**20. Challenges of genotypic methods**

Genotypic predictions are relatively satisfactory but because not all determinants of coreceptor usage lie within the V3 loop, the region employed by most current predictors, causing occasional disagreements. Accurate prediction is also complicated by the fact that the V3-C4 region of the *env* gene, which has the greatest influence on tropism, also has a relatively high rate of diversity such that the sensitivity drops with uncloned sequences and HIV-1 non-B subtypes. Since non-B subtypes show a wide genetic variability in the V3 region and taking cognisance that X4 viruses might be more prevalent in some subtypes than others, there is an urgent need to know the reliability of genotypic tools for inferring HIV-1 tropism in non-B subtypes, especially in regions where these HIV-1 variants are quite prevalent and may soon have access to CCR5 antagonists. Moreover, technical limitations to the generation of unambiguous DNA sequences from the HIV-1 env region that has insertions and deletions may interfere with the generation of clean and clear electropherograms thereby interfering with a predictive determination of tropism in a significant portion of patients' samples. Prospective studies are needed to firmly establish the clinical usefulness of genotypic tropism determination. Further research is also warranted regarding the need for specific genetic characteristics of dual/mixed-tropic HIV-1 strains which also exist in a significant proportion of patients.

#### **21. HIV-1 coreceptor usage and genetic subtypes**

There are remarkable differences in the prevalence of CXCR4-using variants among different HIV-1 genetic subtypes and circulating recombinant forms (CRFs). Since CXCR4 using variants emerge after an accumulation of mutations, the different prevalence observed may reflect the same phenomenon at the population level. Infection with subtype-C accounts for over half of the worldwide HIV-1 epidemics and is rapidly expanding in Southern Africa, South East Asia and India. Studies have shown this rapidly expanding subtype C isolates almost exclusively use the CCR5 coreceptor, with CXCR4 usage being rarely observed. Some authors argue that the predominant usage of CCR5 by HIV-1 subtype C isolates is more due to sampling artifacts rather than any fundamental biological properties of these viruses. Unique to subtype C is the determinant of coreceptor usage, the V3 regions which has been shown to be highly conserved and have a low overall positive charge, which is consistent with the NSI phenotypes compared to other subtypes. Moreover, this atypical property of the subtype C envelope glycoproteins might be the reason behind the rapid expansion of the virus being currently observed. In view of this, there is need for intervention strategies that are subtype specific to curb this pandemic tailor designed for use in areas where subtype C viruses predominate. R5-using viruses have also been found to be more common in subtype A than subtype D HIV-1 infections. The emergence of X4 viruses occurs very early among subtype D-infected individuals. More so, a high proportion of subtype D infections have been shown to display D/M tropism throughout the course of disease. An inverse skewing in coreceptor usage, with an increased presence of CXCR4-using strains, has instead been reported for subtype-D HIV-1. This observation is consistent with the faster pace of disease progression reported for subtype-D infection both in Africa and abroad. An increased rate of CXCR4 usage has also been reported for CRF AE isolates common in South East Asia. There are proposals to the effect that the increase in prevalence of CXCR4-using HIV-1 variants increases with the age of the subtype epidemic. Indeed recent phylogenetic studies suggest that the proportion of patients with detectable CXCR4 using HIV-1 variants varies with subtype D having the highest CXCR4 switch rate being the oldest whilst subtype C with the lowest CXCR4 switch rate being the youngest. Subtype B predominant in North America and Europe has demonstrated that CXCR4 coreceptor usage increases with time following infection with or without concurrent use of R5 in 50% of HIV-1 infected individuals. The HIV-1 subtype-B epidemic has an intermediate pattern, both in terms of age and prevalence of CXCR4-using HIV-1 variants. This assumption is highly speculative and not supported by all the data available at present. However, if confirmed it would imply that all the subtype epidemics are evolving towards a higher prevalence of CXCR4-using HIV-1 variants although it is plausible that each epidemic would reach a point of equilibrium beyond which such prevalence will not further increase.

#### **22. HIV coreceptor usage and compartmentalization**

244 Immunodeficiency

antagonist-containing regimens.

**20. Challenges of genotypic methods** 

strains which also exist in a significant proportion of patients.

**21. HIV-1 coreceptor usage and genetic subtypes** 

higher CD4 cell counts and non-exposure to antiretroviral therapy. The global concordance between genotypic and phenotypic data is 91% with the rule combining the amino-acid residues at positions 11/25 and V3 net charge. Gaining a better understanding of the output of these assays and correlating them with clinical progression and therapy response will provide some indication on how both genotype-based and phenotypic assays for determining HIV coreceptor usage can be improved. Deep V3 sequencing is a promising tool for identifying treatment-experienced individuals who could benefit from CCR5-

Genotypic predictions are relatively satisfactory but because not all determinants of coreceptor usage lie within the V3 loop, the region employed by most current predictors, causing occasional disagreements. Accurate prediction is also complicated by the fact that the V3-C4 region of the *env* gene, which has the greatest influence on tropism, also has a relatively high rate of diversity such that the sensitivity drops with uncloned sequences and HIV-1 non-B subtypes. Since non-B subtypes show a wide genetic variability in the V3 region and taking cognisance that X4 viruses might be more prevalent in some subtypes than others, there is an urgent need to know the reliability of genotypic tools for inferring HIV-1 tropism in non-B subtypes, especially in regions where these HIV-1 variants are quite prevalent and may soon have access to CCR5 antagonists. Moreover, technical limitations to the generation of unambiguous DNA sequences from the HIV-1 env region that has insertions and deletions may interfere with the generation of clean and clear electropherograms thereby interfering with a predictive determination of tropism in a significant portion of patients' samples. Prospective studies are needed to firmly establish the clinical usefulness of genotypic tropism determination. Further research is also warranted regarding the need for specific genetic characteristics of dual/mixed-tropic HIV-1

There are remarkable differences in the prevalence of CXCR4-using variants among different HIV-1 genetic subtypes and circulating recombinant forms (CRFs). Since CXCR4 using variants emerge after an accumulation of mutations, the different prevalence observed may reflect the same phenomenon at the population level. Infection with subtype-C accounts for over half of the worldwide HIV-1 epidemics and is rapidly expanding in Southern Africa, South East Asia and India. Studies have shown this rapidly expanding subtype C isolates almost exclusively use the CCR5 coreceptor, with CXCR4 usage being rarely observed. Some authors argue that the predominant usage of CCR5 by HIV-1 subtype C isolates is more due to sampling artifacts rather than any fundamental biological properties of these viruses. Unique to subtype C is the determinant of coreceptor usage, the V3 regions which has been shown to be highly conserved and have a low overall positive Compartmentalization is the occurrence of distinct yet phylogenetically related HIV-1 phenotypes or genotypes within different anatomic sites, an observation common amongst both treated and untreated individuals. Differences in selective pressures may shape the distinct viral populations in different compartments. Anatomic compartmentalization of HIV coreceptor usage variants has been described in diverse tissues including in blood, lungs, brain, central nervous system, breast milk and genital tract. Studies have shown that the distribution of R5 and CXCR4-using variants differ in different blood compartments. Higher prevalence of predicted CXCR4-using variants in PBMC than in plasma has been reported. The limited compartmentalization and the clonal amplification of evolving functional viruses in milk indicate continual seeding of the mammary gland by blood virus variants, followed by transient local replication of these variants in the breast compartment.

Gender studies have demonstrated different viral variants between genital tract and blood for both women and men. Differences in genetic strains between blood- and semen-derived HIV isolates within the same individual have been documented. Male genital tract tissues such as the prostate, seminal vesicles, and epididymis which serve as sites of viral replication have been found to develop distinct, compartment-specific HIV strains in response to these local selective pressures. Studies seeking to determine chemokine receptor preference for all sequences derived from patients with compartmentalized virus to determine if seminal tropism correlated with altered coreceptor usage have shown a trend towards reduced CXCR4 usage in the male genital tract.

Coreceptor Usage in HIV Infection 247

**Figure 3.** Interaction between HIV-1 and the cell surface Molecules, adopted from Levy J, 1996

Other environmental factors such as sexually transmitted infections (STIs) have been also shown to exert selective pressures. Genital inflammation can stimulate the expression of R5 receptors dramatically, conferring a selective advantage on R5 virus in the genital tract of women with STIs. A history of intravenous drug use (IDU) among women has been shown to correlate with larger proportions of X4 strains in plasma relative to those without an IDU record. Quantifying the proportion of R5 and X4 viruses in each compartment has been found to vary significantly between them. Thus, the proportion of X4 strains in one compartment does not necessarily reflect coreceptor usage in the other suggesting that measuring coreceptor usage in say the genital tract and blood may aid in effective monitoring of disease progression and response to therapy as efficiencies of antiretroviral drug penetration has also been found to differ with compartments. Hence, there is need for compartment specific treatment outcome monitoring of patients and also the most appropriate choice of patient material for the determination of HIV-1 coreceptor usage remains to be established.

### **23. Chemokine receptors and viral entry into host cells**

The entry of HIV into cells is critically dependent on the sequential interaction of the viral envelope with two cell-surface receptors, the CD4 glycoprotein and CCR5 or CXCR4. The evolutionary choice of HIV of exploiting chemokine receptors as entry gateways has established a tight biological bond between HIV and the chemokine system, making the respective natural ligands of these receptors potent viral inhibitors. Entry into target cells by HIV occurs by a multi-step process that culminates with the fusion of viral and cellular membrane as shown in **figure 3** below. Many enveloped viruses including HIV possess a fusion protein in their envelopes which confers the ability of the virion to fuse with the host cell membrane and thus allowing entry of the infectious genomic material into the cell cytoplasm. Receptor interactions then trigger gp41 to promote membrane fusion. This reaction is thought to involve extension of the gp41 subunit to allow insertion of its Nterminal 'fusion peptide' into the target cell membrane, followed by refolding the prefusion intermediate into an energetically favorable six-helix bundle that brings the two membranes together so that fusion can occur. During replication of the virus, expression of the fusion protein on the cell membrane can result in the fusion of neighbouring cells forming multinucleate cells or syncytia.

remains to be established.

nucleate cells or syncytia.

Gender studies have demonstrated different viral variants between genital tract and blood for both women and men. Differences in genetic strains between blood- and semen-derived HIV isolates within the same individual have been documented. Male genital tract tissues such as the prostate, seminal vesicles, and epididymis which serve as sites of viral replication have been found to develop distinct, compartment-specific HIV strains in response to these local selective pressures. Studies seeking to determine chemokine receptor preference for all sequences derived from patients with compartmentalized virus to determine if seminal tropism correlated with altered coreceptor usage have shown a trend

Other environmental factors such as sexually transmitted infections (STIs) have been also shown to exert selective pressures. Genital inflammation can stimulate the expression of R5 receptors dramatically, conferring a selective advantage on R5 virus in the genital tract of women with STIs. A history of intravenous drug use (IDU) among women has been shown to correlate with larger proportions of X4 strains in plasma relative to those without an IDU record. Quantifying the proportion of R5 and X4 viruses in each compartment has been found to vary significantly between them. Thus, the proportion of X4 strains in one compartment does not necessarily reflect coreceptor usage in the other suggesting that measuring coreceptor usage in say the genital tract and blood may aid in effective monitoring of disease progression and response to therapy as efficiencies of antiretroviral drug penetration has also been found to differ with compartments. Hence, there is need for compartment specific treatment outcome monitoring of patients and also the most appropriate choice of patient material for the determination of HIV-1 coreceptor usage

The entry of HIV into cells is critically dependent on the sequential interaction of the viral envelope with two cell-surface receptors, the CD4 glycoprotein and CCR5 or CXCR4. The evolutionary choice of HIV of exploiting chemokine receptors as entry gateways has established a tight biological bond between HIV and the chemokine system, making the respective natural ligands of these receptors potent viral inhibitors. Entry into target cells by HIV occurs by a multi-step process that culminates with the fusion of viral and cellular membrane as shown in **figure 3** below. Many enveloped viruses including HIV possess a fusion protein in their envelopes which confers the ability of the virion to fuse with the host cell membrane and thus allowing entry of the infectious genomic material into the cell cytoplasm. Receptor interactions then trigger gp41 to promote membrane fusion. This reaction is thought to involve extension of the gp41 subunit to allow insertion of its Nterminal 'fusion peptide' into the target cell membrane, followed by refolding the prefusion intermediate into an energetically favorable six-helix bundle that brings the two membranes together so that fusion can occur. During replication of the virus, expression of the fusion protein on the cell membrane can result in the fusion of neighbouring cells forming multi-

towards reduced CXCR4 usage in the male genital tract.

**23. Chemokine receptors and viral entry into host cells** 

**Figure 3.** Interaction between HIV-1 and the cell surface Molecules, adopted from Levy J, 1996

#### **24. Coreceptor usage and HIV-1 transmission**

Irrespective of the transmission route or HIV-1 subtype, R5 viruses are preferentially transmitted in both horizontal and vertical transmission events except for subtype D. HIV transmission via breastfeeding accounts for a considerable proportion of infant HIV acquisition. However, no conclusive evidence has been provided to indicate that CXCR4 using strains are less able or unable to sustain mucosal transmission. For example simian chimeric immunodeficiency viruses (SHIV) bearing an X4 HIV-1 envelope can be readily transmitted via the mucosal route in macaques, and have widely been used as a reference model. Another important element that is rarely taken into consideration in the HIV-1 transmission equation is the transmitter bias which suggests that individuals with replicating CXCR4- using viruses are more likely to be in a more advanced stage of their disease progression and hence are more likely to be too ill to engage in risky sexual behavior. Majority of transmissions occur from asymptomatic individuals who generally harbor R5 variants. Consequently, the transmission of CXCR4-using variants may in fact be more frequent than it appears, albeit underestimated due to late sampling. Although primary infection with CXCR4-using HIV-1 strains is believed to be a rare event, mixed R5/X4 primary infections have been documented. Vertical transmission of dual tropic HIV-1 has also been demonstrated. Genotypic characteristics of HIV-1 V3 loop that are preferentially vertically transmitted for different subtypes remain unclear yet this information is critical for the development of effective transmission preventive strategies. At least for HIV-1 subtype B maternal viral phenotype can be predictive of the newborn's viral phenotype whilst the dual R5X4 phenotype is predominantly lost during vertical transmission. Antenatal HIV-1 subtype C coreceptor usage is generally preserved in vertical transmission and can be predictive of the newborn's viral genotype.

Coreceptor Usage in HIV Infection 249

tropic R5 HIV-1 quasi-species even before the progression to AIDS. However, studies have shown that these late stage homogeneous CCR5 isolates are more pathogenic than the earlier isolates. In line with this observation is the ability of late-stage CCR5-restricted HIV-1 variants to use chimeric coreceptors where some parts of CCR5 would have been replaced with segments of CXCR4 (R5 broad), whilst early CCR5-using HIV-1 variants are restricted to the use of wild-type CCR5 (R5 narrow). This *in vivo* evolution of CCR5-restricted HIV-1 in humans is similar to that observed in non-human primates infected with SIV, which never acquires CXCR4 usage even though its pathogenicity increases during the late disease stages. This evolution is accompanied by improved coreceptor-binding affinity, which in turn is reflected in decreasing sensitivities of R5 variants to inhibition by CCR5-binding

Some HIV-1 variants can use either coreceptor hence they are termed dual/mixed (DM) tropic. These have been detected in all stages of infection although they are more common in infections of longer duration, with lower CD4+ cell counts and higher viral loads. Such strains produce gp120 molecules capable of recognizing the CXCR4 protein on CD4-bearing Tcells. During this phase HIV-1 may infect both macrophages and T-cells. Still later, the bulk of the viral population may switch it's preference to the CXCR4 receptor and become T-tropic. Ttropic viruses readily destroy infected T-cells, contributing to the collapse of the immune system and the onset of AIDS. Evidence suggests that the evolutionary changes in the V3 loop involved in the coreceptor-usage switch are gradual with dual coreceptor usage (R5X4) representing an intermediate transitional phase. Once established the DM–tropic viruses have been shown to develop the optimal fitness to predominate during the transition phase, although they may eventually be outcompeted by HIV-1 variants with a pure X4 phenotype.

Following years of chronic HIV infection X4 using strains emerge although this phenomenon is not consistently observed in all patients progressing to AIDS. This switch of coreceptor usage has been shown to be associated with accelerated decrease in CD4 cells and hence it could be an important determinant of HIV pathogenesis and disease progression. The emergence of X4 variants has also been shown to coincide with disease progression and has been associated with longer duration of antiretroviral treatment including higher risk of death. The mechanism by which X4 viruses are associated with accelerated disease progression has never been properly elucidated although one theory proposes that R5-viruses lose their fitness with time, showing an abrupt decline in their ability to use CCR5 coreceptors and to infect cell lines with low CCR5 expression, demonstrating an increased susceptibility to CCR5 inhibitors consequently creating a pro-X4-virus environment. It has also been postulated that the decline of the host immune system associated with clinical AIDS may allow X4 viruses to evolve and replicate freely in late-stage infection. Furthermore, it has also been reported that disease progression among

chemokines and small- molecule CCR5 antagonists.

**28. X4 variants** 

**27. Co-existence of R5 and CXCR4- HIV-1 variants** 

#### **25. Co receptor usage and HIV Disease progression**

Coreceptor usage is a marker for disease progression. There is a continued evolution in viral coreceptor usage in vivo, resulting in a broad range of coreceptor affinities within the HIV-1 quasi-species. Discriminating between these and other alternatives is central to increasing our understanding of the fundamental pathogenic processes involved in HIV-1 infection.

#### **26. CCR5 HIV-1 variants**

During the asymptomatic phase of HIV-1 infection a homogeneous R5 virus population is commonly present that can replicate efficiently in both T cells and macrophages. The early stages of HIV infection and the latency phase are characterised by CCR5 coreceptor using viral variants which are less virulent, non-syncytium-inducing and are associated with reduced progression to AIDS. A significant proportion of patients progresses to full-blown AIDS without experiencing an overt switch to CXCR4 usage, indicating that CCR5 usage remains a critical coreceptor throughout the course of HIV infection. This has been supported by the observation that the ability of R5 isolates to replicate in macrophages is progressively reduced during the course of infection, resulting in a predominantly T-cell tropic R5 HIV-1 quasi-species even before the progression to AIDS. However, studies have shown that these late stage homogeneous CCR5 isolates are more pathogenic than the earlier isolates. In line with this observation is the ability of late-stage CCR5-restricted HIV-1 variants to use chimeric coreceptors where some parts of CCR5 would have been replaced with segments of CXCR4 (R5 broad), whilst early CCR5-using HIV-1 variants are restricted to the use of wild-type CCR5 (R5 narrow). This *in vivo* evolution of CCR5-restricted HIV-1 in humans is similar to that observed in non-human primates infected with SIV, which never acquires CXCR4 usage even though its pathogenicity increases during the late disease stages. This evolution is accompanied by improved coreceptor-binding affinity, which in turn is reflected in decreasing sensitivities of R5 variants to inhibition by CCR5-binding chemokines and small- molecule CCR5 antagonists.

#### **27. Co-existence of R5 and CXCR4- HIV-1 variants**

Some HIV-1 variants can use either coreceptor hence they are termed dual/mixed (DM) tropic. These have been detected in all stages of infection although they are more common in infections of longer duration, with lower CD4+ cell counts and higher viral loads. Such strains produce gp120 molecules capable of recognizing the CXCR4 protein on CD4-bearing Tcells. During this phase HIV-1 may infect both macrophages and T-cells. Still later, the bulk of the viral population may switch it's preference to the CXCR4 receptor and become T-tropic. Ttropic viruses readily destroy infected T-cells, contributing to the collapse of the immune system and the onset of AIDS. Evidence suggests that the evolutionary changes in the V3 loop involved in the coreceptor-usage switch are gradual with dual coreceptor usage (R5X4) representing an intermediate transitional phase. Once established the DM–tropic viruses have been shown to develop the optimal fitness to predominate during the transition phase, although they may eventually be outcompeted by HIV-1 variants with a pure X4 phenotype.

#### **28. X4 variants**

248 Immunodeficiency

**24. Coreceptor usage and HIV-1 transmission** 

transmission and can be predictive of the newborn's viral genotype.

Coreceptor usage is a marker for disease progression. There is a continued evolution in viral coreceptor usage in vivo, resulting in a broad range of coreceptor affinities within the HIV-1 quasi-species. Discriminating between these and other alternatives is central to increasing our understanding of the fundamental pathogenic processes involved in HIV-1 infection.

During the asymptomatic phase of HIV-1 infection a homogeneous R5 virus population is commonly present that can replicate efficiently in both T cells and macrophages. The early stages of HIV infection and the latency phase are characterised by CCR5 coreceptor using viral variants which are less virulent, non-syncytium-inducing and are associated with reduced progression to AIDS. A significant proportion of patients progresses to full-blown AIDS without experiencing an overt switch to CXCR4 usage, indicating that CCR5 usage remains a critical coreceptor throughout the course of HIV infection. This has been supported by the observation that the ability of R5 isolates to replicate in macrophages is progressively reduced during the course of infection, resulting in a predominantly T-cell

**25. Co receptor usage and HIV Disease progression** 

**26. CCR5 HIV-1 variants** 

Irrespective of the transmission route or HIV-1 subtype, R5 viruses are preferentially transmitted in both horizontal and vertical transmission events except for subtype D. HIV transmission via breastfeeding accounts for a considerable proportion of infant HIV acquisition. However, no conclusive evidence has been provided to indicate that CXCR4 using strains are less able or unable to sustain mucosal transmission. For example simian chimeric immunodeficiency viruses (SHIV) bearing an X4 HIV-1 envelope can be readily transmitted via the mucosal route in macaques, and have widely been used as a reference model. Another important element that is rarely taken into consideration in the HIV-1 transmission equation is the transmitter bias which suggests that individuals with replicating CXCR4- using viruses are more likely to be in a more advanced stage of their disease progression and hence are more likely to be too ill to engage in risky sexual behavior. Majority of transmissions occur from asymptomatic individuals who generally harbor R5 variants. Consequently, the transmission of CXCR4-using variants may in fact be more frequent than it appears, albeit underestimated due to late sampling. Although primary infection with CXCR4-using HIV-1 strains is believed to be a rare event, mixed R5/X4 primary infections have been documented. Vertical transmission of dual tropic HIV-1 has also been demonstrated. Genotypic characteristics of HIV-1 V3 loop that are preferentially vertically transmitted for different subtypes remain unclear yet this information is critical for the development of effective transmission preventive strategies. At least for HIV-1 subtype B maternal viral phenotype can be predictive of the newborn's viral phenotype whilst the dual R5X4 phenotype is predominantly lost during vertical transmission. Antenatal HIV-1 subtype C coreceptor usage is generally preserved in vertical

> Following years of chronic HIV infection X4 using strains emerge although this phenomenon is not consistently observed in all patients progressing to AIDS. This switch of coreceptor usage has been shown to be associated with accelerated decrease in CD4 cells and hence it could be an important determinant of HIV pathogenesis and disease progression. The emergence of X4 variants has also been shown to coincide with disease progression and has been associated with longer duration of antiretroviral treatment including higher risk of death. The mechanism by which X4 viruses are associated with accelerated disease progression has never been properly elucidated although one theory proposes that R5-viruses lose their fitness with time, showing an abrupt decline in their ability to use CCR5 coreceptors and to infect cell lines with low CCR5 expression, demonstrating an increased susceptibility to CCR5 inhibitors consequently creating a pro-X4-virus environment. It has also been postulated that the decline of the host immune system associated with clinical AIDS may allow X4 viruses to evolve and replicate freely in late-stage infection. Furthermore, it has also been reported that disease progression among

individuals infected with subtypes D and C is faster than in those infected with subtypes A and A/G in Africa and that subtype D infection leads to faster rates of CD4 cell decline and subsequent virological failure compared to infection with subtype B and other non-subtype B HIV strains in England.

Coreceptor Usage in HIV Infection 251

looking for other possible host factors, including genetic defects involving other coreceptors. It was this protective property of CCR5∆32 against HIV infection that has prompted pharmaceutical companies to develop a CCR5 antagonist for clinical use in the treatment of HIV/AIDS. Studies have shown that inhibition of CCR5 coreceptor seems not to cause significant clinical harmful consequences yet surprising to date there has not been any description of natural genetic alteration in CXCR4 human gene, suggestive that mutations in

A general North to South downhill gradient in CCR5∆32 gene frequency has been observed. The highest frequency has been found in Northern and North-eastern Europe especially amongst the Finnish and Swedish populations. Data confirm the high frequency of CCR5- Delta 32 among northern European Caucasians, a gene frequency declining across Europe and Asia reflecting recent population admixture. The virtual absence of CCR5-Delta 32 deletion among native Africans, East Asians, and American-Indians is suggestive that the mutation arose in northern Europe in response to selective pressures due to other factors including infection epidemics. The CCR5∆32 has a prevalence rate of between 20-35% among the Jewish population. In Africa studies indicated that the allelic frequency of

A CCR2 –V641 mutation from a conservative valine to isoleucine substitution in the transmembrane region has also been associated with some protective effects against HIV infection and reduction in progression of HIV to AIDS. The protective effect of CCR2 –V641 is believed is to be through regulation linkage disequilibrium in the regulatory region or promoter region of this gene. CCR2-V64I is common among Africans, yet this race is one of the most affected populations by the HIV pandemic. Hence, the protective effect of CCR2 – V641 against HIV infection remains controversial. Despite the availability of evidence linking some host genetic factors to protection against HIV infection, very little information is available regarding the role of CCR5-∆32 and CCR2-V64I polymorphism on HIV

To successfully infect an immune cell HIV env gp 120 has to interact with the host cellular receptor CD4 and either a CCR5 or CXCR4. Both coreceptors are recognized as novel targets for anti-HIV-therapy consequently resulting in the development of a new class of antiretroviral drugs called coreceptor antagonists or blockers. Blocking these coreceptors would protect the host cell from viral entry and would reduce the viral transmission and pathogenesis. Interestingly coreceptor antagonists differ from the other antiretroviral agents that target HIV proteins in the sense that they bind and inhibit receptors encoded by the

this gene are incompatible with life.

**32. CCR2 –V641 mutation** 

transmission.

**31. Epidemiology of CCR5∆32 gene** 

CCR5∆32 mutation is 0.1% in the black South African population.

**33. Coreceptor antagonists and antiretroviral therapy** 
