage and microglia get infected most commonly which are the resident immunocompetent cells of the brain (Gen‐ dleman *et al*., 1985). Expression of CCL2/MCP-1 in astrocytes is enhanced by nef via calmodulin dependent pathway. Consequently, increased CCL2/MCP-1 functions as a chemoattractant for monocytes, thereby facilitating entry of monocytes into the brain (Lehmann *et al.,* 2006). Peripheral macrophage population is necessary to be refilled, which is compensated by the migration of monocytes into the CNS, resulting in major drawback of facilitating the entry of intracellular virus. Microglia and monocyte-derived macrophages are the main culprits of HIV-1 CNS infection. Immunostaining experiments have shown HIV-1 infection in parenchy‐ mal microglia, but it is still unclear that whether the HIV-1 immunopositive microglia receives influx of infected cells from blood or directly results from prolonged infection in the CNS. *Invitro* experiments demonstrate that HIV-1 replication takes place in primary microglia isolated from adults and infants leading to cytopathology. Microglial cells are the major targets as they express CD4/CCR5 major receptors/co-receptors which is a necessity for HIV-1 infection. On the other hand astrocytes express CXCR4 and other HIV-1 coreceptors like CCR5, but do not express CD4 receptors and are still reported to be infected by HIV-1 mechanisms to which are still unclear. Also i*n vivo*, oligodendrocytes infection by HIV-1 remains unclear and less understood as they do not have CD4 receptors. Mostly there is absence of *in vivo* infection in neurons, however sometimes presence of HIV-1 DNA and proteins in neurons have been reported too, leading to need of further studies. Various pathways for the entry of virus into the brain have been studied like (i) direct entry, (ii) transcytosis, (iii) Trojan horse hypothesis for entry, which states that HIV enters the CNS via infected CD4 + AND T-cells which are capable of crossing BBB and they reach CNS and are also capable of transferring infection to other CNS cells too (Fig. 2).

cellular entry via BBB (Kraft-Terry *et al.,* 2010). Also CD16+ monocytes are linked to infection of the brain as they can be easily infected by the virus, they carry virus into the brain and help in viral dissemination and serve as viral reservoirs as they are apoptosis resistant. HIV proteins like nef require adaptive selection in brain for efficient replication in macrophages or when it is exposed to brain specific immune selection (Olivieri *et al.,* 2010). Neuropsychiatric disorders associated with HIV infection result in substantial morbidity and fatality. HIV injures the CNS and PNS, leading to neuropsychiatric disorders, which together constitute for neuroAIDS (McCombe *et al*.,2009), which includes neurocognitive disorders like HAD, minor neurocog‐ nitive disorder (HAND), mania, anxiety, depression, seizures, myelopathy and neuropathy, and also involves display of several symptoms like neurocognitive impairment, mood disorders, neuropathic pain, epilepsy, addiction, physical disability, loss of memory, mood

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**Figure 3.** Associated disorders and symptoms which are commonly seen in patients suffering from neuroAIDS.

swings etc (Fig.3).

**Figure 2.** HIV-1 neuroinvasion. 1) "Trojan Horse hypothesis" for entry of HIV-1 into the brain via migration of infected monocytes which differentiate into perivascular macrophage. 2) The passage of infected CD4+ T cells into the brain. Other probable causes of CNS infection might be: 3) the direct entrance of the virus via tight junctions across the membrane and 4) entrance of HIV-1 by transcytosis phenomenon.

### **7. Crosstalk between the peripheral and CNS immunity**

The way by which HIV-1-infected monocytes escape immune surveillance can be explained by "Trojan horse cell" model. The "support" needed for the viral entry is through CNSproduced chemokines like MCP-1 and IFN-γ-inducible peptide, CXCL10, whereas the "opposition" is through peripheral immune activation (Yadav *et al*., 2009). Upon entry in the brain, HIV-1-infected blood-borne macrophages secrete proinflammatory cytokines like tumor necrosis factor alpha (TNF-α), interleukin-1 beta (IL-1β), and viral proteins which affect neuronal function (Brabers and Nottet, 2006). Within the brain, astrocytes serve as principal regulators for neural homeostasis. They bring out a neurotoxic secretory response in macro‐ phages, resulting to upregulation of certain acids and metabolites, chemokines, and cytokine secretions. They can also alter macrophage phenotype, which may help in neuroprotection. But on the contrary astrocytes can also influence autocrine and paracrine inflammatory cascades, which may lead to immune activation, increased viral infection, and allowance of cellular entry via BBB (Kraft-Terry *et al.,* 2010). Also CD16+ monocytes are linked to infection of the brain as they can be easily infected by the virus, they carry virus into the brain and help in viral dissemination and serve as viral reservoirs as they are apoptosis resistant. HIV proteins like nef require adaptive selection in brain for efficient replication in macrophages or when it is exposed to brain specific immune selection (Olivieri *et al.,* 2010). Neuropsychiatric disorders associated with HIV infection result in substantial morbidity and fatality. HIV injures the CNS and PNS, leading to neuropsychiatric disorders, which together constitute for neuroAIDS (McCombe *et al*.,2009), which includes neurocognitive disorders like HAD, minor neurocog‐ nitive disorder (HAND), mania, anxiety, depression, seizures, myelopathy and neuropathy, and also involves display of several symptoms like neurocognitive impairment, mood disorders, neuropathic pain, epilepsy, addiction, physical disability, loss of memory, mood swings etc (Fig.3).

for entry, which states that HIV enters the CNS via infected CD4 + AND T-cells which are capable of crossing BBB and they reach CNS and are also capable of transferring infection to

**Figure 2.** HIV-1 neuroinvasion. 1) "Trojan Horse hypothesis" for entry of HIV-1 into the brain via migration of infected monocytes which differentiate into perivascular macrophage. 2) The passage of infected CD4+ T cells into the brain. Other probable causes of CNS infection might be: 3) the direct entrance of the virus via tight junctions across the

The way by which HIV-1-infected monocytes escape immune surveillance can be explained by "Trojan horse cell" model. The "support" needed for the viral entry is through CNSproduced chemokines like MCP-1 and IFN-γ-inducible peptide, CXCL10, whereas the "opposition" is through peripheral immune activation (Yadav *et al*., 2009). Upon entry in the brain, HIV-1-infected blood-borne macrophages secrete proinflammatory cytokines like tumor necrosis factor alpha (TNF-α), interleukin-1 beta (IL-1β), and viral proteins which affect neuronal function (Brabers and Nottet, 2006). Within the brain, astrocytes serve as principal regulators for neural homeostasis. They bring out a neurotoxic secretory response in macro‐ phages, resulting to upregulation of certain acids and metabolites, chemokines, and cytokine secretions. They can also alter macrophage phenotype, which may help in neuroprotection. But on the contrary astrocytes can also influence autocrine and paracrine inflammatory cascades, which may lead to immune activation, increased viral infection, and allowance of

membrane and 4) entrance of HIV-1 by transcytosis phenomenon.

**7. Crosstalk between the peripheral and CNS immunity**

other CNS cells too (Fig. 2).

114 Current Perspectives in HIV Infection

**Figure 3.** Associated disorders and symptoms which are commonly seen in patients suffering from neuroAIDS.

### **8. Forms of dementia**

One form of dementia is Alzheimer's disease caused by amyloid pathology, during which peptides of amyloid-β generate and clump together into plaques which release toxic fragments of amyloid-β leading to neuropathogenesis. Another form of dementia is caused by vascular pathology in which blood vessels leak and hence deprives small areas of the brain of blood and oxygen, which damage brain tissue resulting in cognitive defects. Both forms exist equally, even though Alzheimer pathology is more common, but it coexists with vascular pathology. (Abott *et al.,* 2011).

decline in memory and disturbance in several cognitive abilities like coherent speech, understanding spoken or written language, recognizing objects, executing motor activi‐ ties, sensory function, thinking abstractly, making sound judgments, planning and carrying out complex tasks. Dementia reduces the lifespan of affected people. In the developed countries life span after dementia diagnosis can be expected to be ~7 years, but in low and middle income countries survival may be shorter. Dementia symptoms and linked issues can be understood in three stages of early stage (1-2 years) which is often overlooked because the onset of dementia is gradual, making it difficult to predict when it begins, leading to problems in talking, memory loss. Secondly, the middle stage (2-5 years) which makes patients life more difficult and restricted, giving them difficulty in day-to-day living and forgetting recent events and people's names, etc. Thirdly, the late stage (>5 years) leading to total dependence and inactivity, serious memory disturbances difficulty in physical works like walking, eating, incapability of communicating, not recognizing familiar

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HIV associated dementia, referred as the syndrome of cognitive and motor dysfunction resulting in progressive neurodegeneration observed after infection with human HIV-1, also known as HIV encephalopathy (HIV-E) and AIDS dementia complex (ADC) (Kaul *et al.,* 2001). In the last stage of HIV, HAD a severe neurological complication affects 15–20% of the patients (Van de Bovenkamp *et al.,* 2002). The relationship between spreading of HIV in brain tissue and pathology has not been thoroughly assessed in HAART era (Lamers *et al.,* 2010). Inspite of preventing former end stage complications of AIDS by HAART however, with increased survival times, the prevalence of minor HIV-1 associated cognitive impairment appears to be rising among AIDS patients. Further, HIV-1 associated dementia (HAD) is still prevalent in treated patients as well as attenuated forms of HAD and CNS opportunistic disorders (Ghafouri *et al.,* 2006). Infected macrophages with HIV have an ability to cross BBB infect inhabitant brain macrophages initiating the development of HAD. Cytokines are released from infected resident brain macrophages which further attract more macrophages to sites of infection and a series of self-inflammatory process emerges (Williams *et al.,* 2002). Studies have suggested that the process of entering in the CNS causing HAD mostly depends on the HIV variants as some HIV variants have capability of entering in the CNS and develops HAD but in contrast other variants don't have capability to develop HAD even after entering

Some studies suggest that neurological involvement of infected patients occurs at differ‐ ent frequencies, depending on the HIV subtype involved in the infection (Liner 2nd *et al.,* 2007). HIV-1 Subtype D has more prominent chance for developing dementia (89%) than subtype A (24%) in the patients localized in a region of Uganda, Africa suggesting genetic determinants exist within HIV that influence the ability of the virus to replicate in the central nervous system. HIV-1 proteins have been shown to be released from HIV infected cell and/ or they have found to be present in the extracellular milieu in the HIV-1-

objects, displaying inappropriate behavior in public etc.

in the CNS (Fischer-Smith *et al.,* 2008; Fischer-Smith *et al.,* 2005).

**10. Underlying mechanisms and issues**


**Table 1.** Displaying the types of dementia and their prevelance. (Source: Abbott A. Dementia: a problem for our age. *Nature.* 2011; 475(7355): S2-4)

### **9. Knowing dementia and its diagnosis**

Dementia is considered as loss of memory and other cognitive abilities which reduces the lifespan of patients. Dementia is often associated with physical, mental and financial burden. 37% of the dementic population in developing countries have vulnerable living environ‐ ment and they require specialised care. Diagnosis of dementia involves investigations for

decline in memory and disturbance in several cognitive abilities like coherent speech, understanding spoken or written language, recognizing objects, executing motor activi‐ ties, sensory function, thinking abstractly, making sound judgments, planning and carrying out complex tasks. Dementia reduces the lifespan of affected people. In the developed countries life span after dementia diagnosis can be expected to be ~7 years, but in low and middle income countries survival may be shorter. Dementia symptoms and linked issues can be understood in three stages of early stage (1-2 years) which is often overlooked because the onset of dementia is gradual, making it difficult to predict when it begins, leading to problems in talking, memory loss. Secondly, the middle stage (2-5 years) which makes patients life more difficult and restricted, giving them difficulty in day-to-day living and forgetting recent events and people's names, etc. Thirdly, the late stage (>5 years) leading to total dependence and inactivity, serious memory disturbances difficulty in physical works like walking, eating, incapability of communicating, not recognizing familiar objects, displaying inappropriate behavior in public etc.

HIV associated dementia, referred as the syndrome of cognitive and motor dysfunction resulting in progressive neurodegeneration observed after infection with human HIV-1, also known as HIV encephalopathy (HIV-E) and AIDS dementia complex (ADC) (Kaul *et al.,* 2001). In the last stage of HIV, HAD a severe neurological complication affects 15–20% of the patients (Van de Bovenkamp *et al.,* 2002). The relationship between spreading of HIV in brain tissue and pathology has not been thoroughly assessed in HAART era (Lamers *et al.,* 2010). Inspite of preventing former end stage complications of AIDS by HAART however, with increased survival times, the prevalence of minor HIV-1 associated cognitive impairment appears to be rising among AIDS patients. Further, HIV-1 associated dementia (HAD) is still prevalent in treated patients as well as attenuated forms of HAD and CNS opportunistic disorders (Ghafouri *et al.,* 2006). Infected macrophages with HIV have an ability to cross BBB infect inhabitant brain macrophages initiating the development of HAD. Cytokines are released from infected resident brain macrophages which further attract more macrophages to sites of infection and a series of self-inflammatory process emerges (Williams *et al.,* 2002). Studies have suggested that the process of entering in the CNS causing HAD mostly depends on the HIV variants as some HIV variants have capability of entering in the CNS and develops HAD but in contrast other variants don't have capability to develop HAD even after entering in the CNS (Fischer-Smith *et al.,* 2008; Fischer-Smith *et al.,* 2005).

### **10. Underlying mechanisms and issues**

**8. Forms of dementia**

116 Current Perspectives in HIV Infection

(Abott *et al.,* 2011).

Alzheimer's

Vascular dementia

Frontotemporal dementia

Dementia with Lewy bodies

*Nature.* 2011; 475(7355): S2-4)

One form of dementia is Alzheimer's disease caused by amyloid pathology, during which peptides of amyloid-β generate and clump together into plaques which release toxic fragments of amyloid-β leading to neuropathogenesis. Another form of dementia is caused by vascular pathology in which blood vessels leak and hence deprives small areas of the brain of blood and oxygen, which damage brain tissue resulting in cognitive defects. Both forms exist equally, even though Alzheimer pathology is more common, but it coexists with vascular pathology.

**TYPES OF DEMENTIA**

Formation of amyloid plaques and also neurofibrillary tangles.

Causing microstrokes due to reduced blood flow to brain

Damage limited to frontal and

Cortical Lewy bodies (of the protein a-synuclein) inside

temporal lobes

neurons.

**Table 1.** Displaying the types of dementia and their prevelance. (Source: Abbott A. Dementia: a problem for our age.

Dementia is considered as loss of memory and other cognitive abilities which reduces the lifespan of patients. Dementia is often associated with physical, mental and financial burden. 37% of the dementic population in developing countries have vulnerable living environ‐ ment and they require specialised care. Diagnosis of dementia involves investigations for

**Percentage of total dementia**

**cases**

50–80%

20–30%

5–10%

<5%

**Dementia type Symptoms Neuropathological findings**

Weakened memory power, leading to confusion, disinterest depression and bad judgement

Memory is weakened, but not as intense as in the case of Alzheimer's patients.

Personality disorders, mood swings and difficulty in understanding different

Weakened memory power, leading to confusion, disinterest depression and bad judgement skills, hallucinations and tremors.

skills.

languages.

**9. Knowing dementia and its diagnosis**

Some studies suggest that neurological involvement of infected patients occurs at differ‐ ent frequencies, depending on the HIV subtype involved in the infection (Liner 2nd *et al.,* 2007). HIV-1 Subtype D has more prominent chance for developing dementia (89%) than subtype A (24%) in the patients localized in a region of Uganda, Africa suggesting genetic determinants exist within HIV that influence the ability of the virus to replicate in the central nervous system. HIV-1 proteins have been shown to be released from HIV infected cell and/ or they have found to be present in the extracellular milieu in the HIV-1infected brain. In vitro, neurotoxic and/or neuromodulatory effects have been shown by HIV proteins: nef, env, tat, rev, vpr and vpu that might play a role in the development of HIV-1-associated dementia in vivo (Sactor *et al.,* 2009).

always a necessity. Adjunctive therapy like platelet-activating factor (PAF) antagonist, PMS-601, are demonstrated to reduce HAND symptoms and even combination of ART and PAF antagonists, are also studied to have role in reducing neurodegeneration. All of these are also being developed as therapies for neurodegenerative disorders which may prove to be a boon in the combat against NeuroAIDS. Need of the hour is to device an exact combination of CNS-penetrating nanoART and adjunctive therapies, which might be able to help us against

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**Figure 4.** Comparative display of nanocarrier mediated method of drug delivery (A) versus the classical method of drug de‐

Since dementia is quite prevalent in HIV patients, in developed countries and has also been reported to extend its grip towards developing countries as well due to increase in patient survival rates and life expectancy due to HAART treatment and increased living standards. Low prevalence of HAD in underdeveloped and developing countries have been attributed to under diagnosis, short life expectancy and short survival following HIV infection associated with opportunistic infections and also low prevalence of HIV related neuroinfections and pathology is not available due to inadequate medical facilities, social stigma and ignorance that lead to under diagnosis (Vivithanaporn *et al.,* 2010). So a need of collaboratory studies is there which can be used, for learning the cause, prevalence and diagnosis of neuropathogen‐

livery across the Blood Brain Barrier (BBB), which is less efficient than the former in the process of drug delivery.

**13. Future implications and need of the hour**

neurocognitive symptoms (Kraft-Terry *et al.,* 2010).

### **11. Fight against dementia**

Dementia is engulfing bigger proportion of HIV patients and is expected to worsen more. It is expected that a significant proportion of dementia is driven by amyloid-β. But so far none of the amyloid-based strategies has been successful, but still drug developers are strategising on the concept which can combat against it. More reliable biomarkers are being developed potentially making it possible to carry out trials on patients before symptoms. Some scientists are also wondering to target vascular pathology as well, which is equally responsible for causing dementia. So cholesterol level lowering drugs and blood pressure reducing drugs are also given long term to patients, who are at higher risk of heart attack which may also help protect from dementias as well (Abott *et al.,* 2011). There are several extracellular and intra‐ cellular signalling pathways, which when activated lead to macrophage or microglial activa‐ tion, and induction in neurons and astrocytes. These pathways may act as a potential therapeutic importance as drug targets against neuropathogenesis. NeuroAIDS is challenge to patients, their families, society and our country, thus development of preclinical models appropriate for new compounds testing with neurotrophic and neuroprotective potential is necessary (Crews *et al.,* 2008; Williams *et al.,* 2008).

### **12. Therapeutic developments**

The biggest issue which comes in front of drug developers is the incapability of the drugs to cross the BBB, which leads to low bioavailability of the drugs into the CNS. HIV-1 protease inhibitors are totally incapable in entering the CNS, while other HIV-1 therapies such as zidovudine (AZT) are reported to have efficient BBB penetration. Recently, a broad range of nanomedicines are being developed to improve drug delivery across BBB, development of nanoparticulate– antiretroviral therapy (nanoART), against CNS disorders as the structure of the BBB, efflux pumps and the expression of metabolic enzymes make it difficult for the regular drug to reach brain. Nanoformulations can evade the BBB and can boost CNS-directed drug delivery (Fig. 4) (Saxena *et al.,* 2012; Nowacek *et al.,* 2010; Nowacek *et al.,* 2009). Efforts are been done in finding long-lasting injectable antiretrovirals to avoid the challenges of therapy adherence (Baert *et al.,* 2009). To specifically target the CNS, NPs are synthesized with various combinations of ART therapies to be taken up by monocytes and carried into the CNS for release at sites of HIV-1 infection, for example Indinavir nanoART and p24 loaded and coated NP, which are providing new avenues for treating or even preventing the spread of HIV-1 in the brain. Adjunctive therapeutics ART is engaged in making combinatory drugs against virus mutation. Efforts are being made to improve penetrability of ART across the BBB, but impor‐ tance of considering drug toxicity and elicited cellular response for various ART regiments is always a necessity. Adjunctive therapy like platelet-activating factor (PAF) antagonist, PMS-601, are demonstrated to reduce HAND symptoms and even combination of ART and PAF antagonists, are also studied to have role in reducing neurodegeneration. All of these are also being developed as therapies for neurodegenerative disorders which may prove to be a boon in the combat against NeuroAIDS. Need of the hour is to device an exact combination of CNS-penetrating nanoART and adjunctive therapies, which might be able to help us against neurocognitive symptoms (Kraft-Terry *et al.,* 2010).

**Figure 4.** Comparative display of nanocarrier mediated method of drug delivery (A) versus the classical method of drug de‐ livery across the Blood Brain Barrier (BBB), which is less efficient than the former in the process of drug delivery.

### **13. Future implications and need of the hour**

infected brain. In vitro, neurotoxic and/or neuromodulatory effects have been shown by HIV proteins: nef, env, tat, rev, vpr and vpu that might play a role in the development of

Dementia is engulfing bigger proportion of HIV patients and is expected to worsen more. It is expected that a significant proportion of dementia is driven by amyloid-β. But so far none of the amyloid-based strategies has been successful, but still drug developers are strategising on the concept which can combat against it. More reliable biomarkers are being developed potentially making it possible to carry out trials on patients before symptoms. Some scientists are also wondering to target vascular pathology as well, which is equally responsible for causing dementia. So cholesterol level lowering drugs and blood pressure reducing drugs are also given long term to patients, who are at higher risk of heart attack which may also help protect from dementias as well (Abott *et al.,* 2011). There are several extracellular and intra‐ cellular signalling pathways, which when activated lead to macrophage or microglial activa‐ tion, and induction in neurons and astrocytes. These pathways may act as a potential therapeutic importance as drug targets against neuropathogenesis. NeuroAIDS is challenge to patients, their families, society and our country, thus development of preclinical models appropriate for new compounds testing with neurotrophic and neuroprotective potential is

The biggest issue which comes in front of drug developers is the incapability of the drugs to cross the BBB, which leads to low bioavailability of the drugs into the CNS. HIV-1 protease inhibitors are totally incapable in entering the CNS, while other HIV-1 therapies such as zidovudine (AZT) are reported to have efficient BBB penetration. Recently, a broad range of nanomedicines are being developed to improve drug delivery across BBB, development of nanoparticulate– antiretroviral therapy (nanoART), against CNS disorders as the structure of the BBB, efflux pumps and the expression of metabolic enzymes make it difficult for the regular drug to reach brain. Nanoformulations can evade the BBB and can boost CNS-directed drug delivery (Fig. 4) (Saxena *et al.,* 2012; Nowacek *et al.,* 2010; Nowacek *et al.,* 2009). Efforts are been done in finding long-lasting injectable antiretrovirals to avoid the challenges of therapy adherence (Baert *et al.,* 2009). To specifically target the CNS, NPs are synthesized with various combinations of ART therapies to be taken up by monocytes and carried into the CNS for release at sites of HIV-1 infection, for example Indinavir nanoART and p24 loaded and coated NP, which are providing new avenues for treating or even preventing the spread of HIV-1 in the brain. Adjunctive therapeutics ART is engaged in making combinatory drugs against virus mutation. Efforts are being made to improve penetrability of ART across the BBB, but impor‐ tance of considering drug toxicity and elicited cellular response for various ART regiments is

HIV-1-associated dementia in vivo (Sactor *et al.,* 2009).

necessary (Crews *et al.,* 2008; Williams *et al.,* 2008).

**12. Therapeutic developments**

**11. Fight against dementia**

118 Current Perspectives in HIV Infection

Since dementia is quite prevalent in HIV patients, in developed countries and has also been reported to extend its grip towards developing countries as well due to increase in patient survival rates and life expectancy due to HAART treatment and increased living standards. Low prevalence of HAD in underdeveloped and developing countries have been attributed to under diagnosis, short life expectancy and short survival following HIV infection associated with opportunistic infections and also low prevalence of HIV related neuroinfections and pathology is not available due to inadequate medical facilities, social stigma and ignorance that lead to under diagnosis (Vivithanaporn *et al.,* 2010). So a need of collaboratory studies is there which can be used, for learning the cause, prevalence and diagnosis of neuropathogen‐

esis. A synchronised effort is needed by researchers, drug makers, physicians, policy makers, government bodies nationally as well as globally. A proper and deep understanding about the entry of the virus into the CNS and the various mechanisms it employs to undertake the host machinery would be of great help in understanding the issue and combating against the virus. [9] Fischer-smith, T, Bell, C, Croul, S, Lewis, M, & Rappaport, J. (2008). Monocyte/ macrophage trafficking in acquired immunodeficiency syndrome encephalitis: les‐ sons from human and nonhuman primate studies." *J Neurovirol*. , 14(4), 318-326.

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121

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### **Author details**

Shailendra K. Saxena1 , Sneham Tiwari1 and Madhavan P.N. Nair2


### **References**


[9] Fischer-smith, T, Bell, C, Croul, S, Lewis, M, & Rappaport, J. (2008). Monocyte/ macrophage trafficking in acquired immunodeficiency syndrome encephalitis: les‐ sons from human and nonhuman primate studies." *J Neurovirol*. , 14(4), 318-326.

esis. A synchronised effort is needed by researchers, drug makers, physicians, policy makers, government bodies nationally as well as globally. A proper and deep understanding about the entry of the virus into the CNS and the various mechanisms it employs to undertake the host machinery would be of great help in understanding the issue and combating against the virus.

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**Author details**

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, Sneham Tiwari1

1 Centre for Cellular and Molecular Biology (CCMB-CSIR), Hyderabad, India

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[30] Sacktor, N, Nakasujja, N, Robertson, K, & Clifford, D. B. (2007). HIV-associated cog‐ nitive impairment in sub-Saharan Africa--the potential effect of clade diversity." *Nat*

[31] Sacktor, N, Nakasujja, N, Skolasky, R. L, Rezapour, M, Robertson, K, Musisi, S, & Quinn, T. C. (2009). HIV subtype D is associated with dementia, compared with sub‐ type A, in immunosuppressed individuals at risk of cognitive impairment in Kampa‐

[32] Saiyed, Z. M, Gandhi, N, Agudelo, M, Napuri, J, Samikkannu, T, Reddy, P. V, Kha‐ tavkar, P, Yndart, A, Saxena, S. K, & Nair, M. P. (2011). HIV-1 Tat upregulates ex‐

population-based survey." *Int J Geriatr Psychiatry*. , 27(7), 670-82.

*Neurosci*. , 34(2), 83-85.

122 Current Perspectives in HIV Infection

tive adults." *Neuropsychology*. , 25(5), 645-654.

livery." *Nanomedicine* (Lond). , 4(5), 557-574.

*Hum Retroviruses.* , 26(4), 495-500.

therapeutics." *J Neuroimmune Pharmacol*. Epub, 5(4), 592-601.

tion-based cohort study." *Lancet. 380*(9836), 50-58.

Disorder." *AIDS Res Treat.* 2012: 953678.

la, Uganda." *Clin Infect Dis*. , 49(5), 780-786.

*Clin Pract Neurol*. , 3(8), 436-443.


[44] Verma, A. S, Singh, U. P, Dwivedi, P. D, & Singh, A. (2010). Contribution of CNS cells in NeuroAIDS." *J Pharm Bioallied Sci.* , 2(4), 300-306.

**Chapter 7**

**Human Immunodeficiency Virus Infection and**

HIV/AIDS is probably the most challenging and pressing health issue of our time. Cur‐ rent estimates show that over 40million people are now living with HIV. Despite the availability of antiretroviral therapy, the provision of this treatment continues to pose a big challenge for various reasons. Globally, of the 6 million people requiring treatment, only 8% receive it – with considerable geographical inequity ie. High income countries vs. low income countries. Despite understanding the risk factors for HIV infection, the incidence of new HIV cases has not reduced at an acceptable rate. An unprecedented number of people still have no access to treatment and continue to die from HIV related problems. This has brought about devastating social and economic consequences at coun‐ try level, family level and at personal level. A considerable number of individuals suffer from mental disorders resulting from being HIV infected. Independently, mental disor‐ ders make a substantial independent contribution to the burden of disease worldwide. The recognition of mental disorders as a major contributor to the global burden of dis‐ ease has led to an increase in the demand for the inclusion of mental health services in primary health care as well as in community-based health surveys in order to improve screening, diagnosis and treatment of mental distress. It is estimated that, neuropsychiat‐ ric conditions account for up to 15% of all disability-adjusted life-years, and up to 30% of those attributable to non-communicable diseases. Neuropsychiatric disorders also ac‐ count for 1.2 million deaths every year. These figures are most likely underestimated as official statistics especially in low and middle income countries are scanty and unrelia‐ ble. In sub-Saharan Africa, it has been reported that 20–30% of primary health care cen‐ tre attendees present with depressive symptoms as the first or secondary reason for seeking medical care. A study conducted in Tanzania revealed a 41.6% prevalence of de‐

> © 2013 Chipimo and Fylkesnes; licensee InTech. This is an open access article distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/3.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.

> © 2013 The Author(s). Licensee InTech. This chapter is distributed under the terms of the Creative Commons Attribution License http://creativecommons.org/licenses/by/3.0), which permits unrestricted use, distribution,

and reproduction in any medium, provided the original work is properly cited.

**Co-Morbid Mental Distress**

Peter J. Chipimo and Knut Fylkesnes

http://dx.doi.org/10.5772/53696

**1. Introduction**

Additional information is available at the end of the chapter


## **Human Immunodeficiency Virus Infection and Co-Morbid Mental Distress**

Peter J. Chipimo and Knut Fylkesnes

Additional information is available at the end of the chapter

http://dx.doi.org/10.5772/53696

### **1. Introduction**

[44] Verma, A. S, Singh, U. P, Dwivedi, P. D, & Singh, A. (2010). Contribution of CNS

[45] Vivithanaporn, P, Heo, G, Gamble, J, Krentz, H. B, Hoke, A, Gill, M. J, & Power, C. (2010). Neurologic disease burden in treated HIV/AIDS predicts survival: a popula‐

[46] Wang, T, Gong, N, Liu, J, Kadiu, I, Kraft-terry, S. D, Schlautman, J. D, Ciborowski, P, Volsky, D. J, & Gendelman, H. E. (2008). HIV-1-infected astrocytes and the microglial

[47] Williams, K. C, & Hickey, W. F. (2002). Central nervous system damage, monocytes and macrophages, and neurological disorders in AIDS." *Annu Rev Neurosci*. , 25,

[48] Williams, R, Bokhari, S, Silverstein, P, Pinson, D, Kumar, A, & Buch, S. (2008). Non‐

[49] Woods, S. P, Moore, D. J, Weber, E, & Grant, I. (2009). Cognitive neuropsychology of HIV-associated neurocognitive disorders." *Neuropsychol Rev*. , 19(2), 152-168.

[50] Yadav, A, & Collman, R. G. (2009). CNS inflammation and macrophage/microglial biology associated with HIV-1 infection." *J Neuroimmune Pharmacol.* , 4(4), 430-447.

human primate models of NeuroAIDS." *J Neurovirol. 14*(4), 292-300.

cells in NeuroAIDS." *J Pharm Bioallied Sci.* , 2(4), 300-306.

tion-based study." *Neurology.* , 75(13), 1150-1158.

proteome." *J Neuroimmune Pharmacol.* , 3(3), 173-186.

537-562.

124 Current Perspectives in HIV Infection

HIV/AIDS is probably the most challenging and pressing health issue of our time. Cur‐ rent estimates show that over 40million people are now living with HIV. Despite the availability of antiretroviral therapy, the provision of this treatment continues to pose a big challenge for various reasons. Globally, of the 6 million people requiring treatment, only 8% receive it – with considerable geographical inequity ie. High income countries vs. low income countries. Despite understanding the risk factors for HIV infection, the incidence of new HIV cases has not reduced at an acceptable rate. An unprecedented number of people still have no access to treatment and continue to die from HIV related problems. This has brought about devastating social and economic consequences at coun‐ try level, family level and at personal level. A considerable number of individuals suffer from mental disorders resulting from being HIV infected. Independently, mental disor‐ ders make a substantial independent contribution to the burden of disease worldwide. The recognition of mental disorders as a major contributor to the global burden of dis‐ ease has led to an increase in the demand for the inclusion of mental health services in primary health care as well as in community-based health surveys in order to improve screening, diagnosis and treatment of mental distress. It is estimated that, neuropsychiat‐ ric conditions account for up to 15% of all disability-adjusted life-years, and up to 30% of those attributable to non-communicable diseases. Neuropsychiatric disorders also ac‐ count for 1.2 million deaths every year. These figures are most likely underestimated as official statistics especially in low and middle income countries are scanty and unrelia‐ ble. In sub-Saharan Africa, it has been reported that 20–30% of primary health care cen‐ tre attendees present with depressive symptoms as the first or secondary reason for seeking medical care. A study conducted in Tanzania revealed a 41.6% prevalence of de‐

© 2013 Chipimo and Fylkesnes; licensee InTech. This is an open access article distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/3.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited. © 2013 The Author(s). Licensee InTech. This chapter is distributed under the terms of the Creative Commons Attribution License http://creativecommons.org/licenses/by/3.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.

pressive symptoms among primary health care patients while a similar study in Uganda reported a 20–30% prevalence of psychological disorders and depression among health care seekers. These research findings have also shown heightened risk for common men‐ tal disorders among the women i.e. a female to male ratio of 1.5–2.0. Other determinants have been found to include low socioeconomic position indicated by poor access to re‐ sources, unemployment and low educational attainment. It has also been shown to be higher among those with poor socio-support networks such as the unmarried, widowed and divorced. Mental disorders interact with many other health conditions, communica‐ ble and non-communicable. They commonly affect individuals with medical conditions and have been associated with adverse impacts on several measures of morbidity and mortality. Depressed patients have been shown to have worse physical, social and over‐ all health than other patients. Of particular interest to this chapter is the interaction be‐ tween HIV and mental distress

**Category of factor Frequency Symptoms/comments**

Relationship with spouse and

used interchangeably.

**Double tragedy**

family members

Worries about money 51 Concerns about rent, day-to-day living, school fees

Problems of the mind 47 Recurrent headaches, sleeplessness, unhappiness, trouble thinking,

Unknown cause of symptoms 32 Most common among informants not acknowledging symptoms as

Ill health 24 Sleeplessness, daily life suffering, inability to play useful role in life, tiredness

Low self-esteem 16 Worthlessness, loss of interest, unhappiness, crying more than usual,

The term mental distress is seen by users of mental health services as less stigmatizing as it fits better with the social model of disability, since everyone experiences mental distress at one time or the other. The other synonym is psychological distress. The term is also often preferred as they feel it better captures the uniqueness and personal nature of their experi‐ ences. Mental distress is often thought of as being a concept with a wider scope than the reg‐ ularly used traditional term, mental illness. The later being a specific set of symptoms medically defined in psychiatry, for example: Mania, schizophrenia, anxiety disorders, de‐ pression etc. Difficult life situations such as: poor social-support structures, bereavement, stress, poor sleep, drug and alcohol abuse can induce mental distress. These inducers could be temporary and resolve without further medical intervention. However individuals who have protracted episodes and endure such symptoms longer are more likely to be diagnosed with mental illness. This definition is not without controversy and often these terms are

Mental distress has been recognised as a crucial factor to some individual's ability to modify their behaviour to prevent HIV infection. With effective treatment options now available, care for HIV has become more dynamic and has transformed the HIV squeal from terminal care to chronic care. This further complicates the scenario as mental disorders have further been recognised as severely complicating treatment. These factors work in tandem with HIV causing direct damage on the brain, creating turmoil in the lives of the infected and further exacerbates mental disorders. Further the mental disorders reduce the individual's ability to effectively change behaviour thus increasing the risk of infection and morbidity. Published

Recent life events 6 Bereavement, divorces, newly diagnosed with chronic disease

**Table 1.** Factors associated with Mental Distress as identified by the informants (Chipimo & Fylkesnes, 2011)

loss of appetite, night mares

an illness or as mental distress, suggested witchcraft

Human Immunodeficiency Virus Infection and Co-Morbid Mental Distress

http://dx.doi.org/10.5772/53696

127

difficulty enjoying daily activities, experience of stigma

trouble thinking, headache, unhappiness

including HIV. Included symptoms of restlessness, sleeplessness,

26 Commonest among women, included crying more than usual, unhappiness, headaches, sleeplessness.

### **2. HIV and mental distress**

#### **Early stages of HIV epidemic**

In the early stages of the HIV epidemic, the individuals who were affected did not know that their behaviour predisposed them to a potentially fatal disease. The epidemic also mushroomed at the time of a liberal and tolerant culture and dis-inhibited sexual restraint. Hence multiple sexual partners spread the epidemic in communities where these behaviours were more rampant. Intravenous drug use also contributed to the early spread of the epi‐ demic. In the low and middle income countries, factors surrounding poor socio-economic position (poor education and low income) and inability to negotiate for condom use due to the disparity between the male and female gender have emerged as stronger predictors. Several early and recent epidemiologic studies elucidated these risk factors and more con‐ certed effort was placed on public education directed at prevention. Other more recent inno‐ vations directed at rolling-back HIV infection have included massive male circumcision campaigns, innovation directed at the girl child to reduce early teenage pregnancies and ear‐ ly marriages and the introduction of Highly Active Anti-Retroviral Therapy (HAART). Re‐ cently efforts have been directed at the role mental distress plays in determining acquisition of HIV infection, initial individual's reaction and post-infection adaptation. Further poor mental health has been associated with subsequent development of AIDS.

#### **Mental distress**

Mental distress in the context of this book chapter refers to a term used by users of mental health services as well as some mental health practitioners in describing a wide array of ex‐ periences of a patient's life that commonly manifest as somatic symptoms and held to be out of the ordinary, distressing, troubling or confusing for the patient, without actually being ill in the medical sense. Chipimo and Fylkesnes identified some of the common causes of men‐ tal distress in a study conducted among primary health care centers in Zambia. (Table 1)


**Table 1.** Factors associated with Mental Distress as identified by the informants (Chipimo & Fylkesnes, 2011)

The term mental distress is seen by users of mental health services as less stigmatizing as it fits better with the social model of disability, since everyone experiences mental distress at one time or the other. The other synonym is psychological distress. The term is also often preferred as they feel it better captures the uniqueness and personal nature of their experi‐ ences. Mental distress is often thought of as being a concept with a wider scope than the reg‐ ularly used traditional term, mental illness. The later being a specific set of symptoms medically defined in psychiatry, for example: Mania, schizophrenia, anxiety disorders, de‐ pression etc. Difficult life situations such as: poor social-support structures, bereavement, stress, poor sleep, drug and alcohol abuse can induce mental distress. These inducers could be temporary and resolve without further medical intervention. However individuals who have protracted episodes and endure such symptoms longer are more likely to be diagnosed with mental illness. This definition is not without controversy and often these terms are used interchangeably.

#### **Double tragedy**

pressive symptoms among primary health care patients while a similar study in Uganda reported a 20–30% prevalence of psychological disorders and depression among health care seekers. These research findings have also shown heightened risk for common men‐ tal disorders among the women i.e. a female to male ratio of 1.5–2.0. Other determinants have been found to include low socioeconomic position indicated by poor access to re‐ sources, unemployment and low educational attainment. It has also been shown to be higher among those with poor socio-support networks such as the unmarried, widowed and divorced. Mental disorders interact with many other health conditions, communica‐ ble and non-communicable. They commonly affect individuals with medical conditions and have been associated with adverse impacts on several measures of morbidity and mortality. Depressed patients have been shown to have worse physical, social and over‐ all health than other patients. Of particular interest to this chapter is the interaction be‐

In the early stages of the HIV epidemic, the individuals who were affected did not know that their behaviour predisposed them to a potentially fatal disease. The epidemic also mushroomed at the time of a liberal and tolerant culture and dis-inhibited sexual restraint. Hence multiple sexual partners spread the epidemic in communities where these behaviours were more rampant. Intravenous drug use also contributed to the early spread of the epi‐ demic. In the low and middle income countries, factors surrounding poor socio-economic position (poor education and low income) and inability to negotiate for condom use due to the disparity between the male and female gender have emerged as stronger predictors. Several early and recent epidemiologic studies elucidated these risk factors and more con‐ certed effort was placed on public education directed at prevention. Other more recent inno‐ vations directed at rolling-back HIV infection have included massive male circumcision campaigns, innovation directed at the girl child to reduce early teenage pregnancies and ear‐ ly marriages and the introduction of Highly Active Anti-Retroviral Therapy (HAART). Re‐ cently efforts have been directed at the role mental distress plays in determining acquisition of HIV infection, initial individual's reaction and post-infection adaptation. Further poor

Mental distress in the context of this book chapter refers to a term used by users of mental health services as well as some mental health practitioners in describing a wide array of ex‐ periences of a patient's life that commonly manifest as somatic symptoms and held to be out of the ordinary, distressing, troubling or confusing for the patient, without actually being ill in the medical sense. Chipimo and Fylkesnes identified some of the common causes of men‐ tal distress in a study conducted among primary health care centers in Zambia. (Table 1)

mental health has been associated with subsequent development of AIDS.

tween HIV and mental distress

126 Current Perspectives in HIV Infection

**2. HIV and mental distress**

**Early stages of HIV epidemic**

**Mental distress**

Mental distress has been recognised as a crucial factor to some individual's ability to modify their behaviour to prevent HIV infection. With effective treatment options now available, care for HIV has become more dynamic and has transformed the HIV squeal from terminal care to chronic care. This further complicates the scenario as mental disorders have further been recognised as severely complicating treatment. These factors work in tandem with HIV causing direct damage on the brain, creating turmoil in the lives of the infected and further exacerbates mental disorders. Further the mental disorders reduce the individual's ability to effectively change behaviour thus increasing the risk of infection and morbidity. Published literature showing that individuals with pre-existing mental disorders are at increased risk for contracting HIV/AIDS has been largely indirect. However consistent reports from sever‐ al countries have suggested that individuals with mental disorders have a higher sero-prev‐ alence for HIV/AIDS and that mental distress generally precedes HIV infection. This is valid given that significant risk of HIV transmission exists within an individual's network. Fre‐ quencies of 30-60% behavioural risk factors that have been identified among individuals with mental distress include: high rates of unprotected sexual contact, poor adherence to condom use and injection-drug abuse. In a study conducted among gay men with depres‐ sive symptoms, use of alcohol and drugs before sex were identified as independent predic‐ tors for sero-conversion. In a systematic review comparing an HIV sero-positive group and HIV sero-negative control group, the prevalence of depression in the sero-positive group was two times higher than in the sero-negative (OR 2.0, 95% CI 1.3-3.0).

the neurons by viral proteins. These toxins overstimulate neurons, resulting in the formation

Human Immunodeficiency Virus Infection and Co-Morbid Mental Distress

http://dx.doi.org/10.5772/53696

129

of free radicals and excitotoxicity, similar to other neurodegenerative diseases.

**Figure 1.** Self-perpetuating cycle of increasing morbidity: HIV/AIDS and Mental Distress (Chipimo, 2011)

ciated with development of manic episodes

**Indirect effect**

Many HIV related opportunistic infections may involve the brain and lead to mental disor‐ ders. The four most frequent conditions are toxoplasmosis, progressive multifocal leukoen‐ cephalopathy (PML), cryptococcosis and cytomegalovirus infection. Although the incidence of these infections among patients with AIDS has decreased in the past years as a conse‐ quence of the introduction of highly active antiretroviral therapy (HAART), they remain a major cause of morbidity and mortality in this patient group. However, highly active antire‐ troviral drugs themselves such as, Zidovudine, Didanosine and Effervirenz have been asso‐

Chipimo and Fylkesnes (2009) studied the relationship between HIV and mental distress in a population with high prevalence of HIV infection and low awareness of own HIV sero-status. In this study structural equation modeling (SEM) was used to establish the relationship between HIV infection and mental distress using maximum likelihood ratio as the method of estimation. The model indicated that underlying factors such as resi‐ dence (rural or urban), level of education, marital status and age were inter-correlated as determinants for mental distress. Further Mental distress was found to be directly relat‐ ed to self-perceived risk and worry about being HIV infected, HIVsero-status and selfrated health. Further indirect inter-relationships were also found between self-rated

### **3. Aetiology of HIV related mental distress**

HIV related mental distress can occur in multiple phases in which premorbid psychological and social adjustment issues play a vital role. Additionally other social factors such as household income, culture, religion and family circumstances also influence and can alter an individual's reaction to a diagnosis of HIV and subsequent adaptation to living with the di‐ agnosis. The same factors have also been shown to influence and pose high risk of being in‐ fected With HIV. Put together all these factors singly or severally affect the clinical presentation and management of HIV patients. It is as such imperative that these factors are addressed and assessed in both the Voluntary-Counselling-and-Testing (VCT) and in the pre-HAART assessment. A self-perpetuating cycle (figure 1) of increasing morbidity ap‐ pears to occur between HIV and mental distress; HIV infection leads to development of mental distress and/or pre-existing mental distress predispose to HIV infection. In their study, Chipimo and Fylkesnes (2009) showed that HIV infection has both a direct and indi‐ rect effects on genesis of mental distress.

#### **Direct effect**

HIV infection has been known to affect all other organ systems in the human body and is said to have replaced syphilis as the "great imitator" in the central nervous system (CNS) and almost any psychiatric or neurological presentation is possible. The CNS is the second most commonly affected organ in patients with AIDS. HIV can cause direct organic brain tissue damage thus leading to the development of mental disorders (Psychotic and non-psy‐ chotic). Virtually any mental disorder is possible. Among the most notable are depression and anxiety, personality disorders and dementia. The mechanisms explaining the develop‐ ment of these mental disorders are largely poorly understood but the presence of HIV-1 binding sites in the brain (chemokine receptors) allows HIV-1 to infect macrophages and microglia. It is however thought that it does not affect neurons, although neurons are in‐ jured and die by apoptosis. The pathway to neuronal injury is thought to be through release of macrophage, microglial and astrocyte toxins alongside the contribution of direct injury on the neurons by viral proteins. These toxins overstimulate neurons, resulting in the formation of free radicals and excitotoxicity, similar to other neurodegenerative diseases.

**Figure 1.** Self-perpetuating cycle of increasing morbidity: HIV/AIDS and Mental Distress (Chipimo, 2011)

Many HIV related opportunistic infections may involve the brain and lead to mental disor‐ ders. The four most frequent conditions are toxoplasmosis, progressive multifocal leukoen‐ cephalopathy (PML), cryptococcosis and cytomegalovirus infection. Although the incidence of these infections among patients with AIDS has decreased in the past years as a conse‐ quence of the introduction of highly active antiretroviral therapy (HAART), they remain a major cause of morbidity and mortality in this patient group. However, highly active antire‐ troviral drugs themselves such as, Zidovudine, Didanosine and Effervirenz have been asso‐ ciated with development of manic episodes

#### **Indirect effect**

literature showing that individuals with pre-existing mental disorders are at increased risk for contracting HIV/AIDS has been largely indirect. However consistent reports from sever‐ al countries have suggested that individuals with mental disorders have a higher sero-prev‐ alence for HIV/AIDS and that mental distress generally precedes HIV infection. This is valid given that significant risk of HIV transmission exists within an individual's network. Fre‐ quencies of 30-60% behavioural risk factors that have been identified among individuals with mental distress include: high rates of unprotected sexual contact, poor adherence to condom use and injection-drug abuse. In a study conducted among gay men with depres‐ sive symptoms, use of alcohol and drugs before sex were identified as independent predic‐ tors for sero-conversion. In a systematic review comparing an HIV sero-positive group and HIV sero-negative control group, the prevalence of depression in the sero-positive group

HIV related mental distress can occur in multiple phases in which premorbid psychological and social adjustment issues play a vital role. Additionally other social factors such as household income, culture, religion and family circumstances also influence and can alter an individual's reaction to a diagnosis of HIV and subsequent adaptation to living with the di‐ agnosis. The same factors have also been shown to influence and pose high risk of being in‐ fected With HIV. Put together all these factors singly or severally affect the clinical presentation and management of HIV patients. It is as such imperative that these factors are addressed and assessed in both the Voluntary-Counselling-and-Testing (VCT) and in the pre-HAART assessment. A self-perpetuating cycle (figure 1) of increasing morbidity ap‐ pears to occur between HIV and mental distress; HIV infection leads to development of mental distress and/or pre-existing mental distress predispose to HIV infection. In their study, Chipimo and Fylkesnes (2009) showed that HIV infection has both a direct and indi‐

HIV infection has been known to affect all other organ systems in the human body and is said to have replaced syphilis as the "great imitator" in the central nervous system (CNS) and almost any psychiatric or neurological presentation is possible. The CNS is the second most commonly affected organ in patients with AIDS. HIV can cause direct organic brain tissue damage thus leading to the development of mental disorders (Psychotic and non-psy‐ chotic). Virtually any mental disorder is possible. Among the most notable are depression and anxiety, personality disorders and dementia. The mechanisms explaining the develop‐ ment of these mental disorders are largely poorly understood but the presence of HIV-1 binding sites in the brain (chemokine receptors) allows HIV-1 to infect macrophages and microglia. It is however thought that it does not affect neurons, although neurons are in‐ jured and die by apoptosis. The pathway to neuronal injury is thought to be through release of macrophage, microglial and astrocyte toxins alongside the contribution of direct injury on

was two times higher than in the sero-negative (OR 2.0, 95% CI 1.3-3.0).

**3. Aetiology of HIV related mental distress**

rect effects on genesis of mental distress.

**Direct effect**

128 Current Perspectives in HIV Infection

Chipimo and Fylkesnes (2009) studied the relationship between HIV and mental distress in a population with high prevalence of HIV infection and low awareness of own HIV sero-status. In this study structural equation modeling (SEM) was used to establish the relationship between HIV infection and mental distress using maximum likelihood ratio as the method of estimation. The model indicated that underlying factors such as resi‐ dence (rural or urban), level of education, marital status and age were inter-correlated as determinants for mental distress. Further Mental distress was found to be directly relat‐ ed to self-perceived risk and worry about being HIV infected, HIVsero-status and selfrated health. Further indirect inter-relationships were also found between self-rated health, self-perceived risk and worry about being HIV infected, and the underlying fac‐ tors, namely age, residence, socio-economic position and education. Therefore self-rated health and self-perceived risk and worry about being HIV infected appear to be impor‐ tant mediators between underlying factors and mental distress. They are also important mediators between HIV status and mental distress. The results suggest that HIV infec‐ tion has a substantial effect on mental distress both directly and indirectly. This effect was mediated through self-perceptions of health status, found to capture changes in health perceptions related to HIV, and self-perceived risk and worry of actually being HIV infected.

the patient, suicide attempts, family history of mental illness, poor social support structures and a history of recent adverse events (deaths in family, physical violence, divorce, stigma).

Human Immunodeficiency Virus Infection and Co-Morbid Mental Distress

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131

Several studies have shown that mental distress often presents as somatisation. In a popula‐ tion based survey, Chipimo and Fylkesnes (2009) reported that the most frequently reported

Among patients attending Primary Health Care, the most commonly reported symptoms

Women reported these symptoms more than men in both studies. Musisi and Akena (2009) reported similar battery of symptoms and further added that, an otherwise asymptomatic HIV infected individual presenting with symptoms of fatigue and insomnia should be as‐ sessed for severe depression. These and other more pathognomonic symptoms put together allow clinicians to make a diagnosis of a full blown psychiatric disorder. The recognised

**6. Impact of HIV related mental distress on course and prognosis**

There is a general lack of reported/ published follow-up studies on HIV related mental dis‐ tress. However left untreated mental distress has an effect on the cell mediated immunity,

**Symptoms**

**3.** poor sleep

**4.** low energy levels.

**2.** loss of interest,

**5.** frequent headaches

**3.** HIV-related Mania **4.** HIV-related Dementia **5.** HIV-related Delirium

**4.** poor sleep

**1.** feelings of unhappiness,

**3.** inability to enjoy daily life,

HIV related psychiatric disorders are: **1.** Anxiety disorders and depression

**2.** Psychotic disorder (Primary or secondary)

**6.** Drug abuse ie. Substance and Alcohol abuse

symptoms among the HIV infected were:

**2.** feeling that their daily life was suffering,

observed by Chipimo and Fylkesnes (2010) were:

**1.** difficulty enjoying life,

### **4. Prevalence of HIV related mental distress**

Prevalence studies conducted world over have shown that when compared to the gener‐ al population, mental disorders where considerably higher among the HIV infected indi‐ viduals. However most of these studies have been conducted in the high income countries were the disease burden is relatively low and confined to selected groups for example Injection drug users and Homosexuals. Similar data in sub-Saharan Africa, where the HIV epidemic has its worse impact is limited. Therefore, given that mental disorders manifest in the majority of HIV infected individuals over the course of the ill‐ ness, a simple assumption would then be that the prevalence reported in published stud‐ ies represent an underestimate of the actual prevalence. A meta-analytic study identified 13 studies on mental disorders and HIV infection in low and middle income countries. The prevalence of mental disorders varied widely among these studies. Most of the stud‐ ies done in Africa with HIV positive participants have shown differing but high percen‐ tages of mental distress, for example, Orange free state, South Africa 40%, rural Ethiopia 14% and Botswana 28%. In a study done in Zambia, Chipimo and Fylkesnes (2009) found a 13% prevalence of mental distress within the general population with a 2.0 high‐ er odds ratio among the HIV infected. In Uganda, Musisi et. al. (2006) showed a 42% prevalence of depression among HIV infected individuals while in another study, Musisi & Kinyanda reported a prevalence of 41% among HIV infected adolenscents.

#### **5. Presentation of HIV related mental distress**

Diagnosis of mental disorders in HIV infection is a relatively rarely made diagnosis in sub-Saharan Africa. Studies have reported that physicians tend to be oblivious to psychological problems in HIV in the presence of a physical ailment. Further, the clinical presentation of mental distress in HIV infection presents a diagnostic challenge. This is often because the clinical Indictors of mental disorders are often masked by the symptoms of HIV infection. It is also a challenge for health care providers to distinguish between mental distress and grief. This calls for careful history taking that probes for previous history of mental disorders in the patient, suicide attempts, family history of mental illness, poor social support structures and a history of recent adverse events (deaths in family, physical violence, divorce, stigma).

#### **Symptoms**

health, self-perceived risk and worry about being HIV infected, and the underlying fac‐ tors, namely age, residence, socio-economic position and education. Therefore self-rated health and self-perceived risk and worry about being HIV infected appear to be impor‐ tant mediators between underlying factors and mental distress. They are also important mediators between HIV status and mental distress. The results suggest that HIV infec‐ tion has a substantial effect on mental distress both directly and indirectly. This effect was mediated through self-perceptions of health status, found to capture changes in health perceptions related to HIV, and self-perceived risk and worry of actually being

Prevalence studies conducted world over have shown that when compared to the gener‐ al population, mental disorders where considerably higher among the HIV infected indi‐ viduals. However most of these studies have been conducted in the high income countries were the disease burden is relatively low and confined to selected groups for example Injection drug users and Homosexuals. Similar data in sub-Saharan Africa, where the HIV epidemic has its worse impact is limited. Therefore, given that mental disorders manifest in the majority of HIV infected individuals over the course of the ill‐ ness, a simple assumption would then be that the prevalence reported in published stud‐ ies represent an underestimate of the actual prevalence. A meta-analytic study identified 13 studies on mental disorders and HIV infection in low and middle income countries. The prevalence of mental disorders varied widely among these studies. Most of the stud‐ ies done in Africa with HIV positive participants have shown differing but high percen‐ tages of mental distress, for example, Orange free state, South Africa 40%, rural Ethiopia 14% and Botswana 28%. In a study done in Zambia, Chipimo and Fylkesnes (2009) found a 13% prevalence of mental distress within the general population with a 2.0 high‐ er odds ratio among the HIV infected. In Uganda, Musisi et. al. (2006) showed a 42% prevalence of depression among HIV infected individuals while in another study, Musisi

& Kinyanda reported a prevalence of 41% among HIV infected adolenscents.

Diagnosis of mental disorders in HIV infection is a relatively rarely made diagnosis in sub-Saharan Africa. Studies have reported that physicians tend to be oblivious to psychological problems in HIV in the presence of a physical ailment. Further, the clinical presentation of mental distress in HIV infection presents a diagnostic challenge. This is often because the clinical Indictors of mental disorders are often masked by the symptoms of HIV infection. It is also a challenge for health care providers to distinguish between mental distress and grief. This calls for careful history taking that probes for previous history of mental disorders in

**5. Presentation of HIV related mental distress**

HIV infected.

130 Current Perspectives in HIV Infection

**4. Prevalence of HIV related mental distress**

Several studies have shown that mental distress often presents as somatisation. In a popula‐ tion based survey, Chipimo and Fylkesnes (2009) reported that the most frequently reported symptoms among the HIV infected were:


Among patients attending Primary Health Care, the most commonly reported symptoms observed by Chipimo and Fylkesnes (2010) were:


Women reported these symptoms more than men in both studies. Musisi and Akena (2009) reported similar battery of symptoms and further added that, an otherwise asymptomatic HIV infected individual presenting with symptoms of fatigue and insomnia should be as‐ sessed for severe depression. These and other more pathognomonic symptoms put together allow clinicians to make a diagnosis of a full blown psychiatric disorder. The recognised HIV related psychiatric disorders are:


### **6. Impact of HIV related mental distress on course and prognosis**

There is a general lack of reported/ published follow-up studies on HIV related mental dis‐ tress. However left untreated mental distress has an effect on the cell mediated immunity, where it causes impairments in T-cell mediated functions, reduced natural-killer cell counts and cytotoxicity. Depression in particular, has reproducibly been associated with decreased numbers and altered functioning of natural killer lymphocytes. It can also lead to an in‐ crease in activated CD8 T lymphocytes and viral load. By so doing mental distress can pre‐ dict the onset and progression of both physical and social disability in HIV infection. Further, Co-morbid mental distress can delay health seeking hence reducing the likelihood of diagnosis and so can affect treatment and outcome in HIV infection. They may also ad‐ versely affect adherence to medication and activities to prevent disease and promote health.

**Author details**

**References**

Peter J. Chipimo1,2 and Knut Fylkesnes1

1 University of Bergen, Faculty of Medicine, Centre for International Health, Norway

Human Immunodeficiency Virus Infection and Co-Morbid Mental Distress

http://dx.doi.org/10.5772/53696

133

[1] Bock PJ, Markovitz D. Infection with HIV-2. AIDS. 2001;15(Suppl 5):S35-45.

www.ncbi.nlm.nih.gov/pmc/articles/PMC2744699/

http://hdl.handle.net/1956/4882

Treament January edition 2005

psychology. 2007;12(3):505-16.

master-theses

tions; 2003.

[2] Chipimo P.J. Fylkesnes K, Mental distress in the general population in Zambia: Im‐ pact of HIV and social factors: BMC Public Health. 2009; 9: 298. http://

[3] Chipimo Peter J, Mental health in the era of HIV. Investigating mental distress, its determinants, conceptual models and the impact of HIV in Zambia. BORA-UiB 2011

[4] Chipimo PJ, Fylkesnes K. Comparative validity of screening instruments for Mental Distress in Zambia. Clinical practice & Epidemiology in Mental Health. 2010;6:4-15. [5] Chipimo PJ, Tuba M, Fylkesnes K, Conceptual models for Mental Distress among HIV infected and uninfected: A contribution to clinical practice and research in pri‐ mary health-care centers in Zambia. BMC Health Services Research 2011; 11:7 1-12 [6] Chipimo, Peter Jay: Mental Distress and the Impact of HIV: Data from a Population-Based Survey in Zambia, Master thesis (2007) http://www.uib.no/cih/en/research/cih-

[7] Department of Health and Human Services (Ed). A Pocket Guide to Adult HIV/AIDS

[8] DeVellis RF. Scale Development: Theory and Application. London: SAGE Publica‐

[9] Escobar JI, Waitzkin H, Silver RC, Gara M, Holman A. A bridged somatization: a

[11] Jenkins R. Sex differences in minor psychiatric morbidity: a survey of a homogene‐

[12] Kigozi FN, Flisher AJ, Lund C, Funk M, Banda M, Bhana A, et al. Mental health poli‐ cy development and implementation in four African Conutries. Journal of health

[10] Gottlinger HG. The HIV-1 assembly machine. AIDS. 2001;15(Suppl 5):S13-20.

ous population. Social Science and Medicine. 1985;20(9):887-99.

study in primary care. Psychosom Med. 1998;60:466-72.

2 University of Zambia, School of Medicine, Department of Public Health, Zambia

### **7. Management**

Mental disorders episodes are known to cluster around specific times in the course of the illness, such as, the period of diagnosis of HIV, period when the infected individual starts declining in health or the period in the early stages of HIV dementia. However, an episode of mental distress can occur at any point in the course of the illness. In the early stages social support alone can suffice alongside psychotherapy. However, in the later stages anti-depres‐ sants such as Imipramine or Amitriptyline can be used. Selective serotonin re-uptake inhibi‐ tors such as Fluoxetine may also be prescribed.

However the mainstay of management should fall around the time of diagnosis with ade‐ quate pre and post testing counseling surrounding the HIV test. The HIV counseling process should also be optimized to conditions that allow for higher acceptability of the counseling process. A Clinical trial study conducted in Zambia showed higher acceptability for Homebased-Voluntary-Counseling and testing as opposed to facility based counseling. Such inno‐ vative means of facilitating the counseling process will by induction lead to better acceptance of the HIV sero-status thus preventing subsequent maladjustment disorders. This has been shown in literature to reduce the risk of suicide at the initial diagnosis. Addi‐ tionally follow-up counseling at every stage in the disease process emphasizing safer sex should be promoted alongside care giver support. This support should especially be extend‐ ed to the most vulnerable; the women, children, orphans and those of low socio-economic position in society.

### **8. Conclusion**

Mental disorders are common place in HIV infection and potentiate the course, progression and prognosis of the HIV disease process. The direct and indirect impact of HIV on the in‐ fected individual has conversely also been associated with mental distress episodes. Mental disorder and HIV/AIDS also have a lot of socio-demographic factors in common that have been attributed to each of their development. Therefore, a combination of these two disease entities leads to devastating morbidity and mortality, especially in the most affected com‐ munities. This thus emphasizes the need for prompt screening, diagnosis and treatment of mental distress in HIV infection.

### **Author details**

where it causes impairments in T-cell mediated functions, reduced natural-killer cell counts and cytotoxicity. Depression in particular, has reproducibly been associated with decreased numbers and altered functioning of natural killer lymphocytes. It can also lead to an in‐ crease in activated CD8 T lymphocytes and viral load. By so doing mental distress can pre‐ dict the onset and progression of both physical and social disability in HIV infection. Further, Co-morbid mental distress can delay health seeking hence reducing the likelihood of diagnosis and so can affect treatment and outcome in HIV infection. They may also ad‐ versely affect adherence to medication and activities to prevent disease and promote health.

Mental disorders episodes are known to cluster around specific times in the course of the illness, such as, the period of diagnosis of HIV, period when the infected individual starts declining in health or the period in the early stages of HIV dementia. However, an episode of mental distress can occur at any point in the course of the illness. In the early stages social support alone can suffice alongside psychotherapy. However, in the later stages anti-depres‐ sants such as Imipramine or Amitriptyline can be used. Selective serotonin re-uptake inhibi‐

However the mainstay of management should fall around the time of diagnosis with ade‐ quate pre and post testing counseling surrounding the HIV test. The HIV counseling process should also be optimized to conditions that allow for higher acceptability of the counseling process. A Clinical trial study conducted in Zambia showed higher acceptability for Homebased-Voluntary-Counseling and testing as opposed to facility based counseling. Such inno‐ vative means of facilitating the counseling process will by induction lead to better acceptance of the HIV sero-status thus preventing subsequent maladjustment disorders. This has been shown in literature to reduce the risk of suicide at the initial diagnosis. Addi‐ tionally follow-up counseling at every stage in the disease process emphasizing safer sex should be promoted alongside care giver support. This support should especially be extend‐ ed to the most vulnerable; the women, children, orphans and those of low socio-economic

Mental disorders are common place in HIV infection and potentiate the course, progression and prognosis of the HIV disease process. The direct and indirect impact of HIV on the in‐ fected individual has conversely also been associated with mental distress episodes. Mental disorder and HIV/AIDS also have a lot of socio-demographic factors in common that have been attributed to each of their development. Therefore, a combination of these two disease entities leads to devastating morbidity and mortality, especially in the most affected com‐ munities. This thus emphasizes the need for prompt screening, diagnosis and treatment of

**7. Management**

132 Current Perspectives in HIV Infection

position in society.

**8. Conclusion**

mental distress in HIV infection.

tors such as Fluoxetine may also be prescribed.

Peter J. Chipimo1,2 and Knut Fylkesnes1

1 University of Bergen, Faculty of Medicine, Centre for International Health, Norway

2 University of Zambia, School of Medicine, Department of Public Health, Zambia

### **References**


[13] Kitahata MM, Gange SJ, Abraham AG, et al. Effect of early verses defered anti-retro‐ viral therapy for HIV on survival. N Engl Med. 2009;360(18):1815-26.

[27] Strong K, Mather C, Leeder S, Beaglehole R. Preventing Chronic diseases: How many

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[28] Tatt ID, Barlow KL, Nicoll A. The public health significance of HIV-1 subtypes.

[29] Vieweg WV, Julius DA, Fernandez A, et al. Treatmeant of depression in patients with

[30] Wilson D, Naidoo S, Bekker L, Cotton M, Maartens G. Handbook of HIV medicine.

[31] Young TN, Arens FJ, Kennedy GE, Laurie JW, Rutherford G. Antiretroviral post-ex‐ posure prophylaxis (PEP) for occupational HIV exposure. Cochrane Database Syst

lives can we save? Lancet. 2005;366:1578-82.

Cape Town: Oxford University press; 2002.

coronary heart disease. Am J Med. 2006;119:567-73.

AIDS. 2001;15(Suppl 5):S59-71.

Rev. 2007;1(CD002835).


[27] Strong K, Mather C, Leeder S, Beaglehole R. Preventing Chronic diseases: How many lives can we save? Lancet. 2005;366:1578-82.

[13] Kitahata MM, Gange SJ, Abraham AG, et al. Effect of early verses defered anti-retro‐

[14] Kroenke K, Spitzer RL, Williams JB, et al. Physical symptoms in primary care: Predic‐ tors of psychiatric disorders and functional impairement. Arch Fam Med.

[15] Kuehner C. Gender diffferences in unipolar depression: an update of epidemiological findings and possible explanations. Acta Psychiatr Scand. 2003;108:163-74.

[16] Maier W, Gansicke M, Gater R, Rezaki M, Tiemens B, Urzua RF. Gender differences in the prevalence of depression: A survey in primary care. J Affect Disord.

[17] Mathers CD, Loncar D. Projections of global mortality and burden of disease from

[18] McCaffery JM, Frasure-Smith N, Dude MP, et al. Common genetic vulnerability to depressive symptoms and coronary artery disease: a review and development of can‐ didate genes related to inflamation and serotonin. Psychosom Med. 2006;68:187-200.

[19] Murray CJL, Lopez AD, et al. The global burden of disease and injuries series: A comprehensive assessment of Mortality and disability, Injuries and Risk factors 1990

[20] Ngoma MC, Prince M, Mann A. Common mental disorders among those attending primary health clinics and traditional healers in urban Tanzania. Br J Psychiatry.

[21] Ovuga EBL, Boardman A, Oluka GAO. Traditional healers and mental illness in

[22] Palella FJ, Delaney KM, Moorman AC, Loveless MO, Fuhrer J, Satten GA, et al. De‐ clining morbidity and mortality among patients with advanced human immunodefi‐

[23] Patel V, Abas M, Broadhead J, Todd CH, Reeler AP. Depression in developing coun‐

[24] Rachlis AR, Zarowny DP. Guidelines for anti-retroviral therapy for HIV infection. Canadian HIV trials Network Antiretroviral Working Group. CMAJ. 1998;158(4):

[25] Sax PE, Baden LR. When to start anti-retroviral therapy- ready when you are? N Engl

[26] Saz P, Dewey ME. Depression symptoms and mortality in persons aged 65 and over living in the community: a systematic review of the literature. Int J Geriatric Psychia‐

and projected to 2020. Volume 1: Cambridge, MA; 1996.

ciency virus infection. N Engl Med. 1998;338(13):853-60.

tries: Lessons from Zimbabwe. BMJ. 2001;322(482).

viral therapy for HIV on survival. N Engl Med. 2009;360(18):1815-26.

1994;3:774-9.

134 Current Perspectives in HIV Infection

1999;53:241-52.

2003;183:349-55.

496-505.

Med. 2009;360(18):1897-9.

try. 2001;16:622-30.

2002 to 2030. Plos Med. 2006;3(e442).

Uganda. Psychiatric Bull. 1999;23:276-9.


**Chapter 8**

**Neurological Manifestations of**

Rehana Basri and Wan Mohamad Wan Majdiah

Additional information is available at the end of the chapter

http://dx.doi.org/10.5772/54026

for HIV infection (Quinn, 1990).

**1. Introduction**

**HIV-1 Infection and Markers for HIV Progression**

Human immunodeficiency virus, or HIV, is the virus that causes acquired immune deficiency syndrome (AIDS). The acquired immunodeficiency syndrome (AIDS) was first described in 1981 in USA. In 1983, human immunodeficiency virus type-1 (HIV-1) was isolated, and in the following year it was demonstrated clearly that it was the causative agent of AIDS. The disease is a major health problem in many parts of the world. The high prevalence and striking diversi‐ ty of neurological disorders complicating AIDS were recognized in 1983 (Snider et al., 1983). AIDS was associated with distinct neurological syndromes, such as dementia, myelopathy and painful neuropathy that appeared to result from the HIV itself. Over the last 30 years, there has been increasing recognition of the role that auto antibodies play in neurological disorders. Dur‐ ing the past decade, AIDS has become a global health problem with 182,000 000 cases reported from 152 countries. It is estimated that nearly five to ten million people are infected worldwide with HIV-1. With a mean incubation period from time of infection to the development of AIDS of eight to 10 years, it is projected that nearly all HIV-1-infected individual will develop AIDS within the next 15 years (Quinn, 1990). It has become increasingly evident that the vast majori‐ ty of HIV-1 infected people will eventually develop AIDS or an AIDS-related condition (De Wolf and Lange, 1991) with a median time of progression to AIDS of 7-10 years from infection in adults (Lui *et al*., 1988; Bacchetti and Moss, 1989) and shorter periods in infants and elderly patients (Medley et al., 1987; Auger et al., 1988; Lagakos & DeGruttola, 1989). In the United States alone, 104, 210 cases of AIDS and more than 61,000 deaths have been reported. Sexual, parenteral as well as perinatal transmission routes have remained the major modes of trans‐ mission, although the proportion of cases within each risk behaviour category has changed. Recently, there has been a dramatic increase in the proportion of AIDS patients who have ac‐ knowledged as IV drug user or have heterosexual contact with other individuals at high risk

> © 2013 Basri and Wan Majdiah; licensee InTech. This is an open access article distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/3.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.

> © 2013 The Author(s). Licensee InTech. This chapter is distributed under the terms of the Creative Commons Attribution License http://creativecommons.org/licenses/by/3.0), which permits unrestricted use, distribution,

and reproduction in any medium, provided the original work is properly cited.

## **Neurological Manifestations of HIV-1 Infection and Markers for HIV Progression**

Rehana Basri and Wan Mohamad Wan Majdiah

Additional information is available at the end of the chapter

http://dx.doi.org/10.5772/54026

### **1. Introduction**

Human immunodeficiency virus, or HIV, is the virus that causes acquired immune deficiency syndrome (AIDS). The acquired immunodeficiency syndrome (AIDS) was first described in 1981 in USA. In 1983, human immunodeficiency virus type-1 (HIV-1) was isolated, and in the following year it was demonstrated clearly that it was the causative agent of AIDS. The disease is a major health problem in many parts of the world. The high prevalence and striking diversi‐ ty of neurological disorders complicating AIDS were recognized in 1983 (Snider et al., 1983). AIDS was associated with distinct neurological syndromes, such as dementia, myelopathy and painful neuropathy that appeared to result from the HIV itself. Over the last 30 years, there has been increasing recognition of the role that auto antibodies play in neurological disorders. Dur‐ ing the past decade, AIDS has become a global health problem with 182,000 000 cases reported from 152 countries. It is estimated that nearly five to ten million people are infected worldwide with HIV-1. With a mean incubation period from time of infection to the development of AIDS of eight to 10 years, it is projected that nearly all HIV-1-infected individual will develop AIDS within the next 15 years (Quinn, 1990). It has become increasingly evident that the vast majori‐ ty of HIV-1 infected people will eventually develop AIDS or an AIDS-related condition (De Wolf and Lange, 1991) with a median time of progression to AIDS of 7-10 years from infection in adults (Lui *et al*., 1988; Bacchetti and Moss, 1989) and shorter periods in infants and elderly patients (Medley et al., 1987; Auger et al., 1988; Lagakos & DeGruttola, 1989). In the United States alone, 104, 210 cases of AIDS and more than 61,000 deaths have been reported. Sexual, parenteral as well as perinatal transmission routes have remained the major modes of trans‐ mission, although the proportion of cases within each risk behaviour category has changed. Recently, there has been a dramatic increase in the proportion of AIDS patients who have ac‐ knowledged as IV drug user or have heterosexual contact with other individuals at high risk for HIV infection (Quinn, 1990).

© 2013 Basri and Wan Majdiah; licensee InTech. This is an open access article distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/3.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited. © 2013 The Author(s). Licensee InTech. This chapter is distributed under the terms of the Creative Commons Attribution License http://creativecommons.org/licenses/by/3.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.

In Sub-Saharan Africa, 22.5 million people living with HIV (68% of the global infections) and 1.6 million AIDS death in 2007 (76% of the AIDS deaths worldwide). In recent years, global ef‐ forts have increased substantially. The most encouraging improvements have been in Sub-Sa‐ haran Africa where the number of people being treated with anti-retrovirals has increased tenfold from 2003 to 2006 (Peters et al., 2008). The decline of HIV infection in some regions was partially offset by a rise in new infections in other parts of the globe, particularly in Asia and Eastern Europe (Delpech & Gahagan, 2009). It was estimated that over 5 million people in South Asia living with HIV/AIDS. Almost 90% of those infected live in India. Other countries in the region such as Bangladesh, Pakistan and Nepal have a low HIV prevalence in general pop‐ ulation (Abeysena & De Silva, 2005).

**3. Neurological menifestations of HIV-1 infections**

myelopathy.

**3.1. HIV encephalopathy**

tis, Herpes encephalitis, Toxoplasma encephalitis (rare).

**Table 1.** Clinical staging of HIV Encephalopathy

HIV is neuroinvasive, it does not directly infect neurons. The major brain reservoirs for HIV infection and replication are microglia and macrophages. Astrocytes can be infected but are not a site of active HIV replication. HIV-associated neurologic complications are indirect effects of viral neurotoxins (viral proteins gp120 and tat) and neurotoxins released by infected or activated microglia, macrophages and astrocytes. Neurologic manifestations occur over the entire spectrum of HIV disease. Fifty to 70% of patients experienced acute clinical syndrome 1 to 6 wks after infection, Neuro Manifestations occur in 10% involves Multiple Parts of nervous system. Some Monophonic illness Meningitis, Meningioencephalitis, Seizures, Myelopathy, Cranial and Peripheral Neuropathy linked to primary HIV and recover within 1 week. Neurological opportunistic infections and malignancies predominated in early reports, but it became also clear that AIDS was associated with distinct neurological syndromes, such as Acute/subacute diffuse encephalopathy Progressive dementia, Focal mass lesions, Acute stroke like presentation, Meningitis, Multiple cranial neuropathies and Acute/subacute

Neurological Manifestations of HIV –1 Infection and Markers for HIV Progression

http://dx.doi.org/10.5772/54026

139

(AIDS Dementia Complex or HIV associated Dementia) is a late complication of HIV infection and progresses slowly over months seen in pts with CD4 T cell Count >350cells/µl. Dementia is a major feature but aphasia, apraxia and afnofia uncommon, motor abnormality like unsteady gait, poor balance, tremor and in late stage develop apathy & lack of initiative – leads to vegeta‐ tive state mania (table 1). Neuro imaging: MRI & CT demonstrate cerebral atrophy, Basal gan‐ glia calcification in children. CSF: MonoNucleatz cells increase, Protein increase, RNA can be detected and HIV can be cultured. Infective: CMV ventriculoencephalitis, Varicella encephali‐

### **2. Back ground of immune defence mechanisms**

Humoral immunity and complement system: immunity that is mediated by secreted antibod‐ ies produced in the cells of the B lymphocyte. Cell mediated immunity : is an immune response that does not involve antibodies but rather involves the activation of macrophages, natural (NK), antigen-specific cytotoxic T-lymphocytes.

### **2.1. Causes of immunosuppression primary: Antibody deficiency, combined antibody**

Antibody deficiency, combined antibody and cellular deficiency, Complement deficiency. Ac‐ quired: Extremes of age, Diabetes, Chronic alcoholism, HIV infection, Connective tissue dis‐ eases, Organ failure (renal, hepatic), Malignancy, Iatrogenic (chemotherapy, radiotherapy, Transplantation). HIV is a retrovirus that primarily infects vital organs of the human immune system such as CD4+ T cells (a subset of T cells), macrophages and dendritic cells. It directly and indirectly destroys CD4+ T cells (Alimonti et al 2003).

### **2.2. Cells affected**

The virus entering through which ever route and acts primarily on the following cells: Lym‐ phoreticular system: CD4+ T-Helper cells, Macrophages, Monocytes, B-lymphocytes, Certain endothelial cells and Central nervous system: Microglia, Astrocytes, Oligodendrocytes, and Neurones.

#### **2.3. Relation of CD4 T cell count**

Neurologic Complications increase with decline in CD4 T cell count. CD4 T cell count > 500/µl – Earlystage – Demyelinating Neuropathies, CD4 T cell count 200 to 500 – Mid stage – Dementia - VZV radiculities and CD4 T cell count <200 –advance stage → Dementia, Myelopathy, Painful‐ neuropathy.

#### **2.4. Immune deficiency & clinical disease**

Clinical manifestations, Susceptibility to infections, Lymphoreticular malignancies, autoim‐ mune disease.

### **3. Neurological menifestations of HIV-1 infections**

HIV is neuroinvasive, it does not directly infect neurons. The major brain reservoirs for HIV infection and replication are microglia and macrophages. Astrocytes can be infected but are not a site of active HIV replication. HIV-associated neurologic complications are indirect effects of viral neurotoxins (viral proteins gp120 and tat) and neurotoxins released by infected or activated microglia, macrophages and astrocytes. Neurologic manifestations occur over the entire spectrum of HIV disease. Fifty to 70% of patients experienced acute clinical syndrome 1 to 6 wks after infection, Neuro Manifestations occur in 10% involves Multiple Parts of nervous system. Some Monophonic illness Meningitis, Meningioencephalitis, Seizures, Myelopathy, Cranial and Peripheral Neuropathy linked to primary HIV and recover within 1 week. Neurological opportunistic infections and malignancies predominated in early reports, but it became also clear that AIDS was associated with distinct neurological syndromes, such as Acute/subacute diffuse encephalopathy Progressive dementia, Focal mass lesions, Acute stroke like presentation, Meningitis, Multiple cranial neuropathies and Acute/subacute myelopathy.

#### **3.1. HIV encephalopathy**

In Sub-Saharan Africa, 22.5 million people living with HIV (68% of the global infections) and 1.6 million AIDS death in 2007 (76% of the AIDS deaths worldwide). In recent years, global ef‐ forts have increased substantially. The most encouraging improvements have been in Sub-Sa‐ haran Africa where the number of people being treated with anti-retrovirals has increased tenfold from 2003 to 2006 (Peters et al., 2008). The decline of HIV infection in some regions was partially offset by a rise in new infections in other parts of the globe, particularly in Asia and Eastern Europe (Delpech & Gahagan, 2009). It was estimated that over 5 million people in South Asia living with HIV/AIDS. Almost 90% of those infected live in India. Other countries in the region such as Bangladesh, Pakistan and Nepal have a low HIV prevalence in general pop‐

Humoral immunity and complement system: immunity that is mediated by secreted antibod‐ ies produced in the cells of the B lymphocyte. Cell mediated immunity : is an immune response that does not involve antibodies but rather involves the activation of macrophages, natural

**2.1. Causes of immunosuppression primary: Antibody deficiency, combined antibody**

Antibody deficiency, combined antibody and cellular deficiency, Complement deficiency. Ac‐ quired: Extremes of age, Diabetes, Chronic alcoholism, HIV infection, Connective tissue dis‐ eases, Organ failure (renal, hepatic), Malignancy, Iatrogenic (chemotherapy, radiotherapy, Transplantation). HIV is a retrovirus that primarily infects vital organs of the human immune system such as CD4+ T cells (a subset of T cells), macrophages and dendritic cells. It directly

The virus entering through which ever route and acts primarily on the following cells: Lym‐ phoreticular system: CD4+ T-Helper cells, Macrophages, Monocytes, B-lymphocytes, Certain endothelial cells and Central nervous system: Microglia, Astrocytes, Oligodendrocytes, and

Neurologic Complications increase with decline in CD4 T cell count. CD4 T cell count > 500/µl – Earlystage – Demyelinating Neuropathies, CD4 T cell count 200 to 500 – Mid stage – Dementia - VZV radiculities and CD4 T cell count <200 –advance stage → Dementia, Myelopathy, Painful‐

Clinical manifestations, Susceptibility to infections, Lymphoreticular malignancies, autoim‐

ulation (Abeysena & De Silva, 2005).

138 Current Perspectives in HIV Infection

**2.2. Cells affected**

**2.3. Relation of CD4 T cell count**

**2.4. Immune deficiency & clinical disease**

Neurones.

neuropathy.

mune disease.

**2. Back ground of immune defence mechanisms**

(NK), antigen-specific cytotoxic T-lymphocytes.

and indirectly destroys CD4+ T cells (Alimonti et al 2003).

(AIDS Dementia Complex or HIV associated Dementia) is a late complication of HIV infection and progresses slowly over months seen in pts with CD4 T cell Count >350cells/µl. Dementia is a major feature but aphasia, apraxia and afnofia uncommon, motor abnormality like unsteady gait, poor balance, tremor and in late stage develop apathy & lack of initiative – leads to vegeta‐ tive state mania (table 1). Neuro imaging: MRI & CT demonstrate cerebral atrophy, Basal gan‐ glia calcification in children. CSF: MonoNucleatz cells increase, Protein increase, RNA can be detected and HIV can be cultured. Infective: CMV ventriculoencephalitis, Varicella encephali‐ tis, Herpes encephalitis, Toxoplasma encephalitis (rare).


**Table 1.** Clinical staging of HIV Encephalopathy

### Treatment:

Combination anti retro viral therapy is beneficial and rapid improvement in cognitive function.

diffuse hyperreflexia, frontal release signs, and sometimes Parkinsonism (Mirsattari et al., 1998). A recent study suggests that antiretroviral drug combinations with drugs that have better CSF penetration are associated with greater CSF viral load suppression and may be associated with greater improvement in neuropsychological test deficits compared to antire‐ troviral drug combinations with drugs that have poor CSF penetration (Letendre et al., 2004). Antiretroviral drugs with the highest CSF:plasma ratios or with profound effects on viral replication in the periphery with a resulting decrease in virus entry into the CNS (e.g., zidovudine, stavudine, abacavir, nevirapine, efavirenz, and indinavir) are likely to be the most efficacious for the treatment of HIV-D. Affective: Apathy (depression-like features), Irritability, Mania, new onset psychosis. Behavioral: Psychomotor retardation (slowed speech or response time), Personality changes, Social withdrawal. Cognitive: Lack of visuospatial memory (misplacing things), Lack of vasomotor coordination, Difficulty with complex sequencing (difficulty in performing previously learned complex tasks), Impaired concentration and attention-Impaired verbal memory (word-finding ability), Mental slowing. Motor: Unsteady gait, loss of balance, Leg weakness, dropping things, Tremors, poor handwriting and decline

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141

Symptomatic neuropathies occur in approximately 10% to 15%. Pathologic evidence of peripheral nerve involvement is present in virtually all end-stage AIDS patients. The most common complaints are numbness, parethesias and painful dysestesias. Zanetti et al., (2004) reported mild distal dysestesia that neither interfered with the activities of daily living nor required specific therapy. The main neurological sign was distal symmetric sensory alteration (in 97.1% of the patients) in the four limbs but mainly in the feet. The etiology and pathogenesis of peripheral neuropathy associated with HIV infection is uncertain. It can be caused by the direct or indirect action of HIV and antibody production, or secondary to infections (CMV, MAC), toxic effects of certain drugs (isoniazid, vincristine, d4T, ddi, ddC), or nutritional deficiencies (vitamin B12) (Rizzuto et al., 1995; Dalakas et al., 1988; Figg, 1991; Browne et al., 1993; Pike, 1993; Abrams et al., 1994; Kieburtz et al., 1991; Norton et al., 1996; Gill et al., 1990; Simpson et al.,1995). Almost all patients with HIV that had diagnosis of peripheral neuropathy were taking drugs probably neurotoxic (ddi, d4t,ddC isoniazid) (Zanetti et al., 2004) to determine the effect of 5 weeks of individualized acupuncture treatment, delivered in a group setting, on pain and symptoms of peripheral neuropathy associated with HIV infection. In addition, the acupuncture regimen reduced pain/aching/burning and pins/needles/numbness

The most common cause of spinal cord disease in AIDS patients is AIDS-associated myelop‐ athy, with a reported prevalence of 20% to 55% in different series (Gray et al., 1990; Henin et al., 1992; Petito et al., 1985; Goldstick, 1985; Dal et al., 1994; Artigas et al., 1990). Clinical symptoms and signs of myelopathy included spastic paraparesis, gait disturbance, urinary problems, and impotence in males, hyperreflexia, and a variable degree of sensory loss. A

in fine motor skills.

**3.3. HIV associated neuropathy**

in the upper and lower limbs (Phillips et al., 2004).

**3.4. HIV related to myelopathy with polyradiculopathy**

### **3.2. HIV-associated dementia**

The major direct effect of HIV infection on the immune system is the profound and progressive loss of CD4 lymphocytes. This leads to impaired cellular immunity, and a dysregulation of mac‐ rophages, with the overproduction of a variety of proinflammatory cytokines and chemokines (Griffin, 1997). HIV can enter the nervous system early after infection, but productive infection is rarely detectable before immunosuppression has developed. Based upon phylogenetic anal‐ ysis of HIV gp160, the route of central nervous system (CNS) infection appears to primarily in‐ volve infected monocytes (Liu et al., 2000) as well as free viral particles and HIV proteins crossing a disrupted blood–brain barrier. The presentation of HIV-D includes cognitive, behav‐ ioral, and motor dysfunction, and suggests a predominant subcortical involvement (Navia et al., 1986). In the early stages, memory loss, mental slowing, reading and comprehension diffi‐ culties, and apathy are frequent com plaints (Fig. 1) (Mc Arthur et al., 2003).

**Figure 1.** Frequency of symptoms in HIV dementia among 300 subjects personally examined at JHU HIV Neurology program (McArthur et al., 2003).

The cognitive deficits of HIV- D are characterized primarily by (1) memory loss that is selective for impaired retrieval; (2) impaired ability to manipulate acquired knowledge; (3) personality changes including apathy, inertia, and irritability; and (4) general slowing of all thought processes. Gait disturbance and impairment of fine manual dexterity are common early manifestations. Examination findings include impaired rapid movements of eyes and limbs, diffuse hyperreflexia, frontal release signs, and sometimes Parkinsonism (Mirsattari et al., 1998). A recent study suggests that antiretroviral drug combinations with drugs that have better CSF penetration are associated with greater CSF viral load suppression and may be associated with greater improvement in neuropsychological test deficits compared to antire‐ troviral drug combinations with drugs that have poor CSF penetration (Letendre et al., 2004). Antiretroviral drugs with the highest CSF:plasma ratios or with profound effects on viral replication in the periphery with a resulting decrease in virus entry into the CNS (e.g., zidovudine, stavudine, abacavir, nevirapine, efavirenz, and indinavir) are likely to be the most efficacious for the treatment of HIV-D. Affective: Apathy (depression-like features), Irritability, Mania, new onset psychosis. Behavioral: Psychomotor retardation (slowed speech or response time), Personality changes, Social withdrawal. Cognitive: Lack of visuospatial memory (misplacing things), Lack of vasomotor coordination, Difficulty with complex sequencing (difficulty in performing previously learned complex tasks), Impaired concentration and attention-Impaired verbal memory (word-finding ability), Mental slowing. Motor: Unsteady gait, loss of balance, Leg weakness, dropping things, Tremors, poor handwriting and decline in fine motor skills.

#### **3.3. HIV associated neuropathy**

Treatment:

**3.2. HIV-associated dementia**

140 Current Perspectives in HIV Infection

program (McArthur et al., 2003).

Combination anti retro viral therapy is beneficial and rapid improvement in cognitive function.

The major direct effect of HIV infection on the immune system is the profound and progressive loss of CD4 lymphocytes. This leads to impaired cellular immunity, and a dysregulation of mac‐ rophages, with the overproduction of a variety of proinflammatory cytokines and chemokines (Griffin, 1997). HIV can enter the nervous system early after infection, but productive infection is rarely detectable before immunosuppression has developed. Based upon phylogenetic anal‐ ysis of HIV gp160, the route of central nervous system (CNS) infection appears to primarily in‐ volve infected monocytes (Liu et al., 2000) as well as free viral particles and HIV proteins crossing a disrupted blood–brain barrier. The presentation of HIV-D includes cognitive, behav‐ ioral, and motor dysfunction, and suggests a predominant subcortical involvement (Navia et al., 1986). In the early stages, memory loss, mental slowing, reading and comprehension diffi‐

**Figure 1.** Frequency of symptoms in HIV dementia among 300 subjects personally examined at JHU HIV Neurology

The cognitive deficits of HIV- D are characterized primarily by (1) memory loss that is selective for impaired retrieval; (2) impaired ability to manipulate acquired knowledge; (3) personality changes including apathy, inertia, and irritability; and (4) general slowing of all thought processes. Gait disturbance and impairment of fine manual dexterity are common early manifestations. Examination findings include impaired rapid movements of eyes and limbs,

culties, and apathy are frequent com plaints (Fig. 1) (Mc Arthur et al., 2003).

Symptomatic neuropathies occur in approximately 10% to 15%. Pathologic evidence of peripheral nerve involvement is present in virtually all end-stage AIDS patients. The most common complaints are numbness, parethesias and painful dysestesias. Zanetti et al., (2004) reported mild distal dysestesia that neither interfered with the activities of daily living nor required specific therapy. The main neurological sign was distal symmetric sensory alteration (in 97.1% of the patients) in the four limbs but mainly in the feet. The etiology and pathogenesis of peripheral neuropathy associated with HIV infection is uncertain. It can be caused by the direct or indirect action of HIV and antibody production, or secondary to infections (CMV, MAC), toxic effects of certain drugs (isoniazid, vincristine, d4T, ddi, ddC), or nutritional deficiencies (vitamin B12) (Rizzuto et al., 1995; Dalakas et al., 1988; Figg, 1991; Browne et al., 1993; Pike, 1993; Abrams et al., 1994; Kieburtz et al., 1991; Norton et al., 1996; Gill et al., 1990; Simpson et al.,1995). Almost all patients with HIV that had diagnosis of peripheral neuropathy were taking drugs probably neurotoxic (ddi, d4t,ddC isoniazid) (Zanetti et al., 2004) to determine the effect of 5 weeks of individualized acupuncture treatment, delivered in a group setting, on pain and symptoms of peripheral neuropathy associated with HIV infection. In addition, the acupuncture regimen reduced pain/aching/burning and pins/needles/numbness in the upper and lower limbs (Phillips et al., 2004).

#### **3.4. HIV related to myelopathy with polyradiculopathy**

The most common cause of spinal cord disease in AIDS patients is AIDS-associated myelop‐ athy, with a reported prevalence of 20% to 55% in different series (Gray et al., 1990; Henin et al., 1992; Petito et al., 1985; Goldstick, 1985; Dal et al., 1994; Artigas et al., 1990). Clinical symptoms and signs of myelopathy included spastic paraparesis, gait disturbance, urinary problems, and impotence in males, hyperreflexia, and a variable degree of sensory loss. A clinical rating of the severity of the myelopathy was established by a neurologist blinded to the MR findings. The myelopathy was rated as mild, moderate, or severe: mild if there were only subjective complaints of leg stiffness, heaviness, cramps, or subjective bladder dysfunc‐ tion (not incontinence), together with objective findings of increased tone, hyperreflexia, or extensor plantar responses; moderate if there was objectively demonstrable weakness of the lower extremities or incontinence; and severe if the patient was not independently ambulatory. The MR findings of the spinal cord were subsequently correlated with the clinical rating of the severity of the myelopathy. June et al, 1999, reported spinal cord MR features were abnormal in 18 (86%) of the 21 patients (table 2). The most common finding was spinal cord atrophy, seen in 15 patients (71%) (Fig 2).

and thoracic cord (Henin et al., 1992; Petito et al., 1985; Dal et al., 1994; Tan et al., 1995). The effect of HAART on improving the symptoms or slowing the progression of HIV-associated myelopathy is not known. A pilot study using high doses of oral L-methionine led to im‐ provement in clinical and electrophysiologic features of the disease in an open-label clinical trial (Dorfman et al., 1997). Uncontrolled clinical experience no benefit from corticosteroids

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143

Toxic events secondary to use of HAART can be observed globally. Recently, Simpson et al. 2004, reported a heterogeneous syndrome termed the HIV-associated neuromuscular weak‐ ness syndrome (HANWS) which seems to be related to hyperlactatemia and stavudine and/or didanosine exposure. Rapidly ascending neuromuscular weakness syndrome," associated with lactic acidosis syndrome in HIV-infected patients. Majority dramatic motor weakness developed over days to weeks (resembling GBSrespiratory failure and death in several patients. Systemic symptoms included nausea, vomiting, weight loss, abdominal distention, hepatomegaly, and lipoatrophy. Stavudine, Lamivudine and Efavirenz are most commonly used ARV agent. Muscle weakness worsened even after discontinuation of ARV therapy. Rapidly progressive sensorimotor polyneuropathy and myopathy observed. In recent years, a spectrum of metabolic and morphologic alterations has emerged among HIV-infected patients receiving HAART. Additionally, neurological syndromes, such as antiretroviral toxic neuropathy, have been clinically well characterized (Höke & Cornblath, 2004; Keswani et al., 2002). Diagnostic information find out by severe axonal neuropathy, increase Serum lactate level twice times than normal, decrease Serum bicarbonate and arterial pH level, increase serum CPK level. Electrophysiology; EMG-NCV: severe axonal neuropathy in most of the cases, demyelinating features may be seen admixed or in isolation and myopathic features may be noted. Nerve and Muscle Biopsy: Important in evaluating patients with HANWS. Mitochondrial studies with morphology assessment and mitochondrial DNA (mtDNA) quantification may be needed to further elucidate the role of mitochondrial toxicity in this syndrome Treatment: As was observed in this report, the antiretroviral most often associated with HANWS was stavudine. Avoiding stavudine or didanosine, the nucleosides with the highest association with mitochondrial toxicity, may be a satisfactory alternative in the long run. The treatment of HANWS is controversial and important since this is potentially a fatal syndrome. Our experience reinforces the recommendation that early interruption of HAART and clinical support is beneficial. Initiate systemic treatment for lactic acidosis syndrome and supportive treatment for the neurologic component in a monitored setting. Neuromuscular weakness - corticosteroids, intravenous immunoglobulins, vitamins (B1, B12), and plasma‐

Toxoplasmosis is the leading cause of focal central nervous system (CNS) disease in AIDS. CNS toxoplasmosis in HIV-infected patients is usually a complication of the late phase of the disease. Toxoplasmosis has been an indicator disease for AIDS since the early days of the

**3.5. HIV-Associated Neuromuscular Weakness Syndrome (HANWS)**

and intravenous immunoglobulin (IVIG).

pheresis have been used (Luciano et al., 2003).

**3.6. Toxoplasmosis**


**Table 2.** American Journal of Neuroradiology 20:1412-1416 (9 1999)

**Figure 2.** American Journal of Neuroradiology 20:1412-1416 (9 1999)

AIDS-associated myelopathy is characterized pathologically by discrete or coalescent intra‐ myelin and periaxonal vacuolation, with cellular debris and lipid-laden macrophages, in the white matter of the spinal cord. The axons are usually intact, but in severe vacuolization, they may become disrupted. It typically involves the lateral and posterior columns of the cervical and thoracic cord (Henin et al., 1992; Petito et al., 1985; Dal et al., 1994; Tan et al., 1995). The effect of HAART on improving the symptoms or slowing the progression of HIV-associated myelopathy is not known. A pilot study using high doses of oral L-methionine led to im‐ provement in clinical and electrophysiologic features of the disease in an open-label clinical trial (Dorfman et al., 1997). Uncontrolled clinical experience no benefit from corticosteroids and intravenous immunoglobulin (IVIG).

#### **3.5. HIV-Associated Neuromuscular Weakness Syndrome (HANWS)**

Toxic events secondary to use of HAART can be observed globally. Recently, Simpson et al. 2004, reported a heterogeneous syndrome termed the HIV-associated neuromuscular weak‐ ness syndrome (HANWS) which seems to be related to hyperlactatemia and stavudine and/or didanosine exposure. Rapidly ascending neuromuscular weakness syndrome," associated with lactic acidosis syndrome in HIV-infected patients. Majority dramatic motor weakness developed over days to weeks (resembling GBSrespiratory failure and death in several patients. Systemic symptoms included nausea, vomiting, weight loss, abdominal distention, hepatomegaly, and lipoatrophy. Stavudine, Lamivudine and Efavirenz are most commonly used ARV agent. Muscle weakness worsened even after discontinuation of ARV therapy. Rapidly progressive sensorimotor polyneuropathy and myopathy observed. In recent years, a spectrum of metabolic and morphologic alterations has emerged among HIV-infected patients receiving HAART. Additionally, neurological syndromes, such as antiretroviral toxic neuropathy, have been clinically well characterized (Höke & Cornblath, 2004; Keswani et al., 2002). Diagnostic information find out by severe axonal neuropathy, increase Serum lactate level twice times than normal, decrease Serum bicarbonate and arterial pH level, increase serum CPK level. Electrophysiology; EMG-NCV: severe axonal neuropathy in most of the cases, demyelinating features may be seen admixed or in isolation and myopathic features may be noted. Nerve and Muscle Biopsy: Important in evaluating patients with HANWS. Mitochondrial studies with morphology assessment and mitochondrial DNA (mtDNA) quantification may be needed to further elucidate the role of mitochondrial toxicity in this syndrome Treatment: As was observed in this report, the antiretroviral most often associated with HANWS was stavudine. Avoiding stavudine or didanosine, the nucleosides with the highest association with mitochondrial toxicity, may be a satisfactory alternative in the long run. The treatment of HANWS is controversial and important since this is potentially a fatal syndrome. Our experience reinforces the recommendation that early interruption of HAART and clinical support is beneficial. Initiate systemic treatment for lactic acidosis syndrome and supportive treatment for the neurologic component in a monitored setting. Neuromuscular weakness - corticosteroids, intravenous immunoglobulins, vitamins (B1, B12), and plasma‐ pheresis have been used (Luciano et al., 2003).

#### **3.6. Toxoplasmosis**

clinical rating of the severity of the myelopathy was established by a neurologist blinded to the MR findings. The myelopathy was rated as mild, moderate, or severe: mild if there were only subjective complaints of leg stiffness, heaviness, cramps, or subjective bladder dysfunc‐ tion (not incontinence), together with objective findings of increased tone, hyperreflexia, or extensor plantar responses; moderate if there was objectively demonstrable weakness of the lower extremities or incontinence; and severe if the patient was not independently ambulatory. The MR findings of the spinal cord were subsequently correlated with the clinical rating of the severity of the myelopathy. June et al, 1999, reported spinal cord MR features were abnormal in 18 (86%) of the 21 patients (table 2). The most common finding was spinal cord atrophy,

seen in 15 patients (71%) (Fig 2).

142 Current Perspectives in HIV Infection

**Table 2.** American Journal of Neuroradiology 20:1412-1416 (9 1999)

**Figure 2.** American Journal of Neuroradiology 20:1412-1416 (9 1999)

AIDS-associated myelopathy is characterized pathologically by discrete or coalescent intra‐ myelin and periaxonal vacuolation, with cellular debris and lipid-laden macrophages, in the white matter of the spinal cord. The axons are usually intact, but in severe vacuolization, they may become disrupted. It typically involves the lateral and posterior columns of the cervical

Toxoplasmosis is the leading cause of focal central nervous system (CNS) disease in AIDS. CNS toxoplasmosis in HIV-infected patients is usually a complication of the late phase of the disease. Toxoplasmosis has been an indicator disease for AIDS since the early days of the human immunodeficiency virus (HIV) epidemic (Horowitz et al., 1983; Luft et al., 1984). CNS toxoplasmosis begins with constitutional symptoms and headache. Later, confusion and drowsiness, seizures, focal weakness, and language disturbance develop. Without treatment, patients progress to coma in days to weeks. On physical examination, personality and mental status changes may be observed. Seizures, hemiparesis, hemianopia, aphasia, ataxia, and cranial nerve palsies may be evident. Occasionally, symptoms and signs of a radiculomyel‐ opathy predominate. Serologic studies in patients with CNS toxoplasmosis may demonstrate rising titers of anti-toxoplasma immunoglobulin G (IgG) antibodies, CD4 counts < 100 cells mm-3 and CSF findings are non-specific. Detection of T.gondii DNA by PCR has only moderate sensitivity. MRI typically reveals multiple enhancing lesions with perifocal oedema and mass effect in the basal ganglia and gray white matter interface of the cerebral hemispheres. Any part of the brain can be affected, mostly solitary in appearance. Standard therapy consists of pyrimethamine, sulfadiazine, and folinic acid in combination. Trimethoprim-sulfamethoxa‐ zole (TMP-SMZ) can be used as an alternative regimen (Dedicoat et al., 2006). A Cochrane data base review failed to find a significant difference between standard therapy and TMP-SMZ. Clindamycin can be used in patients allergic to sulfa drugs. Effective antiretroviral therapy is equally important (Dedicoat et al., 2006; Fung et al., 1996; Bertschy et al., 2006; Behbahani et al., 1995). Most common cause of cerebral mass lesion, Sub acute course with fever, headache, confusion or cognitive disturbances with focal deficits, Seizures 24 – 29 %, rarely psychotic features. Imaging – Multiple mass lesions at grey – white junction & basal ganglia, CSF – Non specific, Antibody to T. Gondi, PCR recently developed.

patients with HIV infection is a potentially curable disease, although the potential for cure is less than in immunocompetent individuals. Appropriate use of supportive care is an important

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QD. Daily; TID, three times daily; BID, two times daily; QID, four times daily; s.c., subcutaneous; G CSF, granulocyte colony stimulating factor; GM,CSF, granulocyte-macrophage colony stimulating factor, NIH, national institute of health; RTIs,

**Table 3.** Suggested supportive care for the patient with HIV infection and lymphoma or other malignancies. European

Appropriate supportive care and CNS prophylaxis might improve outcome. In patients with HIV infection, the differential diagnosis of a patient with focal brain lesions includes PCNSL, cerebral toxoplasmosis, and other infections. Focal brain lesions have also been described in conjunction with relapsed systemic lymphoma (Desai et al., 1999). A proposed algorithm for the diagnostic approach to a patient with HIV infection and focal brain lesions is shown in Fig. 3.

Progressive Multifocal Leukoencephalopathy (PML) is a rare demyelinating disease (focal neurological disease & cognitive impairment) of the CNS caused by reactivation of JC virus (JCV) 1. Radiographic evidence of white matter disease with subcortical involvement – 'scalloped' appearance. CSF – Non specific. Primary infection occurs in childhood and the virus remains latent in the kidney or lymphoid organs thereafter. In the setting of cellular immunosuppression, the virus may spread to the central nervous system, leading to a lytic infection of oligodendrocytes and subsequent demyelination. Classically, PML was observed in patients with advanced HIV infection, lymphoproliferative disorders and transplant

**3.8. HIV related progressive multifocal leukoencephalopathy**

component of therapy (Table 3) (Sparano, 2001).

reserve transcript inhibitors.

Journal of Cancer 37 (2001) 1296–1305

#### **3.7. AIDS related primary CNS lymphoma**

A relationship between congenital or acquired immune deficiency (AIDS) and lymphoma was first recognised more than 30 years ago. An association between non-Hodgkin's lymphoma (NHL) and the acquired immune deficiency syndrome became evident in the early 1980s. Lymphoma occurring in the HIV-infected individual may be systemic, may primarily involve the central nervous system, or may be localised in the body cavities. Systemic lymphoma is the most common presentation, accounting for approximately 80% of all cases. The histology usually is diffuse large cell, immunoblastic, or small non-cleaved cell lymphoma. Primary CNS lymphoma accounts for approximately 20% of all cases. Most patients are profoundly immu‐ nosuppressed and typically have a CD4 lymphocyte count below 50/ml. Approximately twothirds or more of them have AIDS-defining conditions prior to the development of primary CNS lymphoma (Gill et al., 1985; Goldstein, 1991). The lesions are typically few in number (1– 3), large (2–4 cm), and contrast enhances approximately 50% of the time (Fine & Mayer 1993). Lesions are most common in the cerebrum, but also occur frequently in the cerebellum, basal ganglia and brain stem, and are nearly always found to be multifocal at autopsy (Loureiro et al., 1988; MacMahon et al., 1991). The lymphoma cells tend to be distributed along vascular channels as perivascular cuffs, are of B cell origin, display large cell and immunoblastic histologies. Subacute presentation with headache, impaired cognition, focal cerebral dysfunc‐ tion. D/D – Toxoplasmosis, PML. Imaging – Multiple enhancing periventricular or subepen‐ dymal lesions, CSF – EBV nucleic acid in CSF being studied. NHL are of higher grade and advanced stage. Response and tolerance to chemotherapy is poor. Systemic lymphoma in patients with HIV infection is a potentially curable disease, although the potential for cure is less than in immunocompetent individuals. Appropriate use of supportive care is an important component of therapy (Table 3) (Sparano, 2001).

human immunodeficiency virus (HIV) epidemic (Horowitz et al., 1983; Luft et al., 1984). CNS toxoplasmosis begins with constitutional symptoms and headache. Later, confusion and drowsiness, seizures, focal weakness, and language disturbance develop. Without treatment, patients progress to coma in days to weeks. On physical examination, personality and mental status changes may be observed. Seizures, hemiparesis, hemianopia, aphasia, ataxia, and cranial nerve palsies may be evident. Occasionally, symptoms and signs of a radiculomyel‐ opathy predominate. Serologic studies in patients with CNS toxoplasmosis may demonstrate rising titers of anti-toxoplasma immunoglobulin G (IgG) antibodies, CD4 counts < 100 cells mm-3 and CSF findings are non-specific. Detection of T.gondii DNA by PCR has only moderate sensitivity. MRI typically reveals multiple enhancing lesions with perifocal oedema and mass effect in the basal ganglia and gray white matter interface of the cerebral hemispheres. Any part of the brain can be affected, mostly solitary in appearance. Standard therapy consists of pyrimethamine, sulfadiazine, and folinic acid in combination. Trimethoprim-sulfamethoxa‐ zole (TMP-SMZ) can be used as an alternative regimen (Dedicoat et al., 2006). A Cochrane data base review failed to find a significant difference between standard therapy and TMP-SMZ. Clindamycin can be used in patients allergic to sulfa drugs. Effective antiretroviral therapy is equally important (Dedicoat et al., 2006; Fung et al., 1996; Bertschy et al., 2006; Behbahani et al., 1995). Most common cause of cerebral mass lesion, Sub acute course with fever, headache, confusion or cognitive disturbances with focal deficits, Seizures 24 – 29 %, rarely psychotic features. Imaging – Multiple mass lesions at grey – white junction & basal ganglia, CSF – Non

A relationship between congenital or acquired immune deficiency (AIDS) and lymphoma was first recognised more than 30 years ago. An association between non-Hodgkin's lymphoma (NHL) and the acquired immune deficiency syndrome became evident in the early 1980s. Lymphoma occurring in the HIV-infected individual may be systemic, may primarily involve the central nervous system, or may be localised in the body cavities. Systemic lymphoma is the most common presentation, accounting for approximately 80% of all cases. The histology usually is diffuse large cell, immunoblastic, or small non-cleaved cell lymphoma. Primary CNS lymphoma accounts for approximately 20% of all cases. Most patients are profoundly immu‐ nosuppressed and typically have a CD4 lymphocyte count below 50/ml. Approximately twothirds or more of them have AIDS-defining conditions prior to the development of primary CNS lymphoma (Gill et al., 1985; Goldstein, 1991). The lesions are typically few in number (1– 3), large (2–4 cm), and contrast enhances approximately 50% of the time (Fine & Mayer 1993). Lesions are most common in the cerebrum, but also occur frequently in the cerebellum, basal ganglia and brain stem, and are nearly always found to be multifocal at autopsy (Loureiro et al., 1988; MacMahon et al., 1991). The lymphoma cells tend to be distributed along vascular channels as perivascular cuffs, are of B cell origin, display large cell and immunoblastic histologies. Subacute presentation with headache, impaired cognition, focal cerebral dysfunc‐ tion. D/D – Toxoplasmosis, PML. Imaging – Multiple enhancing periventricular or subepen‐ dymal lesions, CSF – EBV nucleic acid in CSF being studied. NHL are of higher grade and advanced stage. Response and tolerance to chemotherapy is poor. Systemic lymphoma in

specific, Antibody to T. Gondi, PCR recently developed.

**3.7. AIDS related primary CNS lymphoma**

144 Current Perspectives in HIV Infection


QD. Daily; TID, three times daily; BID, two times daily; QID, four times daily; s.c., subcutaneous; G CSF, granulocyte colony stimulating factor; GM,CSF, granulocyte-macrophage colony stimulating factor, NIH, national institute of health; RTIs, reserve transcript inhibitors.

**Table 3.** Suggested supportive care for the patient with HIV infection and lymphoma or other malignancies. European Journal of Cancer 37 (2001) 1296–1305

Appropriate supportive care and CNS prophylaxis might improve outcome. In patients with HIV infection, the differential diagnosis of a patient with focal brain lesions includes PCNSL, cerebral toxoplasmosis, and other infections. Focal brain lesions have also been described in conjunction with relapsed systemic lymphoma (Desai et al., 1999). A proposed algorithm for the diagnostic approach to a patient with HIV infection and focal brain lesions is shown in Fig. 3.

#### **3.8. HIV related progressive multifocal leukoencephalopathy**

Progressive Multifocal Leukoencephalopathy (PML) is a rare demyelinating disease (focal neurological disease & cognitive impairment) of the CNS caused by reactivation of JC virus (JCV) 1. Radiographic evidence of white matter disease with subcortical involvement – 'scalloped' appearance. CSF – Non specific. Primary infection occurs in childhood and the virus remains latent in the kidney or lymphoid organs thereafter. In the setting of cellular immunosuppression, the virus may spread to the central nervous system, leading to a lytic infection of oligodendrocytes and subsequent demyelination. Classically, PML was observed in patients with advanced HIV infection, lymphoproliferative disorders and transplant recipients. There is no specific treatment for PML, but the survival in HIV-infected PML patients has increased substantially during the last decade. Before the introduction of highly active antiretroviral therapy (HAART), only 10% patients with PML lived for more than a year. In contrast, recent studies have shown at least 50% one-year survival of HIV- infected PML patients (Falco et al., 2008; De Luca et al., 2008). However, the prognosis of PML associated with other immunosuppressive conditions remains poor. Immune recovery associated with HAART has resulted in a better prognosis for HIV-infected PML patients. The prompt institution of HAART in HIV infected PML patients is the most effective therapeutic approach in increasing survival in this group. Several studies have shown that PML survival increased from 10 to 50% in the last decade (Falco et al., 2008; De Luca et al., 2008; Cinque et al., 2003; Bamford et al., 1989; Du Pasquier et al., 2004; Koralnik et al., 2004; Gasnault et al., 2003; Antinori et al., 2003). In a recent study, JCV-peptide loaded dendritic cells from PML patients, HIVinfected individuals and healthy control subjects could elicit a strong cellular immune response mediated by CD8+ cytotoxic T lymphocytes cell response *in vitro* (Marzocchetti et al, 2009), which suggests that autologous dendritic cell-based immunotherapy could be a potential therapeutic option for PML.

**3.9. Neurological approach to immunocompromized patients due to HIV-1**

Central nervous system pathogens in specific immunocompromised-host (HIV-1) categories based upon presentation like Meningitis, Meningoencephalitis, and Encephalitis. Cryptococ‐ cal meningitis is seen in populations but cryptococcomas are much more frequent in the latter. Encephalitis and cerebral abscesses usually do not produce cerebrospinal fluid (CSF) changes unless the lesion communicates with the ventricular or subarachnoid spaces. Discrete white matter lesions have a narrower differential including calcineurin-induced demyelination usually in the posterior territory and progressive multifocal leukoencephalopathy (JC papova virus) which is characteristically nonenhancing and without mass effect. Meningoencephalitis due to Toxoplasma gondii continues to be the predominant pathogen in HIV-1 disease even

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with highly active antiretroviral therapy (HAART) exposure (Peter K. Linden, 2009).

Twenty percent of children present with severe symptoms or die in infancy, Prognosis is related to: a) Greater inoculation of HIV b) Earlier infection with immature immune system c) Immune escape from mother. Asceptic Meningitis or Meningoencephalitis does not occur in infants. Acquired Microcephali, cerebral vasculopathy and basal ganglia, Calcification are unique in children. OIS are rare in children, here absolute CD4T cell count less helpful. HIV-DNA PCR on peripheral blood lymphocytes can help to diagnosis. Avoid vaginal delivery,

A combination of different markers is required to predict plasma human immunodeficiency virus type 1 (HIV-1) disease progression (Fahey et al., 1990; Saves et al., 2001). Levels of plasma HIV-1 RNA and CD4 + cell count are highly predictive of progression to AIDS or death (Hughes et al., 1997; Mellors et al., 1997; Saves et al., 2001). However, variations of these markers do not explain all variations of disease progression and the relative prognostic value of laboratory markers of HIV disease are not the same at different stages of the disease. Therefore the use of markers of immune activation has been suggested (Graham, 1996; Saves et al., 2001). CD4+ cell count (CD4) and RNA viral loads (RNA) are the two most commonly used prognostic markers of the clinical progression of HIV infection for HIV infection (Hammer et al., 2006; Gilks et al., 2006). Besides, there are various additional markers for HIV progression such as CD8+ cell count, anti-HIV antibodies, p24 antigen, hemoglobin concen‐ tration, platelet concentration as well as erythrocyte sedimentation rate (ESR). Various predictors for progression to AIDS among HIV-positive homosexual men have beed identified. These include low absolute number and/or percentage of CD4+ lymphocytes, low CD8+ cell count, low concentration of anti-HIV antibodies, p24 antigenaemia, decreased concentration of haemoglobin, increased titre of IgG antibody to cytomegalovirus, raised serum IgA and IgM values, raised concentrations in the serum of interleukin-2 receptor, neopterin and beta2 microglobulin (Gafa et al., 1993). Among these markers, the percentage of CD4+ cells was

**3.10. Neurogenic manifestation of HIV infection in children**

plan caesarean section and avoid breast feeding.

**4. Markers for HIV progression**

CSF, cerebrospinal fluid Antitoxo, antitoxoplasmosis RT, radiotherapy

**Figure 3.** Algorithm for management of HIV – infected individuals with focal brain lesions European Journal of Cancer 37 (2001) 1296–1305

### **3.9. Neurological approach to immunocompromized patients due to HIV-1**

Central nervous system pathogens in specific immunocompromised-host (HIV-1) categories based upon presentation like Meningitis, Meningoencephalitis, and Encephalitis. Cryptococ‐ cal meningitis is seen in populations but cryptococcomas are much more frequent in the latter. Encephalitis and cerebral abscesses usually do not produce cerebrospinal fluid (CSF) changes unless the lesion communicates with the ventricular or subarachnoid spaces. Discrete white matter lesions have a narrower differential including calcineurin-induced demyelination usually in the posterior territory and progressive multifocal leukoencephalopathy (JC papova virus) which is characteristically nonenhancing and without mass effect. Meningoencephalitis due to Toxoplasma gondii continues to be the predominant pathogen in HIV-1 disease even with highly active antiretroviral therapy (HAART) exposure (Peter K. Linden, 2009).

#### **3.10. Neurogenic manifestation of HIV infection in children**

Twenty percent of children present with severe symptoms or die in infancy, Prognosis is related to: a) Greater inoculation of HIV b) Earlier infection with immature immune system c) Immune escape from mother. Asceptic Meningitis or Meningoencephalitis does not occur in infants. Acquired Microcephali, cerebral vasculopathy and basal ganglia, Calcification are unique in children. OIS are rare in children, here absolute CD4T cell count less helpful. HIV-DNA PCR on peripheral blood lymphocytes can help to diagnosis. Avoid vaginal delivery, plan caesarean section and avoid breast feeding.

### **4. Markers for HIV progression**

recipients. There is no specific treatment for PML, but the survival in HIV-infected PML patients has increased substantially during the last decade. Before the introduction of highly active antiretroviral therapy (HAART), only 10% patients with PML lived for more than a year. In contrast, recent studies have shown at least 50% one-year survival of HIV- infected PML patients (Falco et al., 2008; De Luca et al., 2008). However, the prognosis of PML associated with other immunosuppressive conditions remains poor. Immune recovery associated with HAART has resulted in a better prognosis for HIV-infected PML patients. The prompt institution of HAART in HIV infected PML patients is the most effective therapeutic approach in increasing survival in this group. Several studies have shown that PML survival increased from 10 to 50% in the last decade (Falco et al., 2008; De Luca et al., 2008; Cinque et al., 2003; Bamford et al., 1989; Du Pasquier et al., 2004; Koralnik et al., 2004; Gasnault et al., 2003; Antinori et al., 2003). In a recent study, JCV-peptide loaded dendritic cells from PML patients, HIVinfected individuals and healthy control subjects could elicit a strong cellular immune response mediated by CD8+ cytotoxic T lymphocytes cell response *in vitro* (Marzocchetti et al, 2009), which suggests that autologous dendritic cell-based immunotherapy could be a potential

**Figure 3.** Algorithm for management of HIV – infected individuals with focal brain lesions European Journal of Cancer

therapeutic option for PML.

146 Current Perspectives in HIV Infection

CSF, cerebrospinal fluid Antitoxo, antitoxoplasmosis

37 (2001) 1296–1305

RT, radiotherapy

A combination of different markers is required to predict plasma human immunodeficiency virus type 1 (HIV-1) disease progression (Fahey et al., 1990; Saves et al., 2001). Levels of plasma HIV-1 RNA and CD4 + cell count are highly predictive of progression to AIDS or death (Hughes et al., 1997; Mellors et al., 1997; Saves et al., 2001). However, variations of these markers do not explain all variations of disease progression and the relative prognostic value of laboratory markers of HIV disease are not the same at different stages of the disease. Therefore the use of markers of immune activation has been suggested (Graham, 1996; Saves et al., 2001). CD4+ cell count (CD4) and RNA viral loads (RNA) are the two most commonly used prognostic markers of the clinical progression of HIV infection for HIV infection (Hammer et al., 2006; Gilks et al., 2006). Besides, there are various additional markers for HIV progression such as CD8+ cell count, anti-HIV antibodies, p24 antigen, hemoglobin concen‐ tration, platelet concentration as well as erythrocyte sedimentation rate (ESR). Various predictors for progression to AIDS among HIV-positive homosexual men have beed identified. These include low absolute number and/or percentage of CD4+ lymphocytes, low CD8+ cell count, low concentration of anti-HIV antibodies, p24 antigenaemia, decreased concentration of haemoglobin, increased titre of IgG antibody to cytomegalovirus, raised serum IgA and IgM values, raised concentrations in the serum of interleukin-2 receptor, neopterin and beta2 microglobulin (Gafa et al., 1993). Among these markers, the percentage of CD4+ cells was found to be the best predictor of HIV progression (Fahey et al., 1990), followed by serum concentrations of neopterin and beta2-microglobulin, IgA, interleukin-2 receptors and p24 antigen. Only a few studies have the predictive values of these serological markers which have been evaluated in cohorts of IVDUs (Gafa et al*.,* 1993). De Wolf & Lange, (1993) observed that several laboratory markers become most noticeably established as predictors of progression from asymptomatic HIV-1 infection to AIDS: (1) Decline in antibody reactivity to HIV core proteins p24 and p17; (2) Appearance of persistent HIV-1 p24 antigenemia; (3) Declining numbers and percentages of peripheral blood CD4-positive lymphocytes; (4) Elevated serum beta2-microglobulin concentration and (4) Elevated serum and urine neopterin concentrations.

#### **4.1. Immunological and virological markers**

Based upon scientific literature, immunological and virological markers have been proven as prognostic indicators for progression of HIV disease. The most widely studied marker, the CD4 + lymphocyte count was found to be the best single indicator of the stage of the illness (Zeller et al., 1996). HIV infects CD4+ T lymphocytes selectively and causes the destruction of CD4+ T cells directly as well as indirectly leading to gradual loss of the CD4 T cell numbers in peripheral circulation. Hence, the CD4+ T cell counts are being used to monitor the disease progression in HIV infection, to decide the threshold for initiation of anti-retro viral therapy, to monitor the efficacy of Anti Retrroviral treatment and to initiate prophylactic treatment for opportunistic infections (OIs) (Atlh Nicholson, 1997; Pattanapanyasat & Thakat, 2005). Measuring the CD4+ lymphocytes count remains the most effective means of evaluating of the clinical prognosis of patients infected with Human Immunodeficiency Virus (HIV) (Stein et al., 1992). This measurement has been universally accepted as a uniform means for the clinical staging of patients infected with HIV and those progressing to AIDS (Levine et al., 2000) and for the determination of the commencement of antiretroviral therapy and for monitoring the response to antiretroviral therapy (Evans-Gilbert et al., 2004).

**Figure 4.** Schematic natural history model of HIV-1 replication driving rates of CD4 decline and clinical progression

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There are two types of T cells carry the CD8 surface molecule: T-suppressor cells, which inhibit immune responses, and killer T cells (also known as cytotoxic T lymphocytes, or CTLs), which target and kill infected or cancerous cells. As with CD4 cells, a variety of factors can cause CD8 cell counts to fluctuate. CD8 cell counts typically rise over time in people with HIV, but (unlike CD4 cells) CD8 cell numbers do not independently predict disease progression, and their

Because absolute CD4 and CD8 cell counts are so variable, some physicians prefer to look at CD4 or CD8 cell percentages, the proportion of all lymphocytes that are CD4 or CD8 cells. Percentages are usually more stable over time than absolute counts. A normal CD4 cell percentage in a healthy person is about 30-60 per cent, while a normal CD8 cell percentage is

The CD4/CD8 cell ratio is calculated by dividing the CD4 cell count by the CD8 cell count. A normal CD4/CD8 cell ratio is about 0.9-3.0 or higher, there are at least 1-3 CD4 cells for every CD8 cell. In people with HIV this ratio may be much lower, with many more CD8 cells than

Viral load tests measure the amount of HIV RNA in the blood. The presence of RNA indicates that the virus is actively replicating or multiplying. Along with the CD4 cell count, viral load

relation to immune status is not well understood (Vajpayee & Mohan 2011).

(Korenromp et al., 2009)

**4.3. CD8+ cell count**

**4.4. CD4 and CD8 cell percentage**

15-40 per cent (Taylor et al., 1989).

**4.5. CD4/CD8 cell ratio**

CD4 cells (Giorgi, 1993).

**4.6. HIV viral load**

#### **4.2. CD4+ cell count**

CD4+ T lymphocyte play a central regulatory role in the immune response. The decrease in CD4+ T cell numbers can compromise the normal immune functions of the body. Hence, the number of CD4+ T cells in the circulation provides important information regarding the immune competence of an individual (Thakar et al., 2011). HIV primarily targets CD4 cells. As HIV disease progresses, CD4 cell counts decline, typically by about 30-100 cells/µl per year (depending on viral load), leaving a person increasingly vulnerable to infections and cancers. People with CD4 cell counts above 500 cells/µl generally have relatively normal immune function and are at low risk for opportunistic infections (Hammer et al., 2006). The clinical staging of HIV disease and the relative risk of developing opportunistic infections have historically relied on the CD4 cell count as the principle laboratory marker of immune status (Kleinman et al., 1998; Patton et al., 2003). HIV disease is commonly categorized on the basis of three levels of immunodeficiency: relative immune competence (CD4 cell count > 500/µl; ≥ 29%), early immune suppression (CD4 cell count between 200/µl and 500/ µl); 4%-28%) and severe immune suppression (CD4 cell count <200/µl and 500/ µl); <14%) (CDC, 1993).

**Figure 4.** Schematic natural history model of HIV-1 replication driving rates of CD4 decline and clinical progression (Korenromp et al., 2009)

#### **4.3. CD8+ cell count**

found to be the best predictor of HIV progression (Fahey et al., 1990), followed by serum concentrations of neopterin and beta2-microglobulin, IgA, interleukin-2 receptors and p24 antigen. Only a few studies have the predictive values of these serological markers which have been evaluated in cohorts of IVDUs (Gafa et al*.,* 1993). De Wolf & Lange, (1993) observed that several laboratory markers become most noticeably established as predictors of progression from asymptomatic HIV-1 infection to AIDS: (1) Decline in antibody reactivity to HIV core proteins p24 and p17; (2) Appearance of persistent HIV-1 p24 antigenemia; (3) Declining numbers and percentages of peripheral blood CD4-positive lymphocytes; (4) Elevated serum beta2-microglobulin concentration and (4) Elevated serum and urine neopterin concentrations.

Based upon scientific literature, immunological and virological markers have been proven as prognostic indicators for progression of HIV disease. The most widely studied marker, the CD4 + lymphocyte count was found to be the best single indicator of the stage of the illness (Zeller et al., 1996). HIV infects CD4+ T lymphocytes selectively and causes the destruction of CD4+ T cells directly as well as indirectly leading to gradual loss of the CD4 T cell numbers in peripheral circulation. Hence, the CD4+ T cell counts are being used to monitor the disease progression in HIV infection, to decide the threshold for initiation of anti-retro viral therapy, to monitor the efficacy of Anti Retrroviral treatment and to initiate prophylactic treatment for opportunistic infections (OIs) (Atlh Nicholson, 1997; Pattanapanyasat & Thakat, 2005). Measuring the CD4+ lymphocytes count remains the most effective means of evaluating of the clinical prognosis of patients infected with Human Immunodeficiency Virus (HIV) (Stein et al., 1992). This measurement has been universally accepted as a uniform means for the clinical staging of patients infected with HIV and those progressing to AIDS (Levine et al., 2000) and for the determination of the commencement of antiretroviral therapy and for monitoring the

CD4+ T lymphocyte play a central regulatory role in the immune response. The decrease in CD4+ T cell numbers can compromise the normal immune functions of the body. Hence, the number of CD4+ T cells in the circulation provides important information regarding the immune competence of an individual (Thakar et al., 2011). HIV primarily targets CD4 cells. As HIV disease progresses, CD4 cell counts decline, typically by about 30-100 cells/µl per year (depending on viral load), leaving a person increasingly vulnerable to infections and cancers. People with CD4 cell counts above 500 cells/µl generally have relatively normal immune function and are at low risk for opportunistic infections (Hammer et al., 2006). The clinical staging of HIV disease and the relative risk of developing opportunistic infections have historically relied on the CD4 cell count as the principle laboratory marker of immune status (Kleinman et al., 1998; Patton et al., 2003). HIV disease is commonly categorized on the basis of three levels of immunodeficiency: relative immune competence (CD4 cell count > 500/µl; ≥ 29%), early immune suppression (CD4 cell count between 200/µl and 500/ µl); 4%-28%) and

severe immune suppression (CD4 cell count <200/µl and 500/ µl); <14%) (CDC, 1993).

**4.1. Immunological and virological markers**

148 Current Perspectives in HIV Infection

response to antiretroviral therapy (Evans-Gilbert et al., 2004).

**4.2. CD4+ cell count**

There are two types of T cells carry the CD8 surface molecule: T-suppressor cells, which inhibit immune responses, and killer T cells (also known as cytotoxic T lymphocytes, or CTLs), which target and kill infected or cancerous cells. As with CD4 cells, a variety of factors can cause CD8 cell counts to fluctuate. CD8 cell counts typically rise over time in people with HIV, but (unlike CD4 cells) CD8 cell numbers do not independently predict disease progression, and their relation to immune status is not well understood (Vajpayee & Mohan 2011).

#### **4.4. CD4 and CD8 cell percentage**

Because absolute CD4 and CD8 cell counts are so variable, some physicians prefer to look at CD4 or CD8 cell percentages, the proportion of all lymphocytes that are CD4 or CD8 cells. Percentages are usually more stable over time than absolute counts. A normal CD4 cell percentage in a healthy person is about 30-60 per cent, while a normal CD8 cell percentage is 15-40 per cent (Taylor et al., 1989).

#### **4.5. CD4/CD8 cell ratio**

The CD4/CD8 cell ratio is calculated by dividing the CD4 cell count by the CD8 cell count. A normal CD4/CD8 cell ratio is about 0.9-3.0 or higher, there are at least 1-3 CD4 cells for every CD8 cell. In people with HIV this ratio may be much lower, with many more CD8 cells than CD4 cells (Giorgi, 1993).

#### **4.6. HIV viral load**

Viral load tests measure the amount of HIV RNA in the blood. The presence of RNA indicates that the virus is actively replicating or multiplying. Along with the CD4 cell count, viral load is one of the most valuable measures for predicting HIV disease progression and gauging when anti-HIV treatment is indicated and how well it is working. Viral load is expressed either as copies of RNA per milliliter of blood (copies/ml) or in terms of logs. A log change is an exponential or 10-fold change. For example, a change from 100 to 1,000 is a 1 log (10-fold) increase, while a change from 1,000,000 to 10,000 is a 2 log (100-fold) decrease. If the level of HIV is too low to be measured, viral load is said to be undetectable, or below the limit of quantification. However, undetectable viral load does not mean that HIV has been eradicated; people with undetectable viral load maintain a very low level of virus. Even when HIV is not detectable in the blood, it may be detectable in the semen, female genital secretions, cerebro‐ spinal fluid, tissues, and lymph nodes (Calmy et al., 2004; Petti et al., 2006; WHO, 2006). In primary HIV infection, patients may present with flu-like symptoms which usually occur during the first weeks of HIV-1 infection. It is associated with peak levels of HIV-1 RNA viremia, which subsequently declines until reaching a set point, where levels remain for months to years. Initial studies suggested that those with more symptomatic acute infection and longer duration of illness have faster rates of progression to AIDS (Koenig et al., 2006). A viral load of 100,000 copies/ml or more is considered high, while levels below 10,000 copies/ml are considered low. Research has consistently shown that higher viral loads are associated with more rapid HIV disease progression and an increased risk of death. Current U.S. HIV treatment guidelines (Koenig et al., 2006) recommend that people should consider starting treatment if their viral load is above 55,000 copies/ml (revised upward from 10,000 copies/ml in the previous guidelines). Importantly, most studies that have correlated viral load and HIV disease progression have been done in men; more recent research indicates that women may progress to AIDS at lower viral load levels, suggesting that the treatment threshold should perhaps be revised downward for women (Monica et al., 2002).

laboratory assay to help determine prognosis. By contrast with CD4 cell count which requires special procedures for specimen handling and processing, β2-microglobin can be measured with a serological assay and equipment available in many laboratories (Vajpayee & Mohan, 2011). Increased concentrations of this molecule are predictive of progression of HIV infection

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Neopterin (6-D- erythrohydroxy-propylpterin) is a low molecular weight compound derived from an intermediate product of the *de novo* biosynthesis of tetrahydrobiopterin from guano‐ sine triphosphate (GTP) (Dar & Singh, 1999; Fauci & Lane, 1998; Quin & Benson, 1994). It is an early marker of HIV infection. The levels rise further on progression from pre AIDS to clinical AIDS (Vajpayee & Mohan 2011). It is produced by macrophages after stimulation with gamma interferon. The levels have also been found to be associated with progression of HIV-1-related disease (Fuchs et al., 1988; Melmed et al., 1989; Kramer et al., 1989; De Wolf and Lange 1991) but the predictive value is slightly inferior to that of β2-microglobulin levels. Since neopterin levels are stimulated by HIV infection, measurement of neopterin levels can be useful in

monitoring progression and evaluating antiviral therapy (Vajpayee & Mohan 2011).

Haematological manifestations of HIV infection are common and more frequently occur with progression of the disease. Therefore the complete blood count (CBC) is one of the important haematological parameters which need to checked for HIV patients. They may have low blood cell counts (cytopenias) due to chronic HIV infection or as a side effect of medications, particularly drugs that damage the bone marrow, where all blood cells are produced. Blood cell counts are typically reported as the number of cells per µl of blood (cells/µl) or as a percentage of all blood cells. HIV patients should be checked for CBC for every six months, and more often if they are experiencing symptoms or taking drugs associated with low blood

Anemia is common in HIV positives. HIV itself and various OIs such as *Mycobacterium avium* complex (MAC) can affect red blood cells and their oxygen-carrying capacity (Volberding et al., 2003; Owiredu et al., 2011). People with HIV infection should be especially concerned with neu‐ trophil and lymphocyte levels, in particular CD4 and CD8 cell counts. Neutrophils normally make up about 50-70 per cent of all white blood cells. Various anti-HIV drugs, OI medications [including ganciclovir (Cytovene), used to treat cytomegalovirus, or CMV], and cancer chemo‐

Platelets are necessary for blood clotting. A normal platelet count is about 130,000-440,000 cells/ µl. Low platelet counts (thrombocytopenia) - which can lead to easy bruising and excessive

therapies that suppress the bone marrow may lead to neutropenia (Firnhaber, 2010).

to AIDS (Moss et al., 1988).

**4.9. Additional markers**

*4.9.1. Red and white blood cells*

*4.9.2. Platelets*

cell counts ( De Santis et al., 2011; Olayemi et al, 2008).

**4.8. Neopterin**

#### **4.7. Beta2-microglobulin (β2-microglobulin)**

β2-microglobulin is a low molecular weight protein that forms light chain of the class I major histocompatibility complex (MHC) which present on the surface of most somatic cells including T and B lymphocytes as well as macrophages (Cresswell et al., 1974; Lawlor et al., 1990; De Wolf and Lange 1991). It exhibits amino acid homology with the constant region of immunoglobins ( Dar & Singh, 1999; Fauci & Lane, 1998; Quin & Benson, 1994). Circulating β2-MG is generated during normal MHC I turnover (Lawlor et al., 1990) and thus is not specific to HIV-related cell death. Stimulation of lymphoid cells increases β2-microglobulinproduc‐ tion. Elevated serum concentration are seen in renal failure, hepatitis, rheumatoid arthritis, myeloproliferative disorders, lymphoproliferative disorders, infectious mononucleosis, influenza A and cytomegalovirus infection (De wolf and Lange, 1991). Free β2-microglobin can be measured in both serum and urine and levels of urine β2-microglobin correlate with the degree of progression of HIV disease. It spikes in acute infection, declines and then rises during the infection. Levels of β2-microglobin are elevated in a variety of conditions charac‐ terized by lymphocyte activation and/ or lymphocyte destruction; *e.g*. lymphoproliferative syndromes, autoimmune diseases, viral infection and in patients with renal diseases. It can be measured in serum or plasma by using radio immunoassay radio immunoassay (RIA) or competivive ELISA based tests. Β2-microglobin measurement has several advantages as a laboratory assay to help determine prognosis. By contrast with CD4 cell count which requires special procedures for specimen handling and processing, β2-microglobin can be measured with a serological assay and equipment available in many laboratories (Vajpayee & Mohan, 2011). Increased concentrations of this molecule are predictive of progression of HIV infection to AIDS (Moss et al., 1988).

### **4.8. Neopterin**

is one of the most valuable measures for predicting HIV disease progression and gauging when anti-HIV treatment is indicated and how well it is working. Viral load is expressed either as copies of RNA per milliliter of blood (copies/ml) or in terms of logs. A log change is an exponential or 10-fold change. For example, a change from 100 to 1,000 is a 1 log (10-fold) increase, while a change from 1,000,000 to 10,000 is a 2 log (100-fold) decrease. If the level of HIV is too low to be measured, viral load is said to be undetectable, or below the limit of quantification. However, undetectable viral load does not mean that HIV has been eradicated; people with undetectable viral load maintain a very low level of virus. Even when HIV is not detectable in the blood, it may be detectable in the semen, female genital secretions, cerebro‐ spinal fluid, tissues, and lymph nodes (Calmy et al., 2004; Petti et al., 2006; WHO, 2006). In primary HIV infection, patients may present with flu-like symptoms which usually occur during the first weeks of HIV-1 infection. It is associated with peak levels of HIV-1 RNA viremia, which subsequently declines until reaching a set point, where levels remain for months to years. Initial studies suggested that those with more symptomatic acute infection and longer duration of illness have faster rates of progression to AIDS (Koenig et al., 2006). A viral load of 100,000 copies/ml or more is considered high, while levels below 10,000 copies/ml are considered low. Research has consistently shown that higher viral loads are associated with more rapid HIV disease progression and an increased risk of death. Current U.S. HIV treatment guidelines (Koenig et al., 2006) recommend that people should consider starting treatment if their viral load is above 55,000 copies/ml (revised upward from 10,000 copies/ml in the previous guidelines). Importantly, most studies that have correlated viral load and HIV disease progression have been done in men; more recent research indicates that women may progress to AIDS at lower viral load levels, suggesting that the treatment

threshold should perhaps be revised downward for women (Monica et al., 2002).

β2-microglobulin is a low molecular weight protein that forms light chain of the class I major histocompatibility complex (MHC) which present on the surface of most somatic cells including T and B lymphocytes as well as macrophages (Cresswell et al., 1974; Lawlor et al., 1990; De Wolf and Lange 1991). It exhibits amino acid homology with the constant region of immunoglobins ( Dar & Singh, 1999; Fauci & Lane, 1998; Quin & Benson, 1994). Circulating β2-MG is generated during normal MHC I turnover (Lawlor et al., 1990) and thus is not specific to HIV-related cell death. Stimulation of lymphoid cells increases β2-microglobulinproduc‐ tion. Elevated serum concentration are seen in renal failure, hepatitis, rheumatoid arthritis, myeloproliferative disorders, lymphoproliferative disorders, infectious mononucleosis, influenza A and cytomegalovirus infection (De wolf and Lange, 1991). Free β2-microglobin can be measured in both serum and urine and levels of urine β2-microglobin correlate with the degree of progression of HIV disease. It spikes in acute infection, declines and then rises during the infection. Levels of β2-microglobin are elevated in a variety of conditions charac‐ terized by lymphocyte activation and/ or lymphocyte destruction; *e.g*. lymphoproliferative syndromes, autoimmune diseases, viral infection and in patients with renal diseases. It can be measured in serum or plasma by using radio immunoassay radio immunoassay (RIA) or competivive ELISA based tests. Β2-microglobin measurement has several advantages as a

**4.7. Beta2-microglobulin (β2-microglobulin)**

150 Current Perspectives in HIV Infection

Neopterin (6-D- erythrohydroxy-propylpterin) is a low molecular weight compound derived from an intermediate product of the *de novo* biosynthesis of tetrahydrobiopterin from guano‐ sine triphosphate (GTP) (Dar & Singh, 1999; Fauci & Lane, 1998; Quin & Benson, 1994). It is an early marker of HIV infection. The levels rise further on progression from pre AIDS to clinical AIDS (Vajpayee & Mohan 2011). It is produced by macrophages after stimulation with gamma interferon. The levels have also been found to be associated with progression of HIV-1-related disease (Fuchs et al., 1988; Melmed et al., 1989; Kramer et al., 1989; De Wolf and Lange 1991) but the predictive value is slightly inferior to that of β2-microglobulin levels. Since neopterin levels are stimulated by HIV infection, measurement of neopterin levels can be useful in monitoring progression and evaluating antiviral therapy (Vajpayee & Mohan 2011).

#### **4.9. Additional markers**

Haematological manifestations of HIV infection are common and more frequently occur with progression of the disease. Therefore the complete blood count (CBC) is one of the important haematological parameters which need to checked for HIV patients. They may have low blood cell counts (cytopenias) due to chronic HIV infection or as a side effect of medications, particularly drugs that damage the bone marrow, where all blood cells are produced. Blood cell counts are typically reported as the number of cells per µl of blood (cells/µl) or as a percentage of all blood cells. HIV patients should be checked for CBC for every six months, and more often if they are experiencing symptoms or taking drugs associated with low blood cell counts ( De Santis et al., 2011; Olayemi et al, 2008).

#### *4.9.1. Red and white blood cells*

Anemia is common in HIV positives. HIV itself and various OIs such as *Mycobacterium avium* complex (MAC) can affect red blood cells and their oxygen-carrying capacity (Volberding et al., 2003; Owiredu et al., 2011). People with HIV infection should be especially concerned with neu‐ trophil and lymphocyte levels, in particular CD4 and CD8 cell counts. Neutrophils normally make up about 50-70 per cent of all white blood cells. Various anti-HIV drugs, OI medications [including ganciclovir (Cytovene), used to treat cytomegalovirus, or CMV], and cancer chemo‐ therapies that suppress the bone marrow may lead to neutropenia (Firnhaber, 2010).

#### *4.9.2. Platelets*

Platelets are necessary for blood clotting. A normal platelet count is about 130,000-440,000 cells/ µl. Low platelet counts (thrombocytopenia) - which can lead to easy bruising and excessive bleeding may be caused by certain drugs, autoimmune reactions, accelerated destruction by the spleen, or HIV disease itself (Torre & Pugliese, 2008). In 2012, Parinitha & Kulkarni study the haematological changes in HIV infection with correlation to CD4+ cell count. In their study, they found that among 250 patients studied, anaemia was seen in 210 (84%) of cases. Throm‐ bocytopenia occurs in 45 (18%) cases. Majority of cases (70%) had CD4+ cell counts below 200 cells/mm3. Fifty-four cases (21.6%) had CD4 cell counts between 200 to 499 cells/mm3 and 21 (8.4%) cases had CD4 count more than 500 cells/mm3. In patients with CD4 counts less than 200 cells/mm3, anaemia was seen in 91.4% cases, leucopenia in 26.8% cases, lymphopenia in 80% cases and thrombocytopenia in 21.7% cases.

[3] Alimonti JB., Ball T.B.& Fowke K.R. (2003). "Mechanisms of CD4+ T lymphocyte cell death in human immunodeficiency virus infection and AIDS". *J Gen Virol* 84: 1649–1661

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### **5. Summary**

The prevalence of neurological associated with HIV-1 is estimated at 15 to 50% of patients (Dalakas et al., 1988; Cornblath et al., 1988; So et al., 1988; Monte et al., 1988; Gabbai et al., 1990). But it may be almost 100% when a pathological study is performed (Rizzuto et al., 1995; Gabbai et al., 1990). The etiology and pathogenesis of neurological disease associated with HIV infection is uncertain. It can be caused by the direct or indirect action of HIV and antibody production, or secondary to infections (CMV, MAC), toxic effects of certain drugs (isoniazid, vincristine, d4T, ddi, ddC), or nutritional deficiencies (vitamin B12) (Rizzuto et al., 1995; Dalakas et al., 1988; Figg et al., 1991; Browone et al., 1993; Pike et al., 1993; Abram et al., 1994; Kieburtz et al., 1991). HIV seropositive patients may be overlooked or misdiagnosed. A discerning clinical analysis may be helpful in the diagnosis of this common disease and several laboratory markers become most noticeably established as predictors of HIV-1 infection.

### **Author details**

Rehana Basri\* and Wan Mohamad Wan Majdiah

\*Address all correspondence to: rehana@kk.usm.my

Neurology Craniofacial Sciences & Oral Biology, School of Dental Science, Universiti Sains, Malaysia

### **References**


[3] Alimonti JB., Ball T.B.& Fowke K.R. (2003). "Mechanisms of CD4+ T lymphocyte cell death in human immunodeficiency virus infection and AIDS". *J Gen Virol* 84: 1649–1661

bleeding may be caused by certain drugs, autoimmune reactions, accelerated destruction by the spleen, or HIV disease itself (Torre & Pugliese, 2008). In 2012, Parinitha & Kulkarni study the haematological changes in HIV infection with correlation to CD4+ cell count. In their study, they found that among 250 patients studied, anaemia was seen in 210 (84%) of cases. Throm‐ bocytopenia occurs in 45 (18%) cases. Majority of cases (70%) had CD4+ cell counts below 200 cells/mm3. Fifty-four cases (21.6%) had CD4 cell counts between 200 to 499 cells/mm3 and 21 (8.4%) cases had CD4 count more than 500 cells/mm3. In patients with CD4 counts less than 200 cells/mm3, anaemia was seen in 91.4% cases, leucopenia in 26.8% cases, lymphopenia in

The prevalence of neurological associated with HIV-1 is estimated at 15 to 50% of patients (Dalakas et al., 1988; Cornblath et al., 1988; So et al., 1988; Monte et al., 1988; Gabbai et al., 1990). But it may be almost 100% when a pathological study is performed (Rizzuto et al., 1995; Gabbai et al., 1990). The etiology and pathogenesis of neurological disease associated with HIV infection is uncertain. It can be caused by the direct or indirect action of HIV and antibody production, or secondary to infections (CMV, MAC), toxic effects of certain drugs (isoniazid, vincristine, d4T, ddi, ddC), or nutritional deficiencies (vitamin B12) (Rizzuto et al., 1995; Dalakas et al., 1988; Figg et al., 1991; Browone et al., 1993; Pike et al., 1993; Abram et al., 1994; Kieburtz et al., 1991). HIV seropositive patients may be overlooked or misdiagnosed. A discerning clinical analysis may be helpful in the diagnosis of this common disease and several laboratory markers become most noticeably established as predictors of HIV-1 infection.

Neurology Craniofacial Sciences & Oral Biology, School of Dental Science, Universiti Sains,

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[1] Abeysena C. & De Silva HJ (2005). HIV in South Asia. Medicine, 33, 42-43

80% cases and thrombocytopenia in 21.7% cases.

and Wan Mohamad Wan Majdiah

\*Address all correspondence to: rehana@kk.usm.my

virus infection. *N Engl J Med* 330: 657-662.

**5. Summary**

152 Current Perspectives in HIV Infection

**Author details**

Rehana Basri\*

Malaysia

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**Chapter 9**

**Persistence of HIV-Associated Neurocognitive**

**Disorders in the Era of Antiretroviral Therapy**

HIV-Associated Neurocognitive Disorders (HAND) is a serious menifestation of HIV in‐ fection in the central nervous system (CNS), and encompassess a wide spectrum of cog‐ nitive, behavioral, and motor deficits [1-3]. While the implementation of combination antiretroviral therapy (ART) has dramatically increased the life expectancy and led to significant improvements in the clinical presentation and progression of HAND, an esti‐ mated 50% of HIV-infected patientscontinue to suffer from implications of HAND in the ART era, with as much as 20% of these exhibiting symptoms of HIV-associated dementia (HAD), the most severe form of HAND [3-6]. The brain regions affected in patients with HAND has changed in the ART era in parallel to the changes observed in the clinical picture; a more subtle and insidious cortical damage mainly in the hippocampus and the temporal cortex is observed, in contrast to the overt subcortical damage seen before ART [7-10]. The underlying causes of these changes are not fully elucidated; however, exami‐ nation of the post-mortem tissue reveals the persistence of synaptic and dendritic dam‐ age in the affected brain regions [3, 11]. Emerging evidence suggests that controlling viral replication in the periphery or in the CNS may not be sufficient to control the un‐ derlying neuropathological processes that culminate in the development of HAND. The impact of HAND on the quality of life, adherence to drug regimens, and co-morbidities especially in an aging HIV population with decreased cognitive reserves, is of major con‐ cern. In this chapter, we will examine the major factors that continue to impact the CNS of HIV-infected individuals, and introduce new challenges in the successful treatment of

> © 2013 King et al.; licensee InTech. This is an open access article distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/3.0), which permits unrestricted use,

© 2013 The Author(s). Licensee InTech. This chapter is distributed under the terms of the Creative Commons Attribution License http://creativecommons.org/licenses/by/3.0), which permits unrestricted use, distribution,

distribution, and reproduction in any medium, provided the original work is properly cited.

and reproduction in any medium, provided the original work is properly cited.

Jennifer M. King, Brigid K. Jensen, Patrick J. Gannon and Cagla Akay

http://dx.doi.org/10.5772/52683

**1. Introduction**

HAND.

Additional information is available at the end of the chapter


### **Persistence of HIV-Associated Neurocognitive Disorders in the Era of Antiretroviral Therapy**

Jennifer M. King, Brigid K. Jensen, Patrick J. Gannon and Cagla Akay

Additional information is available at the end of the chapter

http://dx.doi.org/10.5772/52683

### **1. Introduction**

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patients," *Ann Neurol* 14: 403-418.

160 Current Perspectives in HIV Infection

HIV-Associated Neurocognitive Disorders (HAND) is a serious menifestation of HIV in‐ fection in the central nervous system (CNS), and encompassess a wide spectrum of cog‐ nitive, behavioral, and motor deficits [1-3]. While the implementation of combination antiretroviral therapy (ART) has dramatically increased the life expectancy and led to significant improvements in the clinical presentation and progression of HAND, an esti‐ mated 50% of HIV-infected patientscontinue to suffer from implications of HAND in the ART era, with as much as 20% of these exhibiting symptoms of HIV-associated dementia (HAD), the most severe form of HAND [3-6]. The brain regions affected in patients with HAND has changed in the ART era in parallel to the changes observed in the clinical picture; a more subtle and insidious cortical damage mainly in the hippocampus and the temporal cortex is observed, in contrast to the overt subcortical damage seen before ART [7-10]. The underlying causes of these changes are not fully elucidated; however, exami‐ nation of the post-mortem tissue reveals the persistence of synaptic and dendritic dam‐ age in the affected brain regions [3, 11]. Emerging evidence suggests that controlling viral replication in the periphery or in the CNS may not be sufficient to control the un‐ derlying neuropathological processes that culminate in the development of HAND. The impact of HAND on the quality of life, adherence to drug regimens, and co-morbidities especially in an aging HIV population with decreased cognitive reserves, is of major con‐ cern. In this chapter, we will examine the major factors that continue to impact the CNS of HIV-infected individuals, and introduce new challenges in the successful treatment of HAND.

© 2013 King et al.; licensee InTech. This is an open access article distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/3.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited. © 2013 The Author(s). Licensee InTech. This chapter is distributed under the terms of the Creative Commons Attribution License http://creativecommons.org/licenses/by/3.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.

### **2. Clinical presentation and neuropathology of HAND**

According to the diagnostic criteria established for the assessment of neurocognitive impair‐ ment in HIV-infected individuals, the neurological deficits in HAND patients are divided into three diagnostic groups. This classification is based on the neuropsychological evalua‐ tion of multiple cognitive domains, including simple motor skills or sensory perceptual abil‐ ity, complex perceptual motor skills, attention and working memory, learning and memory recall, verbal and language, abstraction and executive function. Asymptomatic neurocogni‐ tive impairment (ANI) is defined as acquired impairment in at least two cognitive domains without a decline in activities of daily living (ADL), while mild to moderate neurocognitive impairment that affects ADL is termed minor neurocognitive disorder (MND). Moderate to severe impairment in two or more domains with marked impact on ADL is defined as HAD. Additionally, behavioral and emotional problems such as depression, psychosis and anxiety are commonly observed in HAND patients. Since the multi-drug regimens that form the ba‐ sis of ART have become the mainstay of HIV, the clinical presentation and the course of HAND have become more unpredictable. The severity of deficits appears to fluctuate over time during the course of infection: some patients may experience continuing decline in cog‐ nitive abilities, while others may recover from HAD and exhibit only minor deficits for the remainder of the disease. While clinical studies clearly establish that suppression of viral replication below the level of detection is paramount to a more favorable outcome, the clini‐ cal course of HAND, once diagnosed, cannot be predicted successfully in most patients.

ocytes differentiate into macrophages, and constitute the viral reservoirs in the CNS [23-26]. Moreover, these cells release a variety of molecules, some of them known neurotoxins, lead‐ ing to the eventual neuronal damage and dysfunction observed in HAND. Importantly, un‐ like other cell types that readily undergo replication, neurons in their post-mitotic state are more vulnerable to immune cell damage which can disrupt critical neuronal functions. Ad‐ ditionally, recent focus in efforts towards a cure in HIV is purging the virus from its reser‐ voirs, by reactivating pro-viral DNA [27-31]. Thus, it is crucial to examine the impact of HIV infection on immune cells for a better understanding of the neuropathology of HAND, and

Persistence of HIV-Associated Neurocognitive Disorders in the Era of Antiretroviral Therapy

http://dx.doi.org/10.5772/52683

163

HIV initially enters helper T lymphocytes and monocytes in the periphery via viral glyco‐ proteins, gp120 and gp41, which are part of the HIV envelope [32]. These glycoproteins en‐ gage with the CD4 on the host cell membrane; however, this fusion step requires the presence of a chemokine co-receptor, C-X-C chemokine receptor type 4 (CXCR4) in lympho‐ cytes,orC-C chemokine type 5 (CCR5) / C-C chemokine type 3 (CCR3) in macrophages [32, 33]. Of all the cell types in the brain, only macrophages and microglia express CD4 antigen, are commonly infected by HIV, and are capable of productive infection. There is very limit‐ ed evidence for HIV infection of the glial cells, which if present, has not been conclusively shown as being productive [34]. More importantly, HIV cannot infect neurons as these cells

The CNS of a healthy adult human has a relatively low presence of cellular components of the immune system [35, 36]. The CNS presents the immune system with unique prob‐ lems with trafficking of immune cells and the recognition of foreign antigen when present. First, the BBB constitutes a physical barrier for the entry of cells and macromole‐ cules from the periphery into the CNS. Additionally, there is minimal expression of major histocompatibility class II (MHC class II) molecules and an absence of professional anti‐ gen presenting cells such as dendritic cells, all of which are required for antigen presenta‐ tion and adaptive immune response activation. However, it has been extensively shown that brain derived factors act to suppress or counter-regulate the actions of pro-inflamma‐ tory mediators in the CNS where immune surveillance is not sufficient. For example, transforming growth factor-β (TGF-β) has the ability to inhibit the activation of macro‐ phages, T lymphocytes, and natural killer (NK) cells, and has been shown to possess neu‐ roprotective capabilities [37-41]. Interestingly, increased TGF-β protein levels are reported in the frontal cortex of HAD patients, and elevated TGF-βimmunoreactivity has been de‐ tected in reactive astrocytes and mononuclear cells of the white matter in HIV-infected CNS [42, 43]. Similar roles have been proposed for BDNF, NT-3, and NGF, among others,

for the development of successful paradigms for HIV reactivation and purging.

**3. The immunology of HAND**

lack CD4 co-receptors.

**3.1. Initiation of immune response in the CNS**

during HIV infection in the CNS [44, 45].

While microglial nodules, multinucleated giant cells and astrogliosis, all of which are associ‐ ated with HIV-induced inflammatory changes, are not as frequently found in post-mortem HAND brain tissue after ART, dendritic and synaptic damage still persist [12-16]. For exam‐ ple, several studies have reported the presence of deoxynucleotidyltransferase-mediated dUTP nick-end labeling (TUNEL)-positive cells, DNA laddering and structural changes with electron microscopy [17, 18]. Importantly, these markers of neuronal death correlate with activation of immune cell populations suggesting that the inflammatory mediators se‐ creted by these cells may play a role in initiating the death cascades [1, 19]. Given the chron‐ ic nature of the HIV infection in the ART era, co-existing conditions which can activate immune responses and precipitate a neuroinflammatory environment independent of infec‐ tion are likely to contribute to the development of persistent neuropathology, and need to be addressed for a more efficient clinical approach and more favorable outcomes. Foremost, it is necessary to examine the mechanisms of neuronal injury in order to successfully expound on the contribution of confounding factors on the persistence of HAND.

The two major cell types targeted by HIV are CD4+ T cells and the cells of monocyte/macro‐ phage lineage. HIV infection of the CD4+ T cells ends in the selective loss of this cell popula‐ tion, leading to severe immunodeficiency [20]. More relevant to HAND, HIV also targets monocytes early during infection [20]. In the healthy brain, the BBB and the blood-cerebro‐ spinal fluid barriers are the first lines of defense against invading pathogens; however, HIV can circumvent these barriers and enter the CNS within infected monocytes [21, 22]. Accord‐ ing to this model, supported by a multitude of *in vitro* and *in vivo* studies, the infected mon‐ ocytes differentiate into macrophages, and constitute the viral reservoirs in the CNS [23-26]. Moreover, these cells release a variety of molecules, some of them known neurotoxins, lead‐ ing to the eventual neuronal damage and dysfunction observed in HAND. Importantly, un‐ like other cell types that readily undergo replication, neurons in their post-mitotic state are more vulnerable to immune cell damage which can disrupt critical neuronal functions. Ad‐ ditionally, recent focus in efforts towards a cure in HIV is purging the virus from its reser‐ voirs, by reactivating pro-viral DNA [27-31]. Thus, it is crucial to examine the impact of HIV infection on immune cells for a better understanding of the neuropathology of HAND, and for the development of successful paradigms for HIV reactivation and purging.

### **3. The immunology of HAND**

**2. Clinical presentation and neuropathology of HAND**

162 Current Perspectives in HIV Infection

According to the diagnostic criteria established for the assessment of neurocognitive impair‐ ment in HIV-infected individuals, the neurological deficits in HAND patients are divided into three diagnostic groups. This classification is based on the neuropsychological evalua‐ tion of multiple cognitive domains, including simple motor skills or sensory perceptual abil‐ ity, complex perceptual motor skills, attention and working memory, learning and memory recall, verbal and language, abstraction and executive function. Asymptomatic neurocogni‐ tive impairment (ANI) is defined as acquired impairment in at least two cognitive domains without a decline in activities of daily living (ADL), while mild to moderate neurocognitive impairment that affects ADL is termed minor neurocognitive disorder (MND). Moderate to severe impairment in two or more domains with marked impact on ADL is defined as HAD. Additionally, behavioral and emotional problems such as depression, psychosis and anxiety are commonly observed in HAND patients. Since the multi-drug regimens that form the ba‐ sis of ART have become the mainstay of HIV, the clinical presentation and the course of HAND have become more unpredictable. The severity of deficits appears to fluctuate over time during the course of infection: some patients may experience continuing decline in cog‐ nitive abilities, while others may recover from HAD and exhibit only minor deficits for the remainder of the disease. While clinical studies clearly establish that suppression of viral replication below the level of detection is paramount to a more favorable outcome, the clini‐ cal course of HAND, once diagnosed, cannot be predicted successfully in most patients.

While microglial nodules, multinucleated giant cells and astrogliosis, all of which are associ‐ ated with HIV-induced inflammatory changes, are not as frequently found in post-mortem HAND brain tissue after ART, dendritic and synaptic damage still persist [12-16]. For exam‐ ple, several studies have reported the presence of deoxynucleotidyltransferase-mediated dUTP nick-end labeling (TUNEL)-positive cells, DNA laddering and structural changes with electron microscopy [17, 18]. Importantly, these markers of neuronal death correlate with activation of immune cell populations suggesting that the inflammatory mediators se‐ creted by these cells may play a role in initiating the death cascades [1, 19]. Given the chron‐ ic nature of the HIV infection in the ART era, co-existing conditions which can activate immune responses and precipitate a neuroinflammatory environment independent of infec‐ tion are likely to contribute to the development of persistent neuropathology, and need to be addressed for a more efficient clinical approach and more favorable outcomes. Foremost, it is necessary to examine the mechanisms of neuronal injury in order to successfully expound

phage lineage. HIV infection of the CD4+ T cells ends in the selective loss of this cell popula‐ tion, leading to severe immunodeficiency [20]. More relevant to HAND, HIV also targets monocytes early during infection [20]. In the healthy brain, the BBB and the blood-cerebro‐ spinal fluid barriers are the first lines of defense against invading pathogens; however, HIV can circumvent these barriers and enter the CNS within infected monocytes [21, 22]. Accord‐ ing to this model, supported by a multitude of *in vitro* and *in vivo* studies, the infected mon‐

T cells and the cells of monocyte/macro‐

on the contribution of confounding factors on the persistence of HAND.

The two major cell types targeted by HIV are CD4+

#### **3.1. Initiation of immune response in the CNS**

HIV initially enters helper T lymphocytes and monocytes in the periphery via viral glyco‐ proteins, gp120 and gp41, which are part of the HIV envelope [32]. These glycoproteins en‐ gage with the CD4 on the host cell membrane; however, this fusion step requires the presence of a chemokine co-receptor, C-X-C chemokine receptor type 4 (CXCR4) in lympho‐ cytes,orC-C chemokine type 5 (CCR5) / C-C chemokine type 3 (CCR3) in macrophages [32, 33]. Of all the cell types in the brain, only macrophages and microglia express CD4 antigen, are commonly infected by HIV, and are capable of productive infection. There is very limit‐ ed evidence for HIV infection of the glial cells, which if present, has not been conclusively shown as being productive [34]. More importantly, HIV cannot infect neurons as these cells lack CD4 co-receptors.

The CNS of a healthy adult human has a relatively low presence of cellular components of the immune system [35, 36]. The CNS presents the immune system with unique prob‐ lems with trafficking of immune cells and the recognition of foreign antigen when present. First, the BBB constitutes a physical barrier for the entry of cells and macromole‐ cules from the periphery into the CNS. Additionally, there is minimal expression of major histocompatibility class II (MHC class II) molecules and an absence of professional anti‐ gen presenting cells such as dendritic cells, all of which are required for antigen presenta‐ tion and adaptive immune response activation. However, it has been extensively shown that brain derived factors act to suppress or counter-regulate the actions of pro-inflamma‐ tory mediators in the CNS where immune surveillance is not sufficient. For example, transforming growth factor-β (TGF-β) has the ability to inhibit the activation of macro‐ phages, T lymphocytes, and natural killer (NK) cells, and has been shown to possess neu‐ roprotective capabilities [37-41]. Interestingly, increased TGF-β protein levels are reported in the frontal cortex of HAD patients, and elevated TGF-βimmunoreactivity has been de‐ tected in reactive astrocytes and mononuclear cells of the white matter in HIV-infected CNS [42, 43]. Similar roles have been proposed for BDNF, NT-3, and NGF, among others, during HIV infection in the CNS [44, 45].

In the initial stages of HIV infection, the number of CD4+ T cells decreases as a consequence of uncontrolled viral replication. While the impact of primary HIV infection on specific CD8+ T cell subpopulations is not clear, there is an overall expansion of this cell population [46]. In this environment, infected monocytes can enter the CNS, establish and maintain productive infection, and HAND becomes clinically manifest. Perivascular macrophages are replenish‐ ed throughout life by the migration of circulating monocytes to the brain, a process en‐ hanced in an inflammatory environment [47]. Several studies have shown that the number of activated macrophages, rather than the viral load,correlates best with the axonal damage and synaptic loss observed in the HAND brain [11, 14, 48, 49]. In addition, indirect markers of macrophage activation, such as neopterin and β2-microglobulin, are elevated in the CSF of HAND patients [50-52]. Further, soluble factors that are known to be released by macro‐ phages and glia, such as quinolinic acid, tumor necrosis factor-α (TNF-α), reactive oxygen species (ROS), and cytokines such as CXCL12 (stromal cell-derived factor-1, SDF-1), CCL2 (monocyte chemotactic protein-1, MCP-1), and interleukin-6 (IL-6), are also elevated in the CSF of HAND patients [53-57]. These findings reinforce the model which proposes mono‐ cyte-derived macrophages and microglia as major instigators of the neuropathological proc‐ esses in the course of disease development in HAND.

*vivo* studies have shown that the macrophages and B-lymphocytes isolated from HIV-infect‐ ed patients are activated despite viral suppression by ART [71]. Further, *in vitro* experiments show that HIV reactivation can be achieved by cytokine and chemokine stimulation [30, 33]. These findings are especially important in light of recent concerns regarding viral latency

Persistence of HIV-Associated Neurocognitive Disorders in the Era of Antiretroviral Therapy

http://dx.doi.org/10.5772/52683

165

In the CNS,chemoattractant cytokines, or chemokines have been demonstrated as essential factors in neuroinflammation and related neuronal injury and loss through their regulation of inflammatory responses. Post-mortem studies have revealed up-regulation of chemokines and chemokine receptors in the brains of patients with HAND [25, 26, 56, 72-75]. The bestcharacterized chemokines up-regulated in HAND are the β-chemokines CCL2, CCL5, and CX3CL1, and the alpha chemokine CXCL12. For example, the levels of one of the more po‐ tent chemokines, CCL2 correlate with the likelihood and severity of HAND [76, 77]. In addi‐ tion, an intriguing regulatory role for the chemokine CCR5 was demonstrated that its activation led to cell death via caspase-3 mediated apoptosis in a neuroblastoma cell line [78]. Further, induction of apoptosis has also been reported with CXCL12 in primary neuro‐ glial cultures in the absence of the HIV viral protein gp120. However, results from several recent studies suggest that the changes in the expression of these chemokines may indicate neuroprotective efforts in response to the neuroinflammatory environment [79]. Further studies are needed to dissect the roles of chemokines in HAND pathogenesis, as they take part in a crucial phase in immune responses, and provide attractive targets for modulation

The mechanisms by which the neuroinflammatory environment eventually ends in damage to the neurons are not precisely known; however, several mechanisms are likely candidates. Studies suggest that the neuronal damageis a result of indirect effects of viral proteins as well as inflammatory mediators [1, 66]. Gp120 and Tat are reported to induce neuronal apoptosis by activating death-associated proteases, caspases, specifically caspase-3 in *in vitro* and *in vivo* disease models [80]. Another mechanism proposes a role for excitotoxicity secon‐ dary to impaired glutamate reuptake by astrocytes which are overwhelmed by pro-inflam‐ matory factors [81]. The well-defined cascade of excitotoxic injury includes excess Ca2+ influx into the neuronal cytoplasm. Several downstream events secondary to such increases in Ca2+ such as excess free radical production and oxidative stress, and the activation of Ca2+ dependent death proteases, calpains and caspases, will be detrimental to neurons, especially in an environment with inadequate glial support and ongoing inflammation due to immune

The persistence of immune activation in the CNS and the peripheral nervous system (PNS) of HIV-infected individuals in the ART era is supported by several lines of evidence. The relatively low levels of HIV RNA in the presence of widespread neuropathological changes in the CNS and PNS of HAND patients, and the lack of evidence of HIV infection of neuro‐ nal cells *in vivo and in vitro* hint at the possibility of chronic immune activation as a factor in the persistence of HAND. Recent clinical evidence shows that ART reduces intrathecal im‐

and its contribution to the persistence of HAND [29].

in resolving HAND persistence.

cell activation [1, 66].

**3.3. Neuroinflammation in HAND**

It should be noted that viral proteins such as gp120 and transactivator of transcription (Tat) can directly activate uninfected macrophages [58-62]. Additionally, one mechanism of injury that is proposed to account for neuronal damage in the absence of neuronal infection by HIV involves direct neurotoxicity by these viral proteins. Several *in vitro* studies have shown that these viral proteins that are released and/or shed by the infected macrophages/micro‐ glia can induce direct synaptic and neuronal damage [63-65]. However, the indicators of neuroinflammation continue to persist despite successful suppression of replication in the CSF to levels below the limit of detection with ART, suggesting that other, less direct mecha‐ nisms of injury might be major contributors to the underlying neuropathology.

#### **3.2. The role of cytokines and chemokines in HAND neuropathology**

A number of indirect mechanisms for the pathogenesis of HAND have been proposed [1, 25, 66]. These mechanisms are not mutually exclusive, and may be synergistic based on the common background of macrophage activation and release of cytokines and chemokines.As a protective measure to suppress viral production, macrophages are responsible for the pro‐ duction of inflammatory mediators including TNF-α, IL (interleukin)-1, interferon-α (IFN-α) and nitric oxide synthase (NOS) [33, 59]. However, the release of these pro-inflammatory cy‐ tokines can activate the uninfected macrophages, and can induce the migration of leuko‐ cytes into the CNS [62]. For example, in HIV-1 transgenic (Tg) rats, elevated levels of IL-1β and TNF-α and increased expression of arachidonic acid cascade enzymes have been impli‐ cated in neuronal damage and cognitive and behavioral impairment [67]. A recent study in‐ dicates that similar changes could contribute to cognitive impairment in HIV-infected patients despite an effective ART [68]. *In vivo* studies suggest that the progression of HAND may be predicted by high concentrations of TNF-α in plasma, and polymorphisms in the TNF-α promoter are associated with HAND to a degree [69, 70]. Interestingly, functional *ex-* *vivo* studies have shown that the macrophages and B-lymphocytes isolated from HIV-infect‐ ed patients are activated despite viral suppression by ART [71]. Further, *in vitro* experiments show that HIV reactivation can be achieved by cytokine and chemokine stimulation [30, 33]. These findings are especially important in light of recent concerns regarding viral latency and its contribution to the persistence of HAND [29].

In the CNS,chemoattractant cytokines, or chemokines have been demonstrated as essential factors in neuroinflammation and related neuronal injury and loss through their regulation of inflammatory responses. Post-mortem studies have revealed up-regulation of chemokines and chemokine receptors in the brains of patients with HAND [25, 26, 56, 72-75]. The bestcharacterized chemokines up-regulated in HAND are the β-chemokines CCL2, CCL5, and CX3CL1, and the alpha chemokine CXCL12. For example, the levels of one of the more po‐ tent chemokines, CCL2 correlate with the likelihood and severity of HAND [76, 77]. In addi‐ tion, an intriguing regulatory role for the chemokine CCR5 was demonstrated that its activation led to cell death via caspase-3 mediated apoptosis in a neuroblastoma cell line [78]. Further, induction of apoptosis has also been reported with CXCL12 in primary neuro‐ glial cultures in the absence of the HIV viral protein gp120. However, results from several recent studies suggest that the changes in the expression of these chemokines may indicate neuroprotective efforts in response to the neuroinflammatory environment [79]. Further studies are needed to dissect the roles of chemokines in HAND pathogenesis, as they take part in a crucial phase in immune responses, and provide attractive targets for modulation in resolving HAND persistence.

The mechanisms by which the neuroinflammatory environment eventually ends in damage to the neurons are not precisely known; however, several mechanisms are likely candidates. Studies suggest that the neuronal damageis a result of indirect effects of viral proteins as well as inflammatory mediators [1, 66]. Gp120 and Tat are reported to induce neuronal apoptosis by activating death-associated proteases, caspases, specifically caspase-3 in *in vitro* and *in vivo* disease models [80]. Another mechanism proposes a role for excitotoxicity secon‐ dary to impaired glutamate reuptake by astrocytes which are overwhelmed by pro-inflam‐ matory factors [81]. The well-defined cascade of excitotoxic injury includes excess Ca2+ influx into the neuronal cytoplasm. Several downstream events secondary to such increases in Ca2+ such as excess free radical production and oxidative stress, and the activation of Ca2+ dependent death proteases, calpains and caspases, will be detrimental to neurons, especially in an environment with inadequate glial support and ongoing inflammation due to immune cell activation [1, 66].

#### **3.3. Neuroinflammation in HAND**

In the initial stages of HIV infection, the number of CD4+

164 Current Perspectives in HIV Infection

esses in the course of disease development in HAND.

of uncontrolled viral replication. While the impact of primary HIV infection on specific CD8+ T cell subpopulations is not clear, there is an overall expansion of this cell population [46]. In this environment, infected monocytes can enter the CNS, establish and maintain productive infection, and HAND becomes clinically manifest. Perivascular macrophages are replenish‐ ed throughout life by the migration of circulating monocytes to the brain, a process en‐ hanced in an inflammatory environment [47]. Several studies have shown that the number of activated macrophages, rather than the viral load,correlates best with the axonal damage and synaptic loss observed in the HAND brain [11, 14, 48, 49]. In addition, indirect markers of macrophage activation, such as neopterin and β2-microglobulin, are elevated in the CSF of HAND patients [50-52]. Further, soluble factors that are known to be released by macro‐ phages and glia, such as quinolinic acid, tumor necrosis factor-α (TNF-α), reactive oxygen species (ROS), and cytokines such as CXCL12 (stromal cell-derived factor-1, SDF-1), CCL2 (monocyte chemotactic protein-1, MCP-1), and interleukin-6 (IL-6), are also elevated in the CSF of HAND patients [53-57]. These findings reinforce the model which proposes mono‐ cyte-derived macrophages and microglia as major instigators of the neuropathological proc‐

It should be noted that viral proteins such as gp120 and transactivator of transcription (Tat) can directly activate uninfected macrophages [58-62]. Additionally, one mechanism of injury that is proposed to account for neuronal damage in the absence of neuronal infection by HIV involves direct neurotoxicity by these viral proteins. Several *in vitro* studies have shown that these viral proteins that are released and/or shed by the infected macrophages/micro‐ glia can induce direct synaptic and neuronal damage [63-65]. However, the indicators of neuroinflammation continue to persist despite successful suppression of replication in the CSF to levels below the limit of detection with ART, suggesting that other, less direct mecha‐

A number of indirect mechanisms for the pathogenesis of HAND have been proposed [1, 25, 66]. These mechanisms are not mutually exclusive, and may be synergistic based on the common background of macrophage activation and release of cytokines and chemokines.As a protective measure to suppress viral production, macrophages are responsible for the pro‐ duction of inflammatory mediators including TNF-α, IL (interleukin)-1, interferon-α (IFN-α) and nitric oxide synthase (NOS) [33, 59]. However, the release of these pro-inflammatory cy‐ tokines can activate the uninfected macrophages, and can induce the migration of leuko‐ cytes into the CNS [62]. For example, in HIV-1 transgenic (Tg) rats, elevated levels of IL-1β and TNF-α and increased expression of arachidonic acid cascade enzymes have been impli‐ cated in neuronal damage and cognitive and behavioral impairment [67]. A recent study in‐ dicates that similar changes could contribute to cognitive impairment in HIV-infected patients despite an effective ART [68]. *In vivo* studies suggest that the progression of HAND may be predicted by high concentrations of TNF-α in plasma, and polymorphisms in the TNF-α promoter are associated with HAND to a degree [69, 70]. Interestingly, functional *ex-*

nisms of injury might be major contributors to the underlying neuropathology.

**3.2. The role of cytokines and chemokines in HAND neuropathology**

T cells decreases as a consequence

The persistence of immune activation in the CNS and the peripheral nervous system (PNS) of HIV-infected individuals in the ART era is supported by several lines of evidence. The relatively low levels of HIV RNA in the presence of widespread neuropathological changes in the CNS and PNS of HAND patients, and the lack of evidence of HIV infection of neuro‐ nal cells *in vivo and in vitro* hint at the possibility of chronic immune activation as a factor in the persistence of HAND. Recent clinical evidence shows that ART reduces intrathecal im‐ munoactivation in treated patients; however, a significant percentage of patients continue to exhibit signs of ongoing inflammation [49, 50, 82, 83]. Further, even after successful reduc‐ tion of HIV RNA levels below the limit of detection for several years, patients present with increased levels of inflammatory markers such as CSF neopterin and intrathecal IgG [52]. It is thus apparent that ART is not sufficient to prevent or control HAND. One major factor to consider in addressing this failure is that ART may not be efficient and/or sufficient in con‐ trolling the inflammatory cascade triggered by HIV infection.

provide neurotrophic support, and are involved in repair processes for neurons. Further, as‐ trocytes are physiological regulators of microglial and macrophage inflammatory responses, and indirectly modulate neuronal survival through reduction of the macrophage inflamma‐ tory response. However, their dysfunction, as a result of HIV infection, will lead to the dys‐ regulation of the local cytokine/chemokine balance. Evidence has shown that astrocytes are key mediators in the regulation of microglial function and its influence on the onset and the progression of HAND [55, 88]. Viral proteins gp120, and Tat both activate astrocytes to pro‐ duce pro-inflammatory cytokines TNF-α, IL-6, and IL-1β as well as the pro-inflammatory chemokines CCL2 and CXCL10 [34, 55, 89-91]. The contribution of these pro-inflammatory mediators by astrocytes as well as the release of pro-inflammatory cytokines IL-1β and TNFα by microglia and macrophage will only exacerbate the inflammatory environment in the

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Although the pathogenic mechanisms of HAND are likely to be multifactorial (Table 1), cel‐ lular activation with the initiation and persistence of the immune system in the CNS play a pivotal role in this disease progression. Continued CNS inflammation is an essential factor in many neurodegenerative diseases and HIV infection induces a cascade of inappropriate immune responses in the CNS. The initial immunological response has protective intentions through macrophage activation, but with persistent infection, the inflammatory response be‐ comes toxic to the neurons through the production of pro-inflammatory cytokines and che‐ mokines. Further, the decreased viral load in the CNS is accompanied by persistent microglial activation and inflammation. Ineffective drug penetrance into the CNS, which continues to be a challenge, can initiate the development of resistance to ART via permitting mutations to the virus which allows the CNS to become a reservoir for the infection. As HIV-infected macrophages are shown to be resistant to apoptosis,this will end in exacerbat‐

HIV-infected CNS.

ing the virus reservoir in the CNS.

**Macrophage Activation (M1 phenotype)**

Transforming Growth Factor-beta (TGF-β) Tumor Necrosis Factor-alpha(TNF-α)

Monocyte Chemotactic Protein-1 (MCP-1) Interferon Gamma Induced Protein-10 (IP-10)

**Micogial nodules**

Interleukin-6 (IL-6) Interleukin-1 (IL-1) **Chemokines**

MHC class II presentation

**Astrogliosis Cytokines**

**Inflammatory Responses During HIV-1 Brain Infection**

**Multinucleated Giant Cells in Central White Matter and Deep Gray Matter**

**Table 1.** Pathological and laboratory evidence for immune activation in the CNS after HIV infection.

Once HIV replication is established in the CNS, the initial chemotactic and inflammatory factor production leads to further recruitment and activation of monocytes/macrophages, creating a perpetual neuroinflammatory environment. The phenomenon of monocyte/ macrophage recruitment can be explained by a "push and pull" mechanism [47]. Two key chemokines that play a role in the recruitment, or "pull", of monocytes are CCL2 and frac‐ talkine (CXCL1).CCL2 is considered to be the more critical factor involved in the infiltration of monocytes and lymphocytes across the BBB in the HAND brain [79]. Multiple cell types of the CNS have been shown to produce CCL2 in models of inflammation, in which CCL2 is a part of a signaling mechanism for recruitment of monocytes/macrophages from the pe‐ riphery. For example, leukocyte infiltration into the brain parenchyma has been demonstrat‐ ed upon pertussis toxin challenge in CCL2 transgenic mice [84]. More importantly, HIVinfected leukocyte transmigration across BBB is dependent on CCL2 in an *in vitro* model of disease [85]. Further, CCL2 has been shown to directly damage the endothelial cell junctions of the BBB [86]. These findings clearly indicate a significant role for CCL2 in the "pull" of monocyte/macrophages across the BBB in HAND. Interestingly, CCL2 levels remain elevat‐ ed in the CSF of HAND patients on ART, implicating that ongoing trafficking might be oc‐ curring despite viral suppression, and warrants further investigations into the persistence of HAND in the era of ART [83].

The "push" aspect of the monocyte/macrophage recruitment involves the expansion in pe‐ ripheral blood neuroinvasive monocyte population. It has been shown that individuals with HAND exhibit an expanded population of CD14+ peripheral blood monocytes that co-ex‐ press CD16, which is considered a more mature population [21]. These CD14+ /CD16+ mono‐ cytes are preferentially susceptible to infection, and can serve as a reservoir harboring proviral DNA. The entry of monocytes into the brain plays a key role in initiating the series of events that lead to HAND, and although antiretrovirals hinder viral replication, they may have minimal effects on the continued transmigration of monocytes into the brain. One study showed that a single exposure of the CNS to the neurotoxic viral protein Tat led to the infiltration of peripheral blood monocytes and resulted in prolonged disruption of CNS function [87]. Thus, continuous and efficient viral suppression in the periphery is critical in achieving suppressed inflammation in the CNS, and is of prime importance in the fight against HAND.

While macrophages and microglia play primary roles in HIV infection in the CNS, other glial cells also contribute to the neuroinflammation and neurotoxicity in the HAND brain. One important cell type that needs to be mentioned in the neuroinflamatory processes in HAND is the astrocytic cell population. As the most abundant cells in the CNS, astrocytes provide neurotrophic support, and are involved in repair processes for neurons. Further, as‐ trocytes are physiological regulators of microglial and macrophage inflammatory responses, and indirectly modulate neuronal survival through reduction of the macrophage inflamma‐ tory response. However, their dysfunction, as a result of HIV infection, will lead to the dys‐ regulation of the local cytokine/chemokine balance. Evidence has shown that astrocytes are key mediators in the regulation of microglial function and its influence on the onset and the progression of HAND [55, 88]. Viral proteins gp120, and Tat both activate astrocytes to pro‐ duce pro-inflammatory cytokines TNF-α, IL-6, and IL-1β as well as the pro-inflammatory chemokines CCL2 and CXCL10 [34, 55, 89-91]. The contribution of these pro-inflammatory mediators by astrocytes as well as the release of pro-inflammatory cytokines IL-1β and TNFα by microglia and macrophage will only exacerbate the inflammatory environment in the HIV-infected CNS.

munoactivation in treated patients; however, a significant percentage of patients continue to exhibit signs of ongoing inflammation [49, 50, 82, 83]. Further, even after successful reduc‐ tion of HIV RNA levels below the limit of detection for several years, patients present with increased levels of inflammatory markers such as CSF neopterin and intrathecal IgG [52]. It is thus apparent that ART is not sufficient to prevent or control HAND. One major factor to consider in addressing this failure is that ART may not be efficient and/or sufficient in con‐

Once HIV replication is established in the CNS, the initial chemotactic and inflammatory factor production leads to further recruitment and activation of monocytes/macrophages, creating a perpetual neuroinflammatory environment. The phenomenon of monocyte/ macrophage recruitment can be explained by a "push and pull" mechanism [47]. Two key chemokines that play a role in the recruitment, or "pull", of monocytes are CCL2 and frac‐ talkine (CXCL1).CCL2 is considered to be the more critical factor involved in the infiltration of monocytes and lymphocytes across the BBB in the HAND brain [79]. Multiple cell types of the CNS have been shown to produce CCL2 in models of inflammation, in which CCL2 is a part of a signaling mechanism for recruitment of monocytes/macrophages from the pe‐ riphery. For example, leukocyte infiltration into the brain parenchyma has been demonstrat‐ ed upon pertussis toxin challenge in CCL2 transgenic mice [84]. More importantly, HIVinfected leukocyte transmigration across BBB is dependent on CCL2 in an *in vitro* model of disease [85]. Further, CCL2 has been shown to directly damage the endothelial cell junctions of the BBB [86]. These findings clearly indicate a significant role for CCL2 in the "pull" of monocyte/macrophages across the BBB in HAND. Interestingly, CCL2 levels remain elevat‐ ed in the CSF of HAND patients on ART, implicating that ongoing trafficking might be oc‐ curring despite viral suppression, and warrants further investigations into the persistence of

The "push" aspect of the monocyte/macrophage recruitment involves the expansion in pe‐ ripheral blood neuroinvasive monocyte population. It has been shown that individuals with

cytes are preferentially susceptible to infection, and can serve as a reservoir harboring proviral DNA. The entry of monocytes into the brain plays a key role in initiating the series of events that lead to HAND, and although antiretrovirals hinder viral replication, they may have minimal effects on the continued transmigration of monocytes into the brain. One study showed that a single exposure of the CNS to the neurotoxic viral protein Tat led to the infiltration of peripheral blood monocytes and resulted in prolonged disruption of CNS function [87]. Thus, continuous and efficient viral suppression in the periphery is critical in achieving suppressed inflammation in the CNS, and is of prime importance in the fight

While macrophages and microglia play primary roles in HIV infection in the CNS, other glial cells also contribute to the neuroinflammation and neurotoxicity in the HAND brain. One important cell type that needs to be mentioned in the neuroinflamatory processes in HAND is the astrocytic cell population. As the most abundant cells in the CNS, astrocytes

press CD16, which is considered a more mature population [21]. These CD14+

peripheral blood monocytes that co-ex‐

/CD16+ mono‐

trolling the inflammatory cascade triggered by HIV infection.

HAND in the era of ART [83].

166 Current Perspectives in HIV Infection

against HAND.

HAND exhibit an expanded population of CD14+

Although the pathogenic mechanisms of HAND are likely to be multifactorial (Table 1), cel‐ lular activation with the initiation and persistence of the immune system in the CNS play a pivotal role in this disease progression. Continued CNS inflammation is an essential factor in many neurodegenerative diseases and HIV infection induces a cascade of inappropriate immune responses in the CNS. The initial immunological response has protective intentions through macrophage activation, but with persistent infection, the inflammatory response be‐ comes toxic to the neurons through the production of pro-inflammatory cytokines and che‐ mokines. Further, the decreased viral load in the CNS is accompanied by persistent microglial activation and inflammation. Ineffective drug penetrance into the CNS, which continues to be a challenge, can initiate the development of resistance to ART via permitting mutations to the virus which allows the CNS to become a reservoir for the infection. As HIV-infected macrophages are shown to be resistant to apoptosis,this will end in exacerbat‐ ing the virus reservoir in the CNS.


**Table 1.** Pathological and laboratory evidence for immune activation in the CNS after HIV infection.

It should also be noted that the impact of HIV infection in the peripheral tissue will ulti‐ mately impact the immune responses in the CNS. Thus, co-morbidities such as co-infections, substance abuse, malignancies and antiretroviral drug toxicities, as well as general inflam‐ matory processes in the periphery, such as oxidative stress should be taken into account when assessing the relationships between immune responses and the neuropathological processes occurring in the HAND brain. This approach will provide more efficient tools, and will have a greater impact on resolving the persistence of HAND.

dialdehyde is increased significantly in infected adults, as well as children [108-118]. The metabolic synthesis of lipids is closely tied to the oxidative state of the cell and the lipids residing in the cell membrane, as certain enzymes such as sphingomyelinase, are sensitive to the oxidative status of the cell and regulate their activity based on cellular need [119]. Stud‐ ies looking into the production of sphingolipids illustrated an overproduction of both sphin‐ gomyelin and ceramides with HIV-infection, suggesting a lipid imbalance caused by the virus [115, 116, 119]. Additionally, studies showed remarkable deficiencies in antioxidant micronutrients including zinc, selenium, Vitamin C, Vitamin D, Vitamin E and beta-carotene (Vitamin A) [109, 110, 118, 120-126]. Conflicting reports exist on perturbation of total antioxi‐ dant status prior to ART, with severalclinical studies reporting decreased total antioxidant capacity [108, 113, 118], while Repetto *et al.* described an increase in the overall antioxidant capacity as individuals progressed to AIDS [114]. The discrepancies between these findings are likely based on the assays utilized to determine "total antioxidant capacity", as different

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Activity levels of superoxide dismutase (SOD), which catalyzes the detoxification of the oxi‐ dant superoxide into hydrogen peroxide and water, were assessed by a variety of laborato‐ ries. Elevated SOD activity was observed in all evaluated HIV-infected individuals, with further increases occuringwith disease progression to AIDS. In addition, increases in SOD mRNA levels were reported in individuals with HAD, as compared to those who were neu‐ rocognitively normal [114, 127, 128]. These changes in SOD were observed in microglial cells, as well as in HIV-infected macrophages, suggesting a virus-triggered induction [128]. An essential antioxidant found in the brain which buffers many reactive oxygen species is glutathione. In HIV-infected patients, overall glutathione levels were found to be reduced, and the remaining glutathione was greatly skewed to the oxidized versus reduced form. [114, 127, 129, 130]. The enzyme glutathione peroxidase, which promotes the conversion of hydrogen peroxide to water through the use of glutathione, was also decreased, illustrating a severe imbalance in this system whose goal is to maintain cellular redox homeostasis [121]. Another deleterioius consequence of rampant pro-oxidants within cells is oxidative modifi‐ cation of DNA bases. Increased levels of 5-hydroxyuracil, 5-hydroxycytosine, 8-hydroxyade‐ nine and 8-hydroxyguanine were found when comparing DNA isolated from lymphocytes of HIV-infected individuals versus uninfected controls [131]. One other common product of an imbalanced oxidative state which is beginning to gain more interest and research focus is peroxynitrite. This compound, which is formed when superoxide reacts with nitric oxide, is detectable through its nitrotyrosine moiety, and is found at higher levels and with more fre‐ quency in the brains of patients with HAD, compared with those who are neurocognitively normal [128]. In addition to the generation of superoxide as a direct result of HIV infection, the virus also increases mRNA expression of inducible nitric oxide synthase (iNOS), which enables a precipitous accumulation of this deleterious oxidation product [128].Further re‐ search in the Nath laboratory has illustrated that thirteen proteins with nitrotyrosine modifi‐ cations are present in the CSF of individuals with HIV-infection. Individuals with dementia had the highest levels of these nitrites and nitrates. Importantly, three of these proteins were significantly elevated in individuals who showed declines in neurocognitive assessment

enzymatic approaches target different portions of the antioxidant system.

over a period of 6 months [101].

### **4. Oxidative stress in neurodegenerative diseases**

Oxidative stress is a shared pathological finding in a myriad of neurodegenerative diseases including Alzheimer Disease, Parkinson Disease, Multiple Sclerosis (MS), Amyotrophic Lat‐ eral Sclerosis (ALS), and HAND [92, 93]. While it is clear that chronic oxidative stress which will overwhelm the protective capacities of the cellular endogenous antioxidant responses may be responsible in part for the neuronal death occurring in these conditions, in many neurodegenerative diseases it is difficult to ascertain whether oxidative stress is the causa‐ tive factor for disease pathology and progression, or rather a resultant downstream event of other cellular dysfunctions [92-95]. Nonetheless, in HAND, several lines of evidence suggest that both HIV and antiretroviral compounds may result in oxidative and nitrosative stress in the periphery and in the CNS [96-102]. Deficits in total antioxidant levels and increases in the markers for oxidative stress are still observed in individuals on stable ART regimens with undetectable viral titers, necessitating the need for adjunctive therapies to ameliorate this imbalance [103, 104]. As has been suggested in a variety of neurodegenerative condi‐ tions, antioxidant supplementation or upregulation of the endogenous antioxidant response in cells of the CNS may ameliorate the neuronal damage and death in HAND [1, 93, 94, 105].

#### **4.1. Oxidative stress in the era of ART**

The evidence of disrupted antioxidant balance and oxidative stress represent a continued concern for HIV-infected individuals even when virus is successfully controlled by ART [102]. To understand the magnitude and implications of this problem, it is important to un‐ derstand the initial disruptions to the antioxidant system that were observed in infected in‐ dividuals, and determine whether ART contributed to the resolution or the exacerbation of these problems.

Oxidative stress prior to ART:As early as 1988, while researchers were just beginning to un‐ derstand the HIV virus, Sönnerborg and colleagues determined that plasma levels of malon‐ dialdehyde in adults with HIV infection were elevated up to 30% when compared with controls [106]. Malondialdehyde is the breakdown product of polyunsaturated lipids by re‐ active oxygen species, and is a mainstay in terms of a biological marker for measuring the relative levels of lipid peroxidation and oxidative stress in individuals [107]. A multitude of studies followed, showing significant increases in the levels of free radicals, hydroperoxides, hydroxynoneal, and oxidation of thiols in infected individuals, and confirming that malon‐ dialdehyde is increased significantly in infected adults, as well as children [108-118]. The metabolic synthesis of lipids is closely tied to the oxidative state of the cell and the lipids residing in the cell membrane, as certain enzymes such as sphingomyelinase, are sensitive to the oxidative status of the cell and regulate their activity based on cellular need [119]. Stud‐ ies looking into the production of sphingolipids illustrated an overproduction of both sphin‐ gomyelin and ceramides with HIV-infection, suggesting a lipid imbalance caused by the virus [115, 116, 119]. Additionally, studies showed remarkable deficiencies in antioxidant micronutrients including zinc, selenium, Vitamin C, Vitamin D, Vitamin E and beta-carotene (Vitamin A) [109, 110, 118, 120-126]. Conflicting reports exist on perturbation of total antioxi‐ dant status prior to ART, with severalclinical studies reporting decreased total antioxidant capacity [108, 113, 118], while Repetto *et al.* described an increase in the overall antioxidant capacity as individuals progressed to AIDS [114]. The discrepancies between these findings are likely based on the assays utilized to determine "total antioxidant capacity", as different enzymatic approaches target different portions of the antioxidant system.

It should also be noted that the impact of HIV infection in the peripheral tissue will ulti‐ mately impact the immune responses in the CNS. Thus, co-morbidities such as co-infections, substance abuse, malignancies and antiretroviral drug toxicities, as well as general inflam‐ matory processes in the periphery, such as oxidative stress should be taken into account when assessing the relationships between immune responses and the neuropathological processes occurring in the HAND brain. This approach will provide more efficient tools,

Oxidative stress is a shared pathological finding in a myriad of neurodegenerative diseases including Alzheimer Disease, Parkinson Disease, Multiple Sclerosis (MS), Amyotrophic Lat‐ eral Sclerosis (ALS), and HAND [92, 93]. While it is clear that chronic oxidative stress which will overwhelm the protective capacities of the cellular endogenous antioxidant responses may be responsible in part for the neuronal death occurring in these conditions, in many neurodegenerative diseases it is difficult to ascertain whether oxidative stress is the causa‐ tive factor for disease pathology and progression, or rather a resultant downstream event of other cellular dysfunctions [92-95]. Nonetheless, in HAND, several lines of evidence suggest that both HIV and antiretroviral compounds may result in oxidative and nitrosative stress in the periphery and in the CNS [96-102]. Deficits in total antioxidant levels and increases in the markers for oxidative stress are still observed in individuals on stable ART regimens with undetectable viral titers, necessitating the need for adjunctive therapies to ameliorate this imbalance [103, 104]. As has been suggested in a variety of neurodegenerative condi‐ tions, antioxidant supplementation or upregulation of the endogenous antioxidant response in cells of the CNS may ameliorate the neuronal damage and death in HAND [1, 93, 94, 105].

The evidence of disrupted antioxidant balance and oxidative stress represent a continued concern for HIV-infected individuals even when virus is successfully controlled by ART [102]. To understand the magnitude and implications of this problem, it is important to un‐ derstand the initial disruptions to the antioxidant system that were observed in infected in‐ dividuals, and determine whether ART contributed to the resolution or the exacerbation of

Oxidative stress prior to ART:As early as 1988, while researchers were just beginning to un‐ derstand the HIV virus, Sönnerborg and colleagues determined that plasma levels of malon‐ dialdehyde in adults with HIV infection were elevated up to 30% when compared with controls [106]. Malondialdehyde is the breakdown product of polyunsaturated lipids by re‐ active oxygen species, and is a mainstay in terms of a biological marker for measuring the relative levels of lipid peroxidation and oxidative stress in individuals [107]. A multitude of studies followed, showing significant increases in the levels of free radicals, hydroperoxides, hydroxynoneal, and oxidation of thiols in infected individuals, and confirming that malon‐

and will have a greater impact on resolving the persistence of HAND.

**4. Oxidative stress in neurodegenerative diseases**

**4.1. Oxidative stress in the era of ART**

168 Current Perspectives in HIV Infection

these problems.

Activity levels of superoxide dismutase (SOD), which catalyzes the detoxification of the oxi‐ dant superoxide into hydrogen peroxide and water, were assessed by a variety of laborato‐ ries. Elevated SOD activity was observed in all evaluated HIV-infected individuals, with further increases occuringwith disease progression to AIDS. In addition, increases in SOD mRNA levels were reported in individuals with HAD, as compared to those who were neu‐ rocognitively normal [114, 127, 128]. These changes in SOD were observed in microglial cells, as well as in HIV-infected macrophages, suggesting a virus-triggered induction [128]. An essential antioxidant found in the brain which buffers many reactive oxygen species is glutathione. In HIV-infected patients, overall glutathione levels were found to be reduced, and the remaining glutathione was greatly skewed to the oxidized versus reduced form. [114, 127, 129, 130]. The enzyme glutathione peroxidase, which promotes the conversion of hydrogen peroxide to water through the use of glutathione, was also decreased, illustrating a severe imbalance in this system whose goal is to maintain cellular redox homeostasis [121]. Another deleterioius consequence of rampant pro-oxidants within cells is oxidative modifi‐ cation of DNA bases. Increased levels of 5-hydroxyuracil, 5-hydroxycytosine, 8-hydroxyade‐ nine and 8-hydroxyguanine were found when comparing DNA isolated from lymphocytes of HIV-infected individuals versus uninfected controls [131]. One other common product of an imbalanced oxidative state which is beginning to gain more interest and research focus is peroxynitrite. This compound, which is formed when superoxide reacts with nitric oxide, is detectable through its nitrotyrosine moiety, and is found at higher levels and with more fre‐ quency in the brains of patients with HAD, compared with those who are neurocognitively normal [128]. In addition to the generation of superoxide as a direct result of HIV infection, the virus also increases mRNA expression of inducible nitric oxide synthase (iNOS), which enables a precipitous accumulation of this deleterious oxidation product [128].Further re‐ search in the Nath laboratory has illustrated that thirteen proteins with nitrotyrosine modifi‐ cations are present in the CSF of individuals with HIV-infection. Individuals with dementia had the highest levels of these nitrites and nitrates. Importantly, three of these proteins were significantly elevated in individuals who showed declines in neurocognitive assessment over a period of 6 months [101].

While it appears that there is not an all-or-nothing increase or decrease in antioxidant ca‐ pacity, the evidence is clear that the components of the antioxidant defense system prior to ART were greatly affected by HIV-infection, and that the capabilities of endogenous an‐ tioxidant response were not able to alleviate damaging oxidative alterations to proteins and DNA.

It has been reported that HIV-positive individuals do not have altered levels of 8-hy‐ droxy-2'-deoxyguanosine [8-oxoG) in their urine regardless of ART or lipodystrophy status [146]. While these findings appear to be promising, in a very recent study, autopsy tissue from frontal cortex was stained for both nuclear and mitochondrial 8-oxoG. The levels of this oxidized DNA product were significantly increased in cases of HAND, suggesting that ART, or ART in combination with ongoing infection may promote DNA oxidative modifica‐ tion, cellular dysfunction damage and death [147]. Additionally, the presence of clastogenic factors, which cause chromosomal breaks and DNA damage and which may be released from cells under conditions of oxidative stress, was observed in the plasma of all HIV-pa‐ tients tested by Edeas *et al*. [148]. This was true ofpatients that were both asymptomatic and symptomatic for AIDS-defining pathologies, and was independent of ART status [148]. The effects of these clastogenic factors appear to persist in multiple cell populations implicated in HAND pathogenesis. For example, in leukocytes obtained from HIV-infected individuals, the percentage of cells exhibiting DNA fragmentation was increased in individuals on ART, as compared with those who were ART- naïve [135]. However, the results of this study have not addressed the possible contribution of latent or low level of infection to the findings. Due to pervasive oxidative damage and antioxidant imbalance despite effective long-term viral control in patients, it is now imperative to recognize the direct effect that viral enclaves and antiretroviral drugs themselves may have on perpetuating these effects. Further studies are needed to investigate the independent effects of ART and the virus on oxidative damage in the CNS, as well as in the periphery in order to better determine therapeutic interventions

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Exhaustive research has been conducted in order to determine the effects of the HIV on in‐ fected cells and the cytotoxic factors released from these cells. As addressed earlier, it is now clear that HIV-infected macrophages secrete a variety of neurotoxic substances including glutamate, nitric oxide, and superoxide [96]. Within actively infected human myeloid-mono‐ cytic cell lines or monocyte-derived macrophages, HIV induces an increase in superoxide anions, with a concomitant increase in superoxide to combat these factors [128, 149]. Mollace and colleagues have demonstrated that the supernatants from HIV-infected human primary macrophages induced oxidative stress in astrocytes, as indicated by increases in malondial‐ deyde levels [150]. They further showed that these supernatants, which contained excess su‐ peroxide, induced astrocytic apoptosis, confirming HIV-mediated toxicity of this secreted product [150]. In a similar fashion, in HIV-infected monocytes, an induction of nitric oxide synthase and subsequent increase nitric oxide was observed [151]. It is also interesting to note that elevated oxidative stress in the form of intracellular singlet oxygen is capable of reactivating latent HIV through long terminal repeat (LTR) transactivation in infected mon‐ ocytes or lymphocytes, suggesting that the virus may rely on oxidative stress signaling cas‐

The amino acid and neurotransmitter glutamate is normally secreted from neurons into the synaptic cleft, and is quickly removed and recycled through the actions of astrocytes. This

cades for continuation of long-term infection or viral rebound [152].

to resolve these dysfunctions.

**4.2. Oxidative stress induction by HIV**

**Persistence of oxidative stress in the era of ART:** In the ART era, oxidative stress is still per‐ vasive in individuals living with well controlled HIV-infection [102]. In 2007, a group at the University of Pennsylvania sought to ascertain whether ART had an effect on inflammation and oxidative stress in the brains of HIV-infected individuals through utilization of chemi‐ cal-shift magnetic resonance spectroscopy. Through careful analysis of lipid, lactate, and creatine levels, they determined that the inflammation and oxidative stress initiated by the HIV infection was not ameliorated in ART-treated individuals, compared to seronegative controls [132]. While these effects were observed in all HAND patients, the levels of oxida‐ tive stress markers were higher in those with more severe cognitive deficits [132].

Lipid peroxidation is still rampant despite effective viral control. While a couple of studies report decreased levels in markers of lipid peroxidation in ART-medicated patients, as com‐ pared with those not receiving ART, multiple studies have shown persistent statistically sig‐ nificant increases in hydroperoxides, isoprostanes, and malondialdehyde in ART-treated HIV-infected individuals, compared to seronegative controls [103, 113, 133-139]. Interesting‐ ly, two independent groups have determined in patient blood samples that the levels of per‐ oxide species and oxidative stress are higher in patients on protease inhibitor (PI) based regimens, as compared with those in individuals on non-nucleoside reverse transcriptase in‐ hibitor (NNRTI) based regimens, implicating a role for the protease inhibitor class in induc‐ tion or exacerbation of oxidative stress [138, 140].

Micronutrient deficiencies are still problematic with ART, and while most patients have ade‐ quate plasma concentrations of vitamins C, D, and E, reported levels are still considered sub-optimal and lower than seronegative patients [123, 141]. While subsequent reports have indicated that zinc and selenium deficits are no longer observed in individuals on ART, fur‐ ther definitive confirmation of these findings is necessary [142, 143]. Additionally, in studies which evaluated the serum of adults and the saliva of children, the total antioxidant status was found to be decreased in ART treated HIV-patients when compared to HIV-negative controls, mirroring findings in studies conducted in the pre-ART era [104, 144].

While several studies have indicated that introduction of ART has been accompanied by an improvement in overall glutathione status, this effect is not totally rectified and imbalances still occur [129]. In particular, numerous groups have shown that circulating glutathione lev‐ els are still markedly reduced in HIV-infected individuals, when compared with age-match‐ ed controls, with the ratio of oxidized to reduced glutathione remaining out of balance [112, 133-135, 145]. Unfortunately, studies investigating nitrosative stress and nitrosylated pro‐ teins in HIV-infected individuals on ART are still lacking; however, the Nath, Hammond, and Sutliff laboratories have been investigating nitrosative stress in HIV, and it is likely that such reports are forthcoming.

It has been reported that HIV-positive individuals do not have altered levels of 8-hy‐ droxy-2'-deoxyguanosine [8-oxoG) in their urine regardless of ART or lipodystrophy status [146]. While these findings appear to be promising, in a very recent study, autopsy tissue from frontal cortex was stained for both nuclear and mitochondrial 8-oxoG. The levels of this oxidized DNA product were significantly increased in cases of HAND, suggesting that ART, or ART in combination with ongoing infection may promote DNA oxidative modifica‐ tion, cellular dysfunction damage and death [147]. Additionally, the presence of clastogenic factors, which cause chromosomal breaks and DNA damage and which may be released from cells under conditions of oxidative stress, was observed in the plasma of all HIV-pa‐ tients tested by Edeas *et al*. [148]. This was true ofpatients that were both asymptomatic and symptomatic for AIDS-defining pathologies, and was independent of ART status [148]. The effects of these clastogenic factors appear to persist in multiple cell populations implicated in HAND pathogenesis. For example, in leukocytes obtained from HIV-infected individuals, the percentage of cells exhibiting DNA fragmentation was increased in individuals on ART, as compared with those who were ART- naïve [135]. However, the results of this study have not addressed the possible contribution of latent or low level of infection to the findings. Due to pervasive oxidative damage and antioxidant imbalance despite effective long-term viral control in patients, it is now imperative to recognize the direct effect that viral enclaves and antiretroviral drugs themselves may have on perpetuating these effects. Further studies are needed to investigate the independent effects of ART and the virus on oxidative damage in the CNS, as well as in the periphery in order to better determine therapeutic interventions to resolve these dysfunctions.

#### **4.2. Oxidative stress induction by HIV**

While it appears that there is not an all-or-nothing increase or decrease in antioxidant ca‐ pacity, the evidence is clear that the components of the antioxidant defense system prior to ART were greatly affected by HIV-infection, and that the capabilities of endogenous an‐ tioxidant response were not able to alleviate damaging oxidative alterations to proteins

**Persistence of oxidative stress in the era of ART:** In the ART era, oxidative stress is still per‐ vasive in individuals living with well controlled HIV-infection [102]. In 2007, a group at the University of Pennsylvania sought to ascertain whether ART had an effect on inflammation and oxidative stress in the brains of HIV-infected individuals through utilization of chemi‐ cal-shift magnetic resonance spectroscopy. Through careful analysis of lipid, lactate, and creatine levels, they determined that the inflammation and oxidative stress initiated by the HIV infection was not ameliorated in ART-treated individuals, compared to seronegative controls [132]. While these effects were observed in all HAND patients, the levels of oxida‐

Lipid peroxidation is still rampant despite effective viral control. While a couple of studies report decreased levels in markers of lipid peroxidation in ART-medicated patients, as com‐ pared with those not receiving ART, multiple studies have shown persistent statistically sig‐ nificant increases in hydroperoxides, isoprostanes, and malondialdehyde in ART-treated HIV-infected individuals, compared to seronegative controls [103, 113, 133-139]. Interesting‐ ly, two independent groups have determined in patient blood samples that the levels of per‐ oxide species and oxidative stress are higher in patients on protease inhibitor (PI) based regimens, as compared with those in individuals on non-nucleoside reverse transcriptase in‐ hibitor (NNRTI) based regimens, implicating a role for the protease inhibitor class in induc‐

Micronutrient deficiencies are still problematic with ART, and while most patients have ade‐ quate plasma concentrations of vitamins C, D, and E, reported levels are still considered sub-optimal and lower than seronegative patients [123, 141]. While subsequent reports have indicated that zinc and selenium deficits are no longer observed in individuals on ART, fur‐ ther definitive confirmation of these findings is necessary [142, 143]. Additionally, in studies which evaluated the serum of adults and the saliva of children, the total antioxidant status was found to be decreased in ART treated HIV-patients when compared to HIV-negative

While several studies have indicated that introduction of ART has been accompanied by an improvement in overall glutathione status, this effect is not totally rectified and imbalances still occur [129]. In particular, numerous groups have shown that circulating glutathione lev‐ els are still markedly reduced in HIV-infected individuals, when compared with age-match‐ ed controls, with the ratio of oxidized to reduced glutathione remaining out of balance [112, 133-135, 145]. Unfortunately, studies investigating nitrosative stress and nitrosylated pro‐ teins in HIV-infected individuals on ART are still lacking; however, the Nath, Hammond, and Sutliff laboratories have been investigating nitrosative stress in HIV, and it is likely that

controls, mirroring findings in studies conducted in the pre-ART era [104, 144].

tive stress markers were higher in those with more severe cognitive deficits [132].

tion or exacerbation of oxidative stress [138, 140].

such reports are forthcoming.

and DNA.

170 Current Perspectives in HIV Infection

Exhaustive research has been conducted in order to determine the effects of the HIV on in‐ fected cells and the cytotoxic factors released from these cells. As addressed earlier, it is now clear that HIV-infected macrophages secrete a variety of neurotoxic substances including glutamate, nitric oxide, and superoxide [96]. Within actively infected human myeloid-mono‐ cytic cell lines or monocyte-derived macrophages, HIV induces an increase in superoxide anions, with a concomitant increase in superoxide to combat these factors [128, 149]. Mollace and colleagues have demonstrated that the supernatants from HIV-infected human primary macrophages induced oxidative stress in astrocytes, as indicated by increases in malondial‐ deyde levels [150]. They further showed that these supernatants, which contained excess su‐ peroxide, induced astrocytic apoptosis, confirming HIV-mediated toxicity of this secreted product [150]. In a similar fashion, in HIV-infected monocytes, an induction of nitric oxide synthase and subsequent increase nitric oxide was observed [151]. It is also interesting to note that elevated oxidative stress in the form of intracellular singlet oxygen is capable of reactivating latent HIV through long terminal repeat (LTR) transactivation in infected mon‐ ocytes or lymphocytes, suggesting that the virus may rely on oxidative stress signaling cas‐ cades for continuation of long-term infection or viral rebound [152].

The amino acid and neurotransmitter glutamate is normally secreted from neurons into the synaptic cleft, and is quickly removed and recycled through the actions of astrocytes. This molecule normally activates the N-methyl D-aspartate (NMDA) receptor on neurons, and allows for Ca2+ entry into the cell. However, it has been clearly demonstrated that excessive extracellular levels of glutamate resulting from overstimulation of neurons, impaired reup‐ take by astrocytes, or release from other cell populations within the brain can lead to hyper‐ activation of NMDA channels, subsequent increases in Ca2+ levels in the neuronal cytoplasm, resulting in excitotoxic neuronal death [153]. In 2001, Jiang *et al.* demonstrated through a series of elegant experiments that the molecule responsible for the neurotoxicity observed on neuronal cultures was a molecule of less than 3,000 kilodaltons, was not sensi‐ tive to trypsin digestion, and that its neurotoxic effect was blocked by a selective NMDA re‐ ceptor antagonist, MK-801. It was through this study, as well as a subsequent study by O'Donnell *et al.* that the increased levels of extracellular glutamate secreted by HIV-infected macrophages may be a major factor in HIV-infected macrophage mediated indirect neuronal death [154]. The increases in extracellular glutamate appears to be an effect of dysregulation of the glutamate synthesis pathway, as inhibition of the mitochondrial glutaminase enzyme blocks the production and the secretion of glutamate from HIV-infected macrophages [155-157]. As was distinctly noted in human patient samples, a marked deficiency of gluta‐ thione and an imbalance between the oxidized and the reduced glutathione was observed. Within cells, glutaminase is the enzyme which converts glutamine to glutamate. It is tempt‐ ing to consider that the oxidative stress resulting from the lack of the antioxidant properties of glutamine may be very tightly coupled to a depletion of glutamine from cells by hyperac‐ tivation of glutaminase enzymes, precipitating an overproduction of glutamate and trigger‐ ing an excitotoxic neuronal death pathway.

leased from intracellular stores,preceeded death, suggesting at a mechanism of activation of

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173

Studies investigating Tat-induced neuronal death have revealed that this viral protein trig‐ gered the accumulation of ROS when exogenously applied to a variety of cell types, in‐ cluding lymphocytes, microglia, brain microvascular endothelial cells (BMECs) and neurons, as well as in HeLa cells expressing Tat [163-166]. When directly injected into striatum of rats, Tat produced dramatic increases in protein oxidative modifications and protein carbonyls [167]. Protein carbonyls were also markedly increased in HeLa cells ex‐ pressing Tat, supporting *in vivo* data [166]. In addition, decreased levels of glutathione were observed in cardiac myocytes and BMECs exposed to recombinant Tat protein, Tatexpressing transgenic mice, and in Tat-expressing HeLa cells [164, 168-170]. Two studies pinpointed the involvement of manganese-dependent superoxide dismutase (Mn-SOD) as a key player in Tat- induced cellular changes. By expressing Tat in HeLa cells, the labora‐ tories of Lehman and McCord convincingly showed that Tat suppressed the RNA, pro‐ tein, and activity levels of Mn-SOD, while inducing no changes in the Cu,Zn SOD enzyme levels [166, 170]. In HIV-infected individuals, plasma levels of SOD were increased in plasma, and these changes were in parallel with disease progression to AIDS. If the re‐ sults from these HeLa cell studies can be expanded to other cell populations, it is tempt‐ ing to speculate that perhaps this overall increase in SOD activity is a compensatory mechanism resulting from the Tat-induced alterations in Mn-SOD activity and the subse‐ quent increases in superoxide ions that cannot be eliminated. The overexpression of Tat in HeLa cells also led to decreases in overall glutathione levels, with a lower ratio of re‐ duced to oxidized glutathione in the remaining supply, mimicking the effect seen in HIV-

infected individuals *in vivo* and in HIV-infected macrophages *in vitro* [166, 170].

in favor of the oxidized versus reduced form [172].

lead to oxidative stress.

**4.3. Oxidative stress and ART**

Finally, studies focusing on microglia have shown that the expression of HIV viral protein R (Vpr) can induce oxidative stress pathways, and can activate HIV latent gene expression [171]. When exogenously applied to human fetal astrocytes, the oxidative stress caused by Vpr causes decreases in intracellular ATP and glutathione, and skews remaining glutathione

In summary, exhaustive *in vivo* and *in vitro* studies indicate that HIV viral proteins them‐ selves can induce, precipitate and augment oxidative stress in multiple cell types, of both peripheral and CNS tissue. These findings further emphasize the importance of complete in‐ hibition of viral replication in alleviating oxidative stress via antiretroviral therapy. Howev‐ er, emerging evidence suggests that antiretroviral drugs themselves might inadvertently

Due to the requirement for lifelong adherence to antiretroviral regimens to prevent viremia and immune system compromise, it is necessary to investigate the effects of these com‐ pounds in a cellular context. Many of these drugs are associated with negative side effects, and have been linked to the metabolic syndrome, atherosclerosis, lipodystrophy, protea‐ some inhibition and the unfolded protein response [173-175]. Additionally, it has become

calpains or other pro-death cellular machinery [63, 160].

Similar to effects of whole virus *in vivo*, when gp120 and Tat were injected into the brains of rats, both of these viral proteins induced lipid peroxidation and glutathione depletion [158]. Additionally, both of these proteins significantly reduced intracellular glutathione, and in‐ creased malondialdehyde in immortalized brain endothelial cells, showing that the oxida‐ tive status of these cells would also be directly affected by the presence of virus. This is of particular importance as the altered oxidative status of these endothelial cells comprising the BBB will have potential impact on not only the integrity of the BBB, but also on the mon‐ ocyte/macrophage transmigration to the CNS, an important factor in the persistence of HAND [159]. Further, when applied to neurons in culture, gp120 and Tat induce disrup‐ tions in the lipid metabolism, leading to increased levels of sphingomyelin, ceramide, and hydroxynoneal,paralleling disruptions in these pathways observed in the neurons of HAND patients [116].

Studies that investigated gp120 separately have revealed that it is capable of inducing ROS formation, and activating the antioxidant response in astrocytes [91, 160]. Studies looking in‐ to the production of oxidant species by gp120 have shown that superoxide ions as well as nitric oxide are involved in neuronal toxicity [100, 161]. Mechanistically, gp120-induced ni‐ tric oxide formation is dependent on a mannose-specific endocytic lectin in macrophages, while gp120-induced expression and upregulation of iNOS selectively occurs in astrocytes in human fetal neuroglial cultures [100, 162]. Multiple studies have shown that in neurons undergoing gp120-induced toxicity, a significant increase in intracellular Ca2+, likely re‐ leased from intracellular stores,preceeded death, suggesting at a mechanism of activation of calpains or other pro-death cellular machinery [63, 160].

Studies investigating Tat-induced neuronal death have revealed that this viral protein trig‐ gered the accumulation of ROS when exogenously applied to a variety of cell types, in‐ cluding lymphocytes, microglia, brain microvascular endothelial cells (BMECs) and neurons, as well as in HeLa cells expressing Tat [163-166]. When directly injected into striatum of rats, Tat produced dramatic increases in protein oxidative modifications and protein carbonyls [167]. Protein carbonyls were also markedly increased in HeLa cells ex‐ pressing Tat, supporting *in vivo* data [166]. In addition, decreased levels of glutathione were observed in cardiac myocytes and BMECs exposed to recombinant Tat protein, Tatexpressing transgenic mice, and in Tat-expressing HeLa cells [164, 168-170]. Two studies pinpointed the involvement of manganese-dependent superoxide dismutase (Mn-SOD) as a key player in Tat- induced cellular changes. By expressing Tat in HeLa cells, the labora‐ tories of Lehman and McCord convincingly showed that Tat suppressed the RNA, pro‐ tein, and activity levels of Mn-SOD, while inducing no changes in the Cu,Zn SOD enzyme levels [166, 170]. In HIV-infected individuals, plasma levels of SOD were increased in plasma, and these changes were in parallel with disease progression to AIDS. If the re‐ sults from these HeLa cell studies can be expanded to other cell populations, it is tempt‐ ing to speculate that perhaps this overall increase in SOD activity is a compensatory mechanism resulting from the Tat-induced alterations in Mn-SOD activity and the subse‐ quent increases in superoxide ions that cannot be eliminated. The overexpression of Tat in HeLa cells also led to decreases in overall glutathione levels, with a lower ratio of re‐ duced to oxidized glutathione in the remaining supply, mimicking the effect seen in HIVinfected individuals *in vivo* and in HIV-infected macrophages *in vitro* [166, 170].

Finally, studies focusing on microglia have shown that the expression of HIV viral protein R (Vpr) can induce oxidative stress pathways, and can activate HIV latent gene expression [171]. When exogenously applied to human fetal astrocytes, the oxidative stress caused by Vpr causes decreases in intracellular ATP and glutathione, and skews remaining glutathione in favor of the oxidized versus reduced form [172].

In summary, exhaustive *in vivo* and *in vitro* studies indicate that HIV viral proteins them‐ selves can induce, precipitate and augment oxidative stress in multiple cell types, of both peripheral and CNS tissue. These findings further emphasize the importance of complete in‐ hibition of viral replication in alleviating oxidative stress via antiretroviral therapy. Howev‐ er, emerging evidence suggests that antiretroviral drugs themselves might inadvertently lead to oxidative stress.

#### **4.3. Oxidative stress and ART**

molecule normally activates the N-methyl D-aspartate (NMDA) receptor on neurons, and allows for Ca2+ entry into the cell. However, it has been clearly demonstrated that excessive extracellular levels of glutamate resulting from overstimulation of neurons, impaired reup‐ take by astrocytes, or release from other cell populations within the brain can lead to hyper‐ activation of NMDA channels, subsequent increases in Ca2+ levels in the neuronal cytoplasm, resulting in excitotoxic neuronal death [153]. In 2001, Jiang *et al.* demonstrated through a series of elegant experiments that the molecule responsible for the neurotoxicity observed on neuronal cultures was a molecule of less than 3,000 kilodaltons, was not sensi‐ tive to trypsin digestion, and that its neurotoxic effect was blocked by a selective NMDA re‐ ceptor antagonist, MK-801. It was through this study, as well as a subsequent study by O'Donnell *et al.* that the increased levels of extracellular glutamate secreted by HIV-infected macrophages may be a major factor in HIV-infected macrophage mediated indirect neuronal death [154]. The increases in extracellular glutamate appears to be an effect of dysregulation of the glutamate synthesis pathway, as inhibition of the mitochondrial glutaminase enzyme blocks the production and the secretion of glutamate from HIV-infected macrophages [155-157]. As was distinctly noted in human patient samples, a marked deficiency of gluta‐ thione and an imbalance between the oxidized and the reduced glutathione was observed. Within cells, glutaminase is the enzyme which converts glutamine to glutamate. It is tempt‐ ing to consider that the oxidative stress resulting from the lack of the antioxidant properties of glutamine may be very tightly coupled to a depletion of glutamine from cells by hyperac‐ tivation of glutaminase enzymes, precipitating an overproduction of glutamate and trigger‐

Similar to effects of whole virus *in vivo*, when gp120 and Tat were injected into the brains of rats, both of these viral proteins induced lipid peroxidation and glutathione depletion [158]. Additionally, both of these proteins significantly reduced intracellular glutathione, and in‐ creased malondialdehyde in immortalized brain endothelial cells, showing that the oxida‐ tive status of these cells would also be directly affected by the presence of virus. This is of particular importance as the altered oxidative status of these endothelial cells comprising the BBB will have potential impact on not only the integrity of the BBB, but also on the mon‐ ocyte/macrophage transmigration to the CNS, an important factor in the persistence of HAND [159]. Further, when applied to neurons in culture, gp120 and Tat induce disrup‐ tions in the lipid metabolism, leading to increased levels of sphingomyelin, ceramide, and hydroxynoneal,paralleling disruptions in these pathways observed in the neurons of HAND

Studies that investigated gp120 separately have revealed that it is capable of inducing ROS formation, and activating the antioxidant response in astrocytes [91, 160]. Studies looking in‐ to the production of oxidant species by gp120 have shown that superoxide ions as well as nitric oxide are involved in neuronal toxicity [100, 161]. Mechanistically, gp120-induced ni‐ tric oxide formation is dependent on a mannose-specific endocytic lectin in macrophages, while gp120-induced expression and upregulation of iNOS selectively occurs in astrocytes in human fetal neuroglial cultures [100, 162]. Multiple studies have shown that in neurons undergoing gp120-induced toxicity, a significant increase in intracellular Ca2+, likely re‐

ing an excitotoxic neuronal death pathway.

172 Current Perspectives in HIV Infection

patients [116].

Due to the requirement for lifelong adherence to antiretroviral regimens to prevent viremia and immune system compromise, it is necessary to investigate the effects of these com‐ pounds in a cellular context. Many of these drugs are associated with negative side effects, and have been linked to the metabolic syndrome, atherosclerosis, lipodystrophy, protea‐ some inhibition and the unfolded protein response [173-175]. Additionally, it has become apparent that these compounds themselves produce oxidative stress, even in the absence of virus, and may in fact be contributing to the persistence of oxidative stress in patients with well controlled viral load [97, 102].

usually based on measurements after a single-dose administration of the drug. Several fac‐ tors, such as poor drug adherence and the impact of co-prescribed drugs on the pharmaco‐ kinetics of antiretroviral drugs can impact the CNS concentrations and can confound the measured outcomes.Additionally, the escape of drug-resistant viral species into the CNS and their establishment in viral reservoirs early during infection can lead to the rise of drugresistant HIV species in the CNS, and can hinder the efforts to assess the impact of CPE scores on neurological outcomes. Further, co-morbidity factors impacting the integrity of the BBB should also be considered in assessing drug availability in the CNS. Among these fac‐ tors are cancer, infections, and drug and alcohol abuse, all of which are shown to alter BBB integrity independent of HIV infection, and should be considered when CPE scores are es‐ tablished and evaluated [185-187]. One final factor to consider in evaluating the long-term effectiveness of ART is the potential direct toxicities of antiretroviral drugs in the CNS, espe‐ cially given the interest in implementation of ART regimens with better CNS penetrance and possibly developing nanoART as part of treatment plans. Antiretroviral drugs have known side-effects in the periphery, including dyslipidemia, and lipohypertrophy. Further, antiretroviral drug-associated toxicity is well documented in the peripheral nervous system, and potential CNS toxicities secondary to ART exist. Oxidative damage elicited by antiretro‐ viral drugs is of particular interest, given ample evidence of ongoing oxidative stress in the

Persistence of HIV-Associated Neurocognitive Disorders in the Era of Antiretroviral Therapy

http://dx.doi.org/10.5772/52683

175

In several cavalier studies, researchers eloquently demonstrated in several cell populations (human adipocytes, monocytes, myeloid cell lines, and human aortic endothelial cells) that a variety of drugs from the PI and NRTI families, alone or in combinations, induced the pro‐ duction of ROS, hydrogen peroxide, and factors promoting monocyte recruitment. The com‐ pounds reported to induce these changes included PIs: indinavir, nelfinavir, lopinavir, ritonavir, saquinavir, atazanavir and NRTIs: stavudine (d4T), zidovudine (AZT), and dida‐ nosine [97-99, 188-191]. The compounds amprenavir (PI) and abacavir (NRTI) were consis‐ tently reported as lacking these effects, making these drugs good candidates for inclusion in

As the first available antiretroviral drug, AZT has been extensively studied. While AZT may not be a mainstay drug of choice for customized optimal regimens, as the primary ART compound available in resource-limited developing countries, it is still of importance to un‐ derstand its cellular effects. AZT was approved for treatment in 1987, and as early as 1992 the Papoian laboratory reported deficits in mitochondrial enzymes and uncoupling of the electron transport chain (ETC) [192]. The disruption of the ETC is a primary cause of mito‐ chondrial based intracellular ROS accumulation and mitochondrial DNA oxidation, an ef‐ fect since expounded upon in multiple laboratories after acute AZT exposure in isolated heart mitochondria and primary human cardiomyocytes, and after chronic gestational AZT exposure in mouse liver and kidney and in the lung and brain of fetal patas monkeys [193-196]. This compound has also been shown to increase mitochondrial lipid peroxidation, deplete intracellular glutathione, and lead to oxidation of remaining glutathione, ultimately inducing a caspase-3- and caspase-7- dependent apoptotic death [193, 195, 197]. When an‐ other NRTI, d4T was investigated, it also was shown to produce ROS, mitochondrial oxida‐

HAND brain, as described above.

regimens to be prescribed to patients with HAND [98].

HIV is highly susceptible to mutations, mostly due to the error-prone reverse transcription step during replication, and underlies the emergence of drug resistant mutations over time in patients treated with single antiretroviral drugs in the early 1990s. Additionally, the de‐ velopment of more sensitive methods for HIV RNA detection revealed the presence of viral reservoirs in multiple tissues, including the CNS. These findings led to the revision of antire‐ troviral therapy, which, until that time included mostly single antiretroviral drug regimens. A multiple drug treatment approach, termed ART, was implemented to aim at different steps in the HIV replication. Currently recommended ART regimens include a cocktail of nucleoside/nucleotide reverse-transcriptaseinhibitors (NRTIs/NtRTIs), non-nucleoside re‐ verse-transcriptase inhibitors (nNRTIs), protease inhibitors (PIs), and to a lesser extent, entry inhibitors and integrase inhibitors(Panel on Antiretroviral Guidelines for Adults and Ado‐ lescents. Guidelines for the use of antiretroviral agents in HIV-1-infected adults and adoles‐ cents.Department of Health and Human Services.Available at http://aidsinfo.nih.gov/ contentfiles/lvguidelines/AdultandAdolescentGL.pdf). This approach has led to improved immune function, long-term viral suppression; and underlies the reductions in HIV-associ‐ ated morbidity and mortality in the era of ART. The recently updated guidelines recom‐ mend ART initiation to all HIV- infected, ART-naive individuals irrespective of CD4+ counts and the impact of early initiation of ART on HIV-associated neurological complications re‐ main to be seen. While a concensus has been reached regarding the time to initiate ART based on CD4 cell counts, AIDS-defining illnesses, and certain co-morbidity factors; the pan‐ el did not clearly outline strategies to best eradicate the viral reservoirs in the CNS, and to decrease the risk of developing HAND among infected patients.

In the meantime, one major approach to better control HAND has been to implement therapies that include drugs which achieve therapeutic concentrations in the CNS. While HIV can circumvent the BBB barrier, complex drug transport and efflux mechanisms at this junction hampers effective antiretroviral concentrations in the brain parenchyma. Re‐ cent efforts to address this hurdle have led to the establishment of CNS penetrance effec‐ tiveness (CPE) score, an algorithm based on the chemical structure, pharmacodynamic and pharmacokinetic data of antiretroviral drugs [176-178]. In summary, an antiretroviral drug with high CPE score is small in size (molecular mass below 400-500 kDa), has high lipid solubility and low protein binding, and it is not a substrate for drug transport or ef‐ flux proteins. Unfortunately, results of several clinical studies which incorporated CPE in‐ to the design and the analysis of outcomes are not conclusive [176, 178-183]. While a positive correlation between CPE scores and neurological outcomes are observed in sever‐ al studies, one study revealed that ART regimens with higher CPE scores might be associ‐ ated with worse neurocognitive performance [184].

These studies investigating the effect of CPE scores on neurological outcomes have inherent caveats. First, due to the limited methodologies, the clinical studies cannot assess the drug concentrations in the brain parenchyma, and instead depend on the CSF levels, which are usually based on measurements after a single-dose administration of the drug. Several fac‐ tors, such as poor drug adherence and the impact of co-prescribed drugs on the pharmaco‐ kinetics of antiretroviral drugs can impact the CNS concentrations and can confound the measured outcomes.Additionally, the escape of drug-resistant viral species into the CNS and their establishment in viral reservoirs early during infection can lead to the rise of drugresistant HIV species in the CNS, and can hinder the efforts to assess the impact of CPE scores on neurological outcomes. Further, co-morbidity factors impacting the integrity of the BBB should also be considered in assessing drug availability in the CNS. Among these fac‐ tors are cancer, infections, and drug and alcohol abuse, all of which are shown to alter BBB integrity independent of HIV infection, and should be considered when CPE scores are es‐ tablished and evaluated [185-187]. One final factor to consider in evaluating the long-term effectiveness of ART is the potential direct toxicities of antiretroviral drugs in the CNS, espe‐ cially given the interest in implementation of ART regimens with better CNS penetrance and possibly developing nanoART as part of treatment plans. Antiretroviral drugs have known side-effects in the periphery, including dyslipidemia, and lipohypertrophy. Further, antiretroviral drug-associated toxicity is well documented in the peripheral nervous system, and potential CNS toxicities secondary to ART exist. Oxidative damage elicited by antiretro‐ viral drugs is of particular interest, given ample evidence of ongoing oxidative stress in the HAND brain, as described above.

apparent that these compounds themselves produce oxidative stress, even in the absence of virus, and may in fact be contributing to the persistence of oxidative stress in patients with

HIV is highly susceptible to mutations, mostly due to the error-prone reverse transcription step during replication, and underlies the emergence of drug resistant mutations over time in patients treated with single antiretroviral drugs in the early 1990s. Additionally, the de‐ velopment of more sensitive methods for HIV RNA detection revealed the presence of viral reservoirs in multiple tissues, including the CNS. These findings led to the revision of antire‐ troviral therapy, which, until that time included mostly single antiretroviral drug regimens. A multiple drug treatment approach, termed ART, was implemented to aim at different steps in the HIV replication. Currently recommended ART regimens include a cocktail of nucleoside/nucleotide reverse-transcriptaseinhibitors (NRTIs/NtRTIs), non-nucleoside re‐ verse-transcriptase inhibitors (nNRTIs), protease inhibitors (PIs), and to a lesser extent, entry inhibitors and integrase inhibitors(Panel on Antiretroviral Guidelines for Adults and Ado‐ lescents. Guidelines for the use of antiretroviral agents in HIV-1-infected adults and adoles‐ cents.Department of Health and Human Services.Available at http://aidsinfo.nih.gov/ contentfiles/lvguidelines/AdultandAdolescentGL.pdf). This approach has led to improved immune function, long-term viral suppression; and underlies the reductions in HIV-associ‐ ated morbidity and mortality in the era of ART. The recently updated guidelines recom‐ mend ART initiation to all HIV- infected, ART-naive individuals irrespective of CD4+

and the impact of early initiation of ART on HIV-associated neurological complications re‐ main to be seen. While a concensus has been reached regarding the time to initiate ART based on CD4 cell counts, AIDS-defining illnesses, and certain co-morbidity factors; the pan‐ el did not clearly outline strategies to best eradicate the viral reservoirs in the CNS, and to

In the meantime, one major approach to better control HAND has been to implement therapies that include drugs which achieve therapeutic concentrations in the CNS. While HIV can circumvent the BBB barrier, complex drug transport and efflux mechanisms at this junction hampers effective antiretroviral concentrations in the brain parenchyma. Re‐ cent efforts to address this hurdle have led to the establishment of CNS penetrance effec‐ tiveness (CPE) score, an algorithm based on the chemical structure, pharmacodynamic and pharmacokinetic data of antiretroviral drugs [176-178]. In summary, an antiretroviral drug with high CPE score is small in size (molecular mass below 400-500 kDa), has high lipid solubility and low protein binding, and it is not a substrate for drug transport or ef‐ flux proteins. Unfortunately, results of several clinical studies which incorporated CPE in‐ to the design and the analysis of outcomes are not conclusive [176, 178-183]. While a positive correlation between CPE scores and neurological outcomes are observed in sever‐ al studies, one study revealed that ART regimens with higher CPE scores might be associ‐

These studies investigating the effect of CPE scores on neurological outcomes have inherent caveats. First, due to the limited methodologies, the clinical studies cannot assess the drug concentrations in the brain parenchyma, and instead depend on the CSF levels, which are

decrease the risk of developing HAND among infected patients.

ated with worse neurocognitive performance [184].

counts

well controlled viral load [97, 102].

174 Current Perspectives in HIV Infection

In several cavalier studies, researchers eloquently demonstrated in several cell populations (human adipocytes, monocytes, myeloid cell lines, and human aortic endothelial cells) that a variety of drugs from the PI and NRTI families, alone or in combinations, induced the pro‐ duction of ROS, hydrogen peroxide, and factors promoting monocyte recruitment. The com‐ pounds reported to induce these changes included PIs: indinavir, nelfinavir, lopinavir, ritonavir, saquinavir, atazanavir and NRTIs: stavudine (d4T), zidovudine (AZT), and dida‐ nosine [97-99, 188-191]. The compounds amprenavir (PI) and abacavir (NRTI) were consis‐ tently reported as lacking these effects, making these drugs good candidates for inclusion in regimens to be prescribed to patients with HAND [98].

As the first available antiretroviral drug, AZT has been extensively studied. While AZT may not be a mainstay drug of choice for customized optimal regimens, as the primary ART compound available in resource-limited developing countries, it is still of importance to un‐ derstand its cellular effects. AZT was approved for treatment in 1987, and as early as 1992 the Papoian laboratory reported deficits in mitochondrial enzymes and uncoupling of the electron transport chain (ETC) [192]. The disruption of the ETC is a primary cause of mito‐ chondrial based intracellular ROS accumulation and mitochondrial DNA oxidation, an ef‐ fect since expounded upon in multiple laboratories after acute AZT exposure in isolated heart mitochondria and primary human cardiomyocytes, and after chronic gestational AZT exposure in mouse liver and kidney and in the lung and brain of fetal patas monkeys [193-196]. This compound has also been shown to increase mitochondrial lipid peroxidation, deplete intracellular glutathione, and lead to oxidation of remaining glutathione, ultimately inducing a caspase-3- and caspase-7- dependent apoptotic death [193, 195, 197]. When an‐ other NRTI, d4T was investigated, it also was shown to produce ROS, mitochondrial oxida‐ tive stress, oxidized mitochondrial DNA, and altered activity of mitochondrial oxidative phosphorylation enzymes [198, 199]. Similarly, NRTI zalcitabine (ddC) also induces oxida‐ tive stress, as evidenced by the accumulation of protein carbonyls and nitrotyrosine modifi‐ cations. Interestingly, this study also reported that the better-tolerated cytidine analog lamivudine (3TC) did not produce these effects, suggesting that 3TC may be considered as an alternative to reduce oxidative stress, and that future compounds generated from this structural base may behave similarly [200]. Interestingly, in contrast to studies in human lymphoid cells, Brandmann and collegues have recently reported that in astrocytes AZT, lamivudine, efavirenz, and nevirapine do not appear to reduce intracellular levels of gluta‐ thione [190]. Whether or not these compounds behave similarly in neurons and other cell populations in the CNS remains to be elucidated.

than one drug in a multi-drug regimen. Thus, designing future combinations which do not precipiateoxidative stressis of utmost importance in efforts to resolve the persistence of

Persistence of HIV-Associated Neurocognitive Disorders in the Era of Antiretroviral Therapy

http://dx.doi.org/10.5772/52683

177

Since the manifestations of oxidative stress induced by HIV and ART have emerged, it has also become evident to scientists that boosting the endogenous antioxidant response may be a valid and encouraging adjunctive therapeutic option. Within the cell, the antioxidant re‐ sponse is mediated through the activation of transcription factor NF-E2 (nuclear factor (er‐ ythroid-derived 2)-related factor-2 (Nrf2)and its myriad of effector phase II and III detoxifying enzymes. Relevant to the previously discussed aberrations in oxidant detoxifica‐ tion, this pathway upregulates superoxide dismutase, peroxiredoxins, thioredoxins, and

*In vitro*, multiple compounds which act upon the Nrf2 pathway have proven effective in ameliorating the oxidative effects of viral infection, viral proteins or antiretroviral drugs. Among these compounds are resveratrol, dimethyl fumarate, N-acetylcysteine, and curcur‐ min [189, 191, 193, 203, 210]. Antioxidants which have not yet been shown to act through the Nrf2 pathway, but which have similar effects *in vitro* include dihydroxybenzyl alcohol, wa‐ ter soluble vitamin E (trolox), glutathione mimetic tricyclodecan-9-yl-xanthogenat, and ace‐ tyl-l-carnitine [188, 200, 201, 211]. An alternative approach to specifically inhibit the actions of NADPH oxidase through the compound diphenyleneiodonium, was able to specifically prevent the effects of PIs, but not NRTIs in human adipocytes [98]. This interesting finding suggests that the different antiretroviral classes may lead to ROS production through differ‐ ent mechanisms, and that specific therapeutics targeting individual oxidant-producing en‐

An alternative approach to activating Nrf2 pathway is supplementation with the antioxi‐ dant vitamin C (ascorbate), which is capable of directly scavenging reactive oxygen and ni‐ trogen species. This method has been shown to be effective in counteracting the deleterious effects of gp120, as well as nelfinavir *in vitro*, and has been shown to have beneficial out‐ comes in patients, when supplemented to ART regimens [100, 195, 204]. Along these same lines, supplementation with a variety of other antioxidants and micronutrients including minocycline, glutathione replenishing peptide alpha-lipoic acid, selenium, vitamin A, Vita‐ min E, and a multivitamin regimen including vitamins A, C, E selenium and coenzyme Q10 have demonstrated partial protection from the deleterious oxidative effects of HIV/SIV and ART *in vivo*, with particular emphasis on restoration of the total blood glutathione levels [127, 195, 212-214]. Finally, the NMDA-receptor blocker memantine, and monoamide oxi‐ dase type B inhibitor selegiline, approved for treatment in Alzheimer and Parkinson Diseas‐ es, respectively, have also been proposed as potential therapeutics for HAND [1, 214]. Memantine might exert therapeutic effects through reduction of residual virus-mediated glutamate excitotoxicity, and selegiline has been reported to be capable of reducing oxygenbased free radicals [215, 216]. The use of these compounds and their efficacy in reducing oxi‐ dative damage in HAND are still in early stages. Initial studies were confounded by the fact

zymes or pathways may need to be considered for specific ART regimens.

**4.4. Potential therapeutic avenues for oxidative stress in ART era**

multiple glutathione biosynthesis enzymes [208, 209].

HAND observed in the ART era.

In the non-nucleoside reverse transcriptase inhibitor (nNRTI) drug class, efavirenz applied to a human hepatoblastoma cell line resulted in superoxide generation, depletion of intracel‐ lular glutathione, and decrease in mitochondrial function and membrane potential that was independent of mitochondrial DNA replication [201]. In addition, efavirenz has also been linked to neuropsychological side effects in HIV-infected patients, and it is probable that the specific oxidative stress effects on mitochondria and glutathione may play a role in the neu‐ rotoxicity of this compound, as neurons are particularly sensitive to perturbations in the an‐ tioxidant system [201, 202].

Within the protease inhibitor class, both ritonavir and amprenavir have been associated with increased superoxide anion production, while ritonavir has been shown to cause in‐ creases in nitrotyrosine levels in porcine coronary arteries [203]. On the other hand, both in‐ dinavir and nelfinavir have been shown to induce a time and concentration dependent depletion of intracellular glutathione in astrocytes as well as in pancreatic beta cells [99, 190]. Nelfinavir is of particular interest, as it suppresses cytosolic, rather than mitochondrial superoxide dismutase levels, and induces a necrotic rather than apoptotic cell death cascade in an adipocyte cell line [99, 204]. Future studies of this compound will undoubtedly prove interesting and may have important implications in patients with regard to their neurocog‐ nitive outcomes associated with this compund. Finally, it is interesting to note that multiple studies investigating the oxidative effects of the thymidine analogs in the NRTI class have reported increased ROS, hydrogen peroxide, and nitric oxide intermediates but no superox‐ ide anions [188, 205].

Currently, there is no information on possible oxidative effects of the entry inhibitor, inte‐ grase inhibitor, and mutation inhibitor drug classes. Similarly, the lack of published studies for the neuroglial cell populations in the brains of HAND patients is surprising. Several posters at national and international meetings over recent years have addressed this impor‐ tant issue, and hopefully these reports will be forthcoming [206, 207]. In order to design cus‐ tom drug regimens which will not precipitate, or can ameloirate oxidative stress, cellular dysfunction and death, it is critical to have an understanding of the cellular effects of each currently approved antiretroviral compound, and to design future compounds with mini‐ mal oxidative effects. Further, it is possible that the continued dysfunction in superoxide production and superoxide dismutase levels in patients may be due to the effects of more than one drug in a multi-drug regimen. Thus, designing future combinations which do not precipiateoxidative stressis of utmost importance in efforts to resolve the persistence of HAND observed in the ART era.

#### **4.4. Potential therapeutic avenues for oxidative stress in ART era**

tive stress, oxidized mitochondrial DNA, and altered activity of mitochondrial oxidative phosphorylation enzymes [198, 199]. Similarly, NRTI zalcitabine (ddC) also induces oxida‐ tive stress, as evidenced by the accumulation of protein carbonyls and nitrotyrosine modifi‐ cations. Interestingly, this study also reported that the better-tolerated cytidine analog lamivudine (3TC) did not produce these effects, suggesting that 3TC may be considered as an alternative to reduce oxidative stress, and that future compounds generated from this structural base may behave similarly [200]. Interestingly, in contrast to studies in human lymphoid cells, Brandmann and collegues have recently reported that in astrocytes AZT, lamivudine, efavirenz, and nevirapine do not appear to reduce intracellular levels of gluta‐ thione [190]. Whether or not these compounds behave similarly in neurons and other cell

In the non-nucleoside reverse transcriptase inhibitor (nNRTI) drug class, efavirenz applied to a human hepatoblastoma cell line resulted in superoxide generation, depletion of intracel‐ lular glutathione, and decrease in mitochondrial function and membrane potential that was independent of mitochondrial DNA replication [201]. In addition, efavirenz has also been linked to neuropsychological side effects in HIV-infected patients, and it is probable that the specific oxidative stress effects on mitochondria and glutathione may play a role in the neu‐ rotoxicity of this compound, as neurons are particularly sensitive to perturbations in the an‐

Within the protease inhibitor class, both ritonavir and amprenavir have been associated with increased superoxide anion production, while ritonavir has been shown to cause in‐ creases in nitrotyrosine levels in porcine coronary arteries [203]. On the other hand, both in‐ dinavir and nelfinavir have been shown to induce a time and concentration dependent depletion of intracellular glutathione in astrocytes as well as in pancreatic beta cells [99, 190]. Nelfinavir is of particular interest, as it suppresses cytosolic, rather than mitochondrial superoxide dismutase levels, and induces a necrotic rather than apoptotic cell death cascade in an adipocyte cell line [99, 204]. Future studies of this compound will undoubtedly prove interesting and may have important implications in patients with regard to their neurocog‐ nitive outcomes associated with this compund. Finally, it is interesting to note that multiple studies investigating the oxidative effects of the thymidine analogs in the NRTI class have reported increased ROS, hydrogen peroxide, and nitric oxide intermediates but no superox‐

Currently, there is no information on possible oxidative effects of the entry inhibitor, inte‐ grase inhibitor, and mutation inhibitor drug classes. Similarly, the lack of published studies for the neuroglial cell populations in the brains of HAND patients is surprising. Several posters at national and international meetings over recent years have addressed this impor‐ tant issue, and hopefully these reports will be forthcoming [206, 207]. In order to design cus‐ tom drug regimens which will not precipitate, or can ameloirate oxidative stress, cellular dysfunction and death, it is critical to have an understanding of the cellular effects of each currently approved antiretroviral compound, and to design future compounds with mini‐ mal oxidative effects. Further, it is possible that the continued dysfunction in superoxide production and superoxide dismutase levels in patients may be due to the effects of more

populations in the CNS remains to be elucidated.

tioxidant system [201, 202].

176 Current Perspectives in HIV Infection

ide anions [188, 205].

Since the manifestations of oxidative stress induced by HIV and ART have emerged, it has also become evident to scientists that boosting the endogenous antioxidant response may be a valid and encouraging adjunctive therapeutic option. Within the cell, the antioxidant re‐ sponse is mediated through the activation of transcription factor NF-E2 (nuclear factor (er‐ ythroid-derived 2)-related factor-2 (Nrf2)and its myriad of effector phase II and III detoxifying enzymes. Relevant to the previously discussed aberrations in oxidant detoxifica‐ tion, this pathway upregulates superoxide dismutase, peroxiredoxins, thioredoxins, and multiple glutathione biosynthesis enzymes [208, 209].

*In vitro*, multiple compounds which act upon the Nrf2 pathway have proven effective in ameliorating the oxidative effects of viral infection, viral proteins or antiretroviral drugs. Among these compounds are resveratrol, dimethyl fumarate, N-acetylcysteine, and curcur‐ min [189, 191, 193, 203, 210]. Antioxidants which have not yet been shown to act through the Nrf2 pathway, but which have similar effects *in vitro* include dihydroxybenzyl alcohol, wa‐ ter soluble vitamin E (trolox), glutathione mimetic tricyclodecan-9-yl-xanthogenat, and ace‐ tyl-l-carnitine [188, 200, 201, 211]. An alternative approach to specifically inhibit the actions of NADPH oxidase through the compound diphenyleneiodonium, was able to specifically prevent the effects of PIs, but not NRTIs in human adipocytes [98]. This interesting finding suggests that the different antiretroviral classes may lead to ROS production through differ‐ ent mechanisms, and that specific therapeutics targeting individual oxidant-producing en‐ zymes or pathways may need to be considered for specific ART regimens.

An alternative approach to activating Nrf2 pathway is supplementation with the antioxi‐ dant vitamin C (ascorbate), which is capable of directly scavenging reactive oxygen and ni‐ trogen species. This method has been shown to be effective in counteracting the deleterious effects of gp120, as well as nelfinavir *in vitro*, and has been shown to have beneficial out‐ comes in patients, when supplemented to ART regimens [100, 195, 204]. Along these same lines, supplementation with a variety of other antioxidants and micronutrients including minocycline, glutathione replenishing peptide alpha-lipoic acid, selenium, vitamin A, Vita‐ min E, and a multivitamin regimen including vitamins A, C, E selenium and coenzyme Q10 have demonstrated partial protection from the deleterious oxidative effects of HIV/SIV and ART *in vivo*, with particular emphasis on restoration of the total blood glutathione levels [127, 195, 212-214]. Finally, the NMDA-receptor blocker memantine, and monoamide oxi‐ dase type B inhibitor selegiline, approved for treatment in Alzheimer and Parkinson Diseas‐ es, respectively, have also been proposed as potential therapeutics for HAND [1, 214]. Memantine might exert therapeutic effects through reduction of residual virus-mediated glutamate excitotoxicity, and selegiline has been reported to be capable of reducing oxygenbased free radicals [215, 216]. The use of these compounds and their efficacy in reducing oxi‐ dative damage in HAND are still in early stages. Initial studies were confounded by the fact that much damage was already present in late stage HAD patients and a protective effect at this stage was not evident [217]. Further work with these compounds will require identify‐ ing patients with ANI or MND to enroll in longitudinal studies to determine whether these compounds will have long-term benefit.

Hepatitis B and C (HBV and HCV) are also commonly found in HIV-infected individuals due to the shared risk factors of contracting the virus. While these viruses are not thought to target the primary cells of the CNS, a recent study has reported the presence of HCV anti‐ gens in astrocytes and the cells of the macrophage/microglial lineage in the human brain. Additionally, there is limited evidence suggesting that HCV core protein might be detrimen‐ tal to neurons *in vitro* and *in vivo*. Further, several studies have suggested that HCV and HIV can potentiate each other's replication. Currently, there is no conclusive data regarding a possible correlation between HCV presence in the CNS and the neurocognitive deficits in HAND patients. However, the potential implications of HCV infection in the CNS are at least three-fold. First, HCV co-infection can hinder the efforts to suppress HIV replication in the CNS. Second, weakened immune system function secondary to HCV will negatively im‐ pact subsequent alleviation of neurocognitive functions. Finally, compromised functioning of CNS support cells, mainly astrocytes, secondary to concomitant HCV infection will aug‐ ment the neuroinflammatory environment with a negative impact on neuronal health. These implications may underlie the evidence that suggests that viral suppression and CD4+ cell recovery is not as successful in the presence of HCV, and might partially explain the spora‐ dic data suggesting that worse neurocognitive impairment is observed in HIV-HCV co-in‐

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179

Illicit drug use, as well as alcohol abuse, put HIV-positive patients at a greater risk for HAND [6, 218-224]. The prevalence of HIV infection is 11-17% among illicit drug users, and methamphetamine (METH) is among the most frequently abused drug with well-known toxic effects on the BBB and in the CNS [220]. HIV-infected patients using METH exhibit more neurocognitive deficits, compared to those not using METH. These findings are likely due to the effects of METH on several fronts in the CNS. First, extensive studies have con‐ clusively shown that METH alters the BBB permeability through direct damage to the BMECs, which in turn can augment HIV access to the CNS. Additionally, METH can exert neurotoxic effects in the CNS through oxidative stress and mitochondrial dysfunction [184], and precipitate further synaptic and neuronal damage. METH may also interfere with the expected benefits of ART in several ways. Most importantly, studies have shown that al‐ tered patient behavior due to METH use can interfere with drug adherence. Secondly, al‐ tered BBB function in a patient using METH can potentially alter antiretroviral access to the

CNS, hindering efforts to establish an efficient regimen with limited side effects.

The widespread use of ART has drastically decreased the incidence of AIDS-related compli‐ cations and improved the long-term prognosis of HIV-positive individuals. Currently, 30% of the HIV-positive population in the United States is over the age of 50,and by 2015 it is estimated that more than 50% will be over the age of 50 [225, 226]. Despite this remarkable development, the life expectancy for ART-treated HIV-positive individuals remains 10-30 years less than that of uninfected individuals [227]. Given the rapid global expansion of this

fected patients [184].

**6. Aging and HAND**

Going forward, it is imperative that the oxidative stress imposed by HIV and ART are tar‐ geted by adjunctive therapies. As research progresses with the quest for eliminating viral reservoirs and designing more effective, less toxic antiretroviral compounds, it is important to keep in mind that oxidative stress is and will continue to be a persistent burden, especial‐ ly in a patient population with a significantly enhanced life expectancy.

### **5. The impact of co-morbidities on HAND**

HIV, once an acute and catastrophic infection, has now become a chronic and manageable disease, with advances made in diagnosis and treatment. These changes are reflected in the increases in life expectancy from 5 years to up to the projected 50 years from the time of di‐ agnosis. However, with the increased lifespan, co-morbidities, such as chronic co-infections, substance abuse, and aging have become major contributors to HAND persistence, and need to be addressed for successful evaluation and treatment of HAND.

The compromised immune system in an HIV-infected individual increases the risk of op‐ portunistic infections in the CNS, much like that observed in the peripheral tissue. Most commonly observed infections, CNS toxoplasmosis, cryptococcosis, CNS tuberculosis, and cytomegalovirus encephalitis can be treated successfully by a combination of antimicrobi‐ als, antiviral and antiretroviral drugs. However, there are several other viral agents that can either directly target or indirectly compromise CNS, and cannot be readily managed by antiretroviral drugs or chemotherapeutics. One important virus with serious complica‐ tions in HAND patients is JC virus, the causative agent of progressive multifocal leukoen‐ cephelopathy (PML). While approximately 60-80% of adults globally are seropositive for JC virus, it leads to the development of PML mostly in individuals who are immuno-com‐ promised, either due to an underlying cancer or immunosuppressive treatment, or who are HIV-positive. The current incidence of PML in HIV patients is 3%. Studies have shown that JC virus can traffic across the BBB within the B cells, can enter the CNS as a free virus, or can infect brain vascular endothelial cells. Once in the CNS, JC virus causes the lytic infection of oligodendrocytes, and results in multifocal demyelination in multiple regions of the white matter. Thus, PML may exacerbate white matter loss that may al‐ ready be occurring in HAND patients. Further, the most efficient, however limited, treat‐ ment for PML, which is immune restoration with aggressive antiretroviral therapy, can potentiate immune reconstitution inflammatory syndrome (IRIS). IRIS, a T-cell mediated encephalitis, can precipitate further injury and worsening of neurological symptoms. While fatality due to PML in HIV-infected individuals can be as high as 50%, the number of cases with non-lethal PML is increasing and PML may be contributing to the persis‐ tence of HIV-associated neurological complications.

Hepatitis B and C (HBV and HCV) are also commonly found in HIV-infected individuals due to the shared risk factors of contracting the virus. While these viruses are not thought to target the primary cells of the CNS, a recent study has reported the presence of HCV anti‐ gens in astrocytes and the cells of the macrophage/microglial lineage in the human brain. Additionally, there is limited evidence suggesting that HCV core protein might be detrimen‐ tal to neurons *in vitro* and *in vivo*. Further, several studies have suggested that HCV and HIV can potentiate each other's replication. Currently, there is no conclusive data regarding a possible correlation between HCV presence in the CNS and the neurocognitive deficits in HAND patients. However, the potential implications of HCV infection in the CNS are at least three-fold. First, HCV co-infection can hinder the efforts to suppress HIV replication in the CNS. Second, weakened immune system function secondary to HCV will negatively im‐ pact subsequent alleviation of neurocognitive functions. Finally, compromised functioning of CNS support cells, mainly astrocytes, secondary to concomitant HCV infection will aug‐ ment the neuroinflammatory environment with a negative impact on neuronal health. These implications may underlie the evidence that suggests that viral suppression and CD4+ cell recovery is not as successful in the presence of HCV, and might partially explain the spora‐ dic data suggesting that worse neurocognitive impairment is observed in HIV-HCV co-in‐ fected patients [184].

Illicit drug use, as well as alcohol abuse, put HIV-positive patients at a greater risk for HAND [6, 218-224]. The prevalence of HIV infection is 11-17% among illicit drug users, and methamphetamine (METH) is among the most frequently abused drug with well-known toxic effects on the BBB and in the CNS [220]. HIV-infected patients using METH exhibit more neurocognitive deficits, compared to those not using METH. These findings are likely due to the effects of METH on several fronts in the CNS. First, extensive studies have con‐ clusively shown that METH alters the BBB permeability through direct damage to the BMECs, which in turn can augment HIV access to the CNS. Additionally, METH can exert neurotoxic effects in the CNS through oxidative stress and mitochondrial dysfunction [184], and precipitate further synaptic and neuronal damage. METH may also interfere with the expected benefits of ART in several ways. Most importantly, studies have shown that al‐ tered patient behavior due to METH use can interfere with drug adherence. Secondly, al‐ tered BBB function in a patient using METH can potentially alter antiretroviral access to the CNS, hindering efforts to establish an efficient regimen with limited side effects.

### **6. Aging and HAND**

that much damage was already present in late stage HAD patients and a protective effect at this stage was not evident [217]. Further work with these compounds will require identify‐ ing patients with ANI or MND to enroll in longitudinal studies to determine whether these

Going forward, it is imperative that the oxidative stress imposed by HIV and ART are tar‐ geted by adjunctive therapies. As research progresses with the quest for eliminating viral reservoirs and designing more effective, less toxic antiretroviral compounds, it is important to keep in mind that oxidative stress is and will continue to be a persistent burden, especial‐

HIV, once an acute and catastrophic infection, has now become a chronic and manageable disease, with advances made in diagnosis and treatment. These changes are reflected in the increases in life expectancy from 5 years to up to the projected 50 years from the time of di‐ agnosis. However, with the increased lifespan, co-morbidities, such as chronic co-infections, substance abuse, and aging have become major contributors to HAND persistence, and need

The compromised immune system in an HIV-infected individual increases the risk of op‐ portunistic infections in the CNS, much like that observed in the peripheral tissue. Most commonly observed infections, CNS toxoplasmosis, cryptococcosis, CNS tuberculosis, and cytomegalovirus encephalitis can be treated successfully by a combination of antimicrobi‐ als, antiviral and antiretroviral drugs. However, there are several other viral agents that can either directly target or indirectly compromise CNS, and cannot be readily managed by antiretroviral drugs or chemotherapeutics. One important virus with serious complica‐ tions in HAND patients is JC virus, the causative agent of progressive multifocal leukoen‐ cephelopathy (PML). While approximately 60-80% of adults globally are seropositive for JC virus, it leads to the development of PML mostly in individuals who are immuno-com‐ promised, either due to an underlying cancer or immunosuppressive treatment, or who are HIV-positive. The current incidence of PML in HIV patients is 3%. Studies have shown that JC virus can traffic across the BBB within the B cells, can enter the CNS as a free virus, or can infect brain vascular endothelial cells. Once in the CNS, JC virus causes the lytic infection of oligodendrocytes, and results in multifocal demyelination in multiple regions of the white matter. Thus, PML may exacerbate white matter loss that may al‐ ready be occurring in HAND patients. Further, the most efficient, however limited, treat‐ ment for PML, which is immune restoration with aggressive antiretroviral therapy, can potentiate immune reconstitution inflammatory syndrome (IRIS). IRIS, a T-cell mediated encephalitis, can precipitate further injury and worsening of neurological symptoms. While fatality due to PML in HIV-infected individuals can be as high as 50%, the number of cases with non-lethal PML is increasing and PML may be contributing to the persis‐

ly in a patient population with a significantly enhanced life expectancy.

to be addressed for successful evaluation and treatment of HAND.

**5. The impact of co-morbidities on HAND**

tence of HIV-associated neurological complications.

compounds will have long-term benefit.

178 Current Perspectives in HIV Infection

The widespread use of ART has drastically decreased the incidence of AIDS-related compli‐ cations and improved the long-term prognosis of HIV-positive individuals. Currently, 30% of the HIV-positive population in the United States is over the age of 50,and by 2015 it is estimated that more than 50% will be over the age of 50 [225, 226]. Despite this remarkable development, the life expectancy for ART-treated HIV-positive individuals remains 10-30 years less than that of uninfected individuals [227]. Given the rapid global expansion of this population, it has become increasingly important to understand the risk factors that lie at the intersection of HIV, ART, and aging.

HIV-positive patients [243]. In addition, older HIV-positive individuals are at increased risk for frailty, bone loss and non-AIDS related cancers [244, 245]. It remains unclear if HIV itself places older individuals at higher risk for heart disease compared to older, HIV-negative in‐ dividuals, though specific classes of antiretrovirals, especially protease inhibitors, have been

Persistence of HIV-Associated Neurocognitive Disorders in the Era of Antiretroviral Therapy

http://dx.doi.org/10.5772/52683

181

The CNS is particularly susceptible to the synergistic neurodegenerative effects of HIV and aging. Several studies have demonstrated that, compared to younger (age 20 to 39 years) co‐ horts, older HIV-positive individuals (age > 50 years) display decreased neurocognitive functioning in several areas including memory, psychomotor speed, and executive functions [225, 248, 249]. The persistence of HAND in individuals with an undetectable viral load and CD4 cell counts greater than 200/µL is not well understood and may be a result of aging-

Several recent neuroimaging studies have begun to address the structural, physiological, and functional changes in the CNS in the context of HIV and aging. Six MRI investigations that assessed the structural changes in the brains of older HIV-positive individuals between 1998 and 2012 found evidence of premature or accelerated aging characterized by significant brain atrophy in the basal ganglia, cerebellum, and frontal and temporal brain regions, when compared to seronegative controls [231]. However, several diffusion tensor imaging (DTI) studies found only normal, age-dependent changes in mean diffusion and fractional anisotropy, which reflects the directionality of water diffusion in the brain, and is greater along organized white matter tracts but decreased in pathologically damaged, disorganized

Other studies have employed proton magnetic resonance spectroscopy (MRS) to assess the changes in brain metabolite levels that are indicative of neuronal damage and death or glial activation. Ernst and Chang demonstrated a five-fold acceleration of aging effects in a rela‐ tively young (mean age 36 years) ART-naïve, HIV-positive cohort, as compared to HIV-neg‐ ative controls, as reflected by increased levels of glial activation markers, myoinositol (MI) and choline compounds (CHO), and a decrease in the neuronal marker, N-acetylaspartate (NAA) [253]. A recent multicenter MRS study of slightly older (ages 30-70], ART-treated HIV-positive individuals demonstrated elevated MI and CHO in all brain regions of pa‐ tients with asymptomatic or mild neurocognitive impairment, but decreased levels of MI in those with dementia, which the authors interpreted as premature microglial senescence [231, 254]. In addition, this study found an age-dependent decrease in NAA in frontal white matter, but only in patients with HAD [254]. Thus, while ART-naïve HIV-positive patients show evidence of increased, age-dependent glial activation and neuronal damage leading to accelerated aging, ART-treated individuals show only signs of premature aging [231].

As mentioned previously, the clinical and pathological hallmarks of post-ART HAND differ from those in the pre-ART era. While HAD presented as a subcortical dementia afflicting the basal ganglia and white matter, some post-ART studies suggest the focus of neuroinflamma‐ tion has shifted primarily to the hippocampus, even in effectively treated patients [255-257]. Furthermore, there is emerging evidence that pathologic similarities exist between HAND and some common neurodegenerative disorders such as Alzheimer Disease, which is char‐

associated processes rendering the cells of the CNS more vulnerable.

linked to atherosclerosis [237, 246, 247].

tracts [231, 250-252].

Older HIV-positive patients, including those treated with ART, are at increased risk for systemic diseases including atherosclerosis, liver and kidney failure, cancer, and osteopo‐ rosis [227, 228]. The aging brain may also be more vulnerable to the effects of HIV as old‐ er adults display an increased susceptibility to HAND, and emerging evidence suggests an increased prevalence of neurodegenerative diseases, including Alzheimer and Parkin‐ son, in this patient population [229, 230]. It remains unclear if the increased prevalence of HAND is a result of HIV and related comorbidities, including hypertension, insulin resist‐ ance, and lipodystrophy, or other confounding factors such as immunosenescence and ART toxicities, all of which are likely to impact CNS disease progression in older HIVpositive individuals [231, 232].

Antiretroviral therapy effectively limits HIV disease progression, maintains patients in a state of partial immune competence, and arrests subjects in a pre-symptomatic state [233]. However, despite the ability of ART to reduce plasma HIV RNA to undetectable levels, HIV-positive individuals remain at higher risk for opportunistic illnesses and premature death [234, 235]. Thus, ART may reduce, but does not appear to eliminate, premature and/or accelerated aging in HIV-infected individuals. This may be attributed to many factors in‐ cluding drug toxicity and slower immune recovery following ART initiation in older pa‐ tients, compared to younger adults [236]. Furthermore, advanced age has been linked to decreased production of T cells, B cells, and cytokines as well as to chronic immune activa‐ tion, the latter of which may be linked to the breakdown of gut-associated lymphoid tissue (GALT) and to the elevated levels of systemic lipopolysaccharide (LPS) [237, 238].

Older patients also display a dampened recovery of CD4 cells following treatment with ART, which may increase their risk for systemic diseases ranging from heart disease to can‐ cer [238]. Thus, it is not surprising that advanced age at seroconversion and/or onset of ART treatment is considered a major risk factor for severe HIV disease [239, 240]. Goetz, *et al.* performed a retrospective study on HIV-positive patients receiving ART treatment at the Veteran's Administration Greater Los Angeles Medical center between 1996 and 1999, and found that for every 10 years of additional age at the onset of ART treatment, the rate of CD4 cell replenishment decreased by 35 cells per microliter of blood [241]. Yet, despite the obvious benefits of beginning ART treatment in asymptomatic HIV-positive individuals, there remain significant concerns for initiating drug therapy sooner than necessary and how this may negatively impact drug toxicity, long-term patient outcome, and the evolution of drug resistant strains of HIV [240, 242]. Based on the updated recommendations for treat‐ ment initiation, as mentioned previously, all HIV-infected individuals will be put on ART regimen upon diagnosis, and the impact of this approach on older patients will be revealing.

Lower CD4 count, in addition to advanced age, also places older patients at a nearly fourfold higher risk for liver-related mortality compared to younger patients [243]. This risk is exacerbated by other factors commonly afflicting ART-treated, HIV-positive individuals in‐ cluding diabetes, alcohol abuse, as well as antiretroviral and cholesterol drug toxicity [243]. Among all non-AIDS-related complications, liver disease is the primary cause of death in HIV-positive patients [243]. In addition, older HIV-positive individuals are at increased risk for frailty, bone loss and non-AIDS related cancers [244, 245]. It remains unclear if HIV itself places older individuals at higher risk for heart disease compared to older, HIV-negative in‐ dividuals, though specific classes of antiretrovirals, especially protease inhibitors, have been linked to atherosclerosis [237, 246, 247].

population, it has become increasingly important to understand the risk factors that lie at

Older HIV-positive patients, including those treated with ART, are at increased risk for systemic diseases including atherosclerosis, liver and kidney failure, cancer, and osteopo‐ rosis [227, 228]. The aging brain may also be more vulnerable to the effects of HIV as old‐ er adults display an increased susceptibility to HAND, and emerging evidence suggests an increased prevalence of neurodegenerative diseases, including Alzheimer and Parkin‐ son, in this patient population [229, 230]. It remains unclear if the increased prevalence of HAND is a result of HIV and related comorbidities, including hypertension, insulin resist‐ ance, and lipodystrophy, or other confounding factors such as immunosenescence and ART toxicities, all of which are likely to impact CNS disease progression in older HIV-

Antiretroviral therapy effectively limits HIV disease progression, maintains patients in a state of partial immune competence, and arrests subjects in a pre-symptomatic state [233]. However, despite the ability of ART to reduce plasma HIV RNA to undetectable levels, HIV-positive individuals remain at higher risk for opportunistic illnesses and premature death [234, 235]. Thus, ART may reduce, but does not appear to eliminate, premature and/or accelerated aging in HIV-infected individuals. This may be attributed to many factors in‐ cluding drug toxicity and slower immune recovery following ART initiation in older pa‐ tients, compared to younger adults [236]. Furthermore, advanced age has been linked to decreased production of T cells, B cells, and cytokines as well as to chronic immune activa‐ tion, the latter of which may be linked to the breakdown of gut-associated lymphoid tissue

(GALT) and to the elevated levels of systemic lipopolysaccharide (LPS) [237, 238].

Older patients also display a dampened recovery of CD4 cells following treatment with ART, which may increase their risk for systemic diseases ranging from heart disease to can‐ cer [238]. Thus, it is not surprising that advanced age at seroconversion and/or onset of ART treatment is considered a major risk factor for severe HIV disease [239, 240]. Goetz, *et al.* performed a retrospective study on HIV-positive patients receiving ART treatment at the Veteran's Administration Greater Los Angeles Medical center between 1996 and 1999, and found that for every 10 years of additional age at the onset of ART treatment, the rate of CD4 cell replenishment decreased by 35 cells per microliter of blood [241]. Yet, despite the obvious benefits of beginning ART treatment in asymptomatic HIV-positive individuals, there remain significant concerns for initiating drug therapy sooner than necessary and how this may negatively impact drug toxicity, long-term patient outcome, and the evolution of drug resistant strains of HIV [240, 242]. Based on the updated recommendations for treat‐ ment initiation, as mentioned previously, all HIV-infected individuals will be put on ART regimen upon diagnosis, and the impact of this approach on older patients will be revealing. Lower CD4 count, in addition to advanced age, also places older patients at a nearly fourfold higher risk for liver-related mortality compared to younger patients [243]. This risk is exacerbated by other factors commonly afflicting ART-treated, HIV-positive individuals in‐ cluding diabetes, alcohol abuse, as well as antiretroviral and cholesterol drug toxicity [243]. Among all non-AIDS-related complications, liver disease is the primary cause of death in

the intersection of HIV, ART, and aging.

180 Current Perspectives in HIV Infection

positive individuals [231, 232].

The CNS is particularly susceptible to the synergistic neurodegenerative effects of HIV and aging. Several studies have demonstrated that, compared to younger (age 20 to 39 years) co‐ horts, older HIV-positive individuals (age > 50 years) display decreased neurocognitive functioning in several areas including memory, psychomotor speed, and executive functions [225, 248, 249]. The persistence of HAND in individuals with an undetectable viral load and CD4 cell counts greater than 200/µL is not well understood and may be a result of agingassociated processes rendering the cells of the CNS more vulnerable.

Several recent neuroimaging studies have begun to address the structural, physiological, and functional changes in the CNS in the context of HIV and aging. Six MRI investigations that assessed the structural changes in the brains of older HIV-positive individuals between 1998 and 2012 found evidence of premature or accelerated aging characterized by significant brain atrophy in the basal ganglia, cerebellum, and frontal and temporal brain regions, when compared to seronegative controls [231]. However, several diffusion tensor imaging (DTI) studies found only normal, age-dependent changes in mean diffusion and fractional anisotropy, which reflects the directionality of water diffusion in the brain, and is greater along organized white matter tracts but decreased in pathologically damaged, disorganized tracts [231, 250-252].

Other studies have employed proton magnetic resonance spectroscopy (MRS) to assess the changes in brain metabolite levels that are indicative of neuronal damage and death or glial activation. Ernst and Chang demonstrated a five-fold acceleration of aging effects in a rela‐ tively young (mean age 36 years) ART-naïve, HIV-positive cohort, as compared to HIV-neg‐ ative controls, as reflected by increased levels of glial activation markers, myoinositol (MI) and choline compounds (CHO), and a decrease in the neuronal marker, N-acetylaspartate (NAA) [253]. A recent multicenter MRS study of slightly older (ages 30-70], ART-treated HIV-positive individuals demonstrated elevated MI and CHO in all brain regions of pa‐ tients with asymptomatic or mild neurocognitive impairment, but decreased levels of MI in those with dementia, which the authors interpreted as premature microglial senescence [231, 254]. In addition, this study found an age-dependent decrease in NAA in frontal white matter, but only in patients with HAD [254]. Thus, while ART-naïve HIV-positive patients show evidence of increased, age-dependent glial activation and neuronal damage leading to accelerated aging, ART-treated individuals show only signs of premature aging [231].

As mentioned previously, the clinical and pathological hallmarks of post-ART HAND differ from those in the pre-ART era. While HAD presented as a subcortical dementia afflicting the basal ganglia and white matter, some post-ART studies suggest the focus of neuroinflamma‐ tion has shifted primarily to the hippocampus, even in effectively treated patients [255-257]. Furthermore, there is emerging evidence that pathologic similarities exist between HAND and some common neurodegenerative disorders such as Alzheimer Disease, which is char‐ acterized by the presence of extracellular beta amyloid (Aβ) plaque deposits, and intracellu‐ lar neurofibrillary tangles composed of hyperphosphorylated Tau [228, 233, 258, 259]. *In vitro* work involving the viral protein Tat has demonstrated the ability of this viral protein to inhibit the activity of the Aβ-degrading enzyme, Neprilysin, and the ability to bind to the receptor for advanced glycation end products, all of which may promote Aβ accumulation in the CNS. Indeed, some individuals with HAND display CSF levels of Aβ42 comparable to those observed in AD patients [228, 260, 261]. However, a recent report utilizing the amy‐ loid-binding, carbon 11-labeled Pittsburgh compound B (11C-PiB) and PET imaging found that irrespective of neurocognitive impairment, HIV-positive individuals showed no in‐ crease in 11C-PiB levels, highlighting a potential key difference between Aβ metabolism in HAND vs. AD despite some overlapping pathological features [258].

penetrant ART regimens and worse neurocognitive and motor performance, despite decreased CSF HIV RNA in a small HIV-positive cohort [181]. In addition, Robertson et al. reported an improvement in neuropsychological outcome in a cohort of patients with interrupted drug treatment [277]. Studies using SCID mice, which display neuropatho‐ logical hallmarks similar to those associated with HIV, showed reduced viral load and astrogliosis following administration of ART, but no improvement in cognitive dysfunc‐ tion [278]. Altogether, these studies reinforce an emerging hypothesis that antiretroviral drugs may be contributing to the rising prevalence of HAND in the aging HIV-positive

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183

However, many clinical studies have demonstrated beneficial effects on neurocognitive functioning by ART regimens with high CPE scores [279, 280]. A cross-sectional study of 2636 adults from the AIDS Clinical Trials Group Longitudinal Linked Randomized Tri‐ als (ALLRT cohort), on effective ART for at least 6 weeks showed better neurocognitive performance in individuals receiving ART medications with higher CPE scores [281]. In some cases, participants required more than 3 antiretrovirals to treat HIV in the CNS. Letendre et al. demonstrated improvements in cognition over a 15-week period in pa‐ tients beginning ART with higher CPE ART regimens [282]. Another recent investigation utilized MRS imaging to investigate the effect of different CPE ART regimens with dif‐ ferent CPE scores on changes in brain NAA metabolite levels. Over 48 weeks, HIV-posi‐ tive, ART-naïve individuals receiving the regimens with highest CPE scores displayed the highest increases in NAA levels, and showed the greatest improvement in a battery of neuropsychological tests [283]. These studies suggest that ART medications with high‐ er CNS penetrance may have a neuroprotective effect in successfully treated HIV-posi‐ tive adults. However, given the well-characterized toxicities of ART medications in the periphery, and the potential impact of related co-morbidities on CNS pathology, it may be necessary to consider adjunctive therapies to minimize the synergistic effects of ART

The advent of ART has profoundly changed the landscape of disease; however, neurocogni‐ tive impairments continue to be debilitating to patients with the expected life expectancy closer to that of the uninfected population. A better understanding and appreciation of the confounding factors has become more acute as the recent focus in the race to cure AIDS has shifted towards the eradication of latent viral reservoirs, including those in the CNS. It is im‐ perative to anticipate and control the immune responses due to viral reactivation, the poten‐ tial neurotoxicities of viral proteins in the brain parenchyma when latent viral progeny is activated, and the oxidative damage that may be precipitated by viral particles and the acti‐ vated immune cells. These factors will be even more crucial to control in the aging brain

population.

and aging in HIV-positive individuals.

with limited cognitive reserves.

**7. Summary**

Among the studies underlining the similarities between HAND and AD, Esiri *et al.* were the first to report a predisposition to plaque formation in the brains of pre-ART HIV-positive individuals [262]. Such pathological changes have been observed in HIV-positive patients despite successful virologic control with ART, suggesting that antiretrovirals either cannot achieve therapeutic concentrations within the brain parenchyma, allowing for ongoing viral replication and neuroinflammation, or may have toxic effects that could facilitate neurode‐ generation [263, 264]. To address the latter concern, several reports investigated differences in either phospho-tau or beta amyloid levels in ART-naïve vs. ART-treated individuals. Two groups independently reported elevated Aβ deposition in the hippocampus of ART-treated individuals compared to pre-ART patients, yet Anthony *et al*. reported only increased hy‐ perphosphorylated tau, but no Aβ deposition in the hippocampus and entorhinal cortex of HIV-positive individuals [257, 259, 265]. To date, no group has reported concomitant phos‐ pho-tau and Aβ plaque depositions in the same brain samples from HIV-positive cohorts. Differences in patient age and ART-regimens, as well as the antibodies used to detect Aβ may account for the varied outcomes of these reports.

Importantly, the aforementioned studies highlight the potentially under-appreciated con‐ cern of antiretroviral-associated toxicity and its effect on neuropsychological outcomes in long-term ART-treated patients. As described earlier, ART drugs have been linked to wide-ranging, peripheral metabolic and neural disturbances that could themselves influ‐ ence the progression of HAND and foretell potential mechanisms of toxicity in the CNS [246, 266-276]. While CNS effects of ART are poorly understood, Schweinsburg et al. dem‐ onstrated an association between NRTIs and decreased levels of frontal white matter NAA, which they attributed to NRTI-mediated mitochondrial dysfunction and depletion of cellular respiration [268]. Confounding the issue of direct CNS toxicity of antiretroviral medications is the variability in BBB permeability amongst different drug classes as deter‐ mined by various physicochemical properties such as plasma protein binding, lipophilici‐ ty, and molecular size.

Although it is a widely held that ART regimens with higher CNS penetrance generally confer greater neuropsychological outcomes in HIV-positive individuals, numerous clini‐ cal studies have suggested these regimens may negatively impact cognition. In a pro‐ spective study, Marra et al. found a significant association between highly CNS- penetrant ART regimens and worse neurocognitive and motor performance, despite decreased CSF HIV RNA in a small HIV-positive cohort [181]. In addition, Robertson et al. reported an improvement in neuropsychological outcome in a cohort of patients with interrupted drug treatment [277]. Studies using SCID mice, which display neuropatho‐ logical hallmarks similar to those associated with HIV, showed reduced viral load and astrogliosis following administration of ART, but no improvement in cognitive dysfunc‐ tion [278]. Altogether, these studies reinforce an emerging hypothesis that antiretroviral drugs may be contributing to the rising prevalence of HAND in the aging HIV-positive population.

However, many clinical studies have demonstrated beneficial effects on neurocognitive functioning by ART regimens with high CPE scores [279, 280]. A cross-sectional study of 2636 adults from the AIDS Clinical Trials Group Longitudinal Linked Randomized Tri‐ als (ALLRT cohort), on effective ART for at least 6 weeks showed better neurocognitive performance in individuals receiving ART medications with higher CPE scores [281]. In some cases, participants required more than 3 antiretrovirals to treat HIV in the CNS. Letendre et al. demonstrated improvements in cognition over a 15-week period in pa‐ tients beginning ART with higher CPE ART regimens [282]. Another recent investigation utilized MRS imaging to investigate the effect of different CPE ART regimens with dif‐ ferent CPE scores on changes in brain NAA metabolite levels. Over 48 weeks, HIV-posi‐ tive, ART-naïve individuals receiving the regimens with highest CPE scores displayed the highest increases in NAA levels, and showed the greatest improvement in a battery of neuropsychological tests [283]. These studies suggest that ART medications with high‐ er CNS penetrance may have a neuroprotective effect in successfully treated HIV-posi‐ tive adults. However, given the well-characterized toxicities of ART medications in the periphery, and the potential impact of related co-morbidities on CNS pathology, it may be necessary to consider adjunctive therapies to minimize the synergistic effects of ART and aging in HIV-positive individuals.

### **7. Summary**

acterized by the presence of extracellular beta amyloid (Aβ) plaque deposits, and intracellu‐ lar neurofibrillary tangles composed of hyperphosphorylated Tau [228, 233, 258, 259]. *In vitro* work involving the viral protein Tat has demonstrated the ability of this viral protein to inhibit the activity of the Aβ-degrading enzyme, Neprilysin, and the ability to bind to the receptor for advanced glycation end products, all of which may promote Aβ accumulation in the CNS. Indeed, some individuals with HAND display CSF levels of Aβ42 comparable to those observed in AD patients [228, 260, 261]. However, a recent report utilizing the amy‐ loid-binding, carbon 11-labeled Pittsburgh compound B (11C-PiB) and PET imaging found that irrespective of neurocognitive impairment, HIV-positive individuals showed no in‐ crease in 11C-PiB levels, highlighting a potential key difference between Aβ metabolism in

Among the studies underlining the similarities between HAND and AD, Esiri *et al.* were the first to report a predisposition to plaque formation in the brains of pre-ART HIV-positive individuals [262]. Such pathological changes have been observed in HIV-positive patients despite successful virologic control with ART, suggesting that antiretrovirals either cannot achieve therapeutic concentrations within the brain parenchyma, allowing for ongoing viral replication and neuroinflammation, or may have toxic effects that could facilitate neurode‐ generation [263, 264]. To address the latter concern, several reports investigated differences in either phospho-tau or beta amyloid levels in ART-naïve vs. ART-treated individuals. Two groups independently reported elevated Aβ deposition in the hippocampus of ART-treated individuals compared to pre-ART patients, yet Anthony *et al*. reported only increased hy‐ perphosphorylated tau, but no Aβ deposition in the hippocampus and entorhinal cortex of HIV-positive individuals [257, 259, 265]. To date, no group has reported concomitant phos‐ pho-tau and Aβ plaque depositions in the same brain samples from HIV-positive cohorts. Differences in patient age and ART-regimens, as well as the antibodies used to detect Aβ

Importantly, the aforementioned studies highlight the potentially under-appreciated con‐ cern of antiretroviral-associated toxicity and its effect on neuropsychological outcomes in long-term ART-treated patients. As described earlier, ART drugs have been linked to wide-ranging, peripheral metabolic and neural disturbances that could themselves influ‐ ence the progression of HAND and foretell potential mechanisms of toxicity in the CNS [246, 266-276]. While CNS effects of ART are poorly understood, Schweinsburg et al. dem‐ onstrated an association between NRTIs and decreased levels of frontal white matter NAA, which they attributed to NRTI-mediated mitochondrial dysfunction and depletion of cellular respiration [268]. Confounding the issue of direct CNS toxicity of antiretroviral medications is the variability in BBB permeability amongst different drug classes as deter‐ mined by various physicochemical properties such as plasma protein binding, lipophilici‐

Although it is a widely held that ART regimens with higher CNS penetrance generally confer greater neuropsychological outcomes in HIV-positive individuals, numerous clini‐ cal studies have suggested these regimens may negatively impact cognition. In a pro‐ spective study, Marra et al. found a significant association between highly CNS-

HAND vs. AD despite some overlapping pathological features [258].

may account for the varied outcomes of these reports.

ty, and molecular size.

182 Current Perspectives in HIV Infection

The advent of ART has profoundly changed the landscape of disease; however, neurocogni‐ tive impairments continue to be debilitating to patients with the expected life expectancy closer to that of the uninfected population. A better understanding and appreciation of the confounding factors has become more acute as the recent focus in the race to cure AIDS has shifted towards the eradication of latent viral reservoirs, including those in the CNS. It is im‐ perative to anticipate and control the immune responses due to viral reactivation, the poten‐ tial neurotoxicities of viral proteins in the brain parenchyma when latent viral progeny is activated, and the oxidative damage that may be precipitated by viral particles and the acti‐ vated immune cells. These factors will be even more crucial to control in the aging brain with limited cognitive reserves.

### **Author details**

Jennifer M. King, Brigid K. Jensen, Patrick J. Gannon and Cagla Akay\*

\*Address all correspondence to: akayc@upenn.edu

Department of Pathology, School of Dental Medicine, University of Pennsylvania, Philadelphia, USA

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**Section 4**

**Manifestations of HIV Infection**

