**3.2. The classification of HIV disease**

**3. Immunological aspects of HIV infection**

108 Trends in Basic and Therapeutic Options in HIV Infection - Towards a Functional Cure

In primary infection of HIV-1, patients may be asymptomatic though sometimes the disease is self-limiting. Within the incubation period of about 6 weeks, patients can present with a mononucleosis-like syndrome, which is characterized by fever, cough, painful swallowing, myalgias, arthralgias, diarrhea as well as maculopapular rash and lymphadenopathy [5]. In most circumstances, the symptoms are usually mild as contrasted to severe cases, where pneumonitis, oropharyngeal and esophageal ulcers may occur. Encephalitis, meningitis, neuropathy, radiculopathy and myelopathy are not common sickneses in HIV infection. Although the true incidence of this syndrome is not precisely known, it may also depend on the degree of exposure to the virus, it may be as high as over 50% in persons who acquire HIV-1

The diagram shows the mechanism of regulation of immune response. Th1 is mainly involved in cell-mediated im‐ munity and offers protection against intracellular pathogens while Th2 is important in humoral immunity, protection

against helminthic infection as well as allergic or atopic diseases such as allergic rhinitis, asthma etc.

World Health Organization [6] categorized an adult or adolescent (aged > 12 years) as having AIDS in presence of at least two of the major signs in combination with one of the minor signs

**3.1. Clinical features of HIV infection**

**Figure 1.** The regulation of immune response [3]

infection [5].

(Table 2).

The staging and classification of HIV disease are standard tools for monitoring HIV epidemic and also serve as a guide for clinicians in managing HIV patients. It provides important information for patients and clinicians regarding the staging of HIV disease and clinical management. Currently, two major classification are used: World Health Organization (WHO) Clinical Staging and Disease Classification System and the United State Centers for Disease Control and Prevention (CDC) Classification System.

The WHO Clinical Staging and Disease Classification System (revised in 2007) is usually used in resource-constrained settings without access to CD4 cell count measurements or other diagnostic and laboratory methods [7] The system classifies the HIV disease based on the clinical manifestations of patients. By contrast, the CDC classification system assesses the HIV disease severity by CD4 cell count as well as by the presence of specific HIV-related conditions [7]. This classification system is usually beneficial in the clinical as well as epidemiologic research.

#### *3.2.1. WHO clinical staging of HIV/AIDS and case definition*

The clinical staging and case definition of HIV was developed by WHO in 1990 and revised in 2007. It is based on the clinical findings rather than CD4 cell count. This staging system has been used by some countries for managing HIV patients where the CD4 cell count testing is not available [7]. The staging was categorized as 1 to 4 based on clinical severity and progres‐ sion from primary infection to advanced stage. The adult and adolescents were defined as individuals aged ≥ 15 years. WHO, 2007 [8] classifies the clinical staging of HIV/AIDS based on the clinical conditions or symptoms (Table 3).



⋅ Symptomatic HIV-associated cardiomyopathy

⋅ Reactivation of American trypanosomiasis (meningoencephalitis or myocarditis)

**Table 3.** WHO Clinical Staging of HIV/AIDS for Adult and Adolescents [8].

#### *3.2.2. CDC classification system for HIV infection*

Clinical Stage 2 ⋅ Moderate unexplained weight loss (<10% of presumed or measured body weight)

Clinical Stage 3 ⋅ Unexplained severe weight loss ("/>10% of presumed or measured body weight)

⋅ Acute necrotizing ulcerative stomatitis, gingivitis or periodontitis

⋅ Esophageal candidiasis (or candidiasis of trachea, bronchi, or lungs)

⋅ Cytomegalovirus infection (retinitis or infection of other organs)

⋅ Disseminated mycosis (e.g., histoplasmosis, coccidioidomycosis, penicilliosis)

⋅ Cryptococcosis, extrapulmonary (including meningitis) ⋅ Disseminated nontuberculosis mycobacteria infection ⋅ Progressive multifocal leukoencephalopathy ⋅ Candida of the trachea, bronchi, or lungs ⋅ Chronic cryptosporidiosis (with diarrhea)

⋅ Recurrent nontyphoidal *Salmonella* bacteremia ⋅ Lymphoma (cerebral or B-cell non-Hodgkin)

⋅ Chronic thrombocytopenia (platelets < 50, 000 cells/ µL)

⋅ Unexplained chronic diarrhea for "/> 1 month

⋅ Unexplained anaemia (haemoglobin<8 g/dl) ⋅ Neutropenia (neutrophils <500 cells/µL)

Clinical Stage 4 ⋅ HIV wasting syndrome, as defined by the CDC (see Table 1, above)

⋅ Recurrent severe bacterial pneumonia

⋅ Central nervous system toxoplasmosis

⋅ Persistent oral candidiasis ⋅ Oral hairy leukoplakia ⋅ Pulmonary tuberculosis

infection, meningitis, bacteremia)

⋅ *Pneumocystis* pneumonia

visceral herpes at any site)

⋅ Kaposi sarcoma

⋅ HIV encephalopathy

⋅ Chronic isosporiasis

⋅ Invasive cervical carcinoma ⋅ Atypical disseminated leishmaniasis ⋅ Symptomatic HIV-associated nephropathy

⋅ Extrapulmonary tuberculosis

⋅ Herpes zoster ⋅ Angular cheilitis ⋅ Recurrent oral ulceration ⋅ Papular pruritic eruptions ⋅ Seborrheic dermatitis ⋅ Fungal nail infections

110 Trends in Basic and Therapeutic Options in HIV Infection - Towards a Functional Cure

⋅ Recurrent respiratory infections (sinusitis, tonsillitis, otitis media, and pharyngitis)

⋅ Unexplained persistent fever for "/> 1 month ("/>37.6ºC, intermittent or constant)

⋅ Severe presumed bacterial infection (e.g., pneumonia, empyema, pyomyositis, bone or joint

⋅ Chronic herpes simplex infection (orolabial, genital, or anorectal site for "/>1 month or

The CDC classification of HIV/AIDS is based on the level of CD4 cell count and on previously diagnosed HIV-related conditions (Table 4) [7]. For example, if a patient had met the criteria for category B but currently is asymptomatic, the patient would remain in category B. The categorization is shown in Table 5. Patients in categories A3, B3 and C1-C3 are considered to have AIDS.


PGL: persistent generalized lymphadenopathy for \*B and \*\*C Clinical Categories refer to Table 5

**Table 4.** CDC Classification System for HIV-Infected Adults and Adolescents [7].



**Table 5.** B and \*\*C Clinical Categories of HIV infection [7].

#### **3.3. Immunologic changes in HIV infection**

#### *3.3.1. Depletion of CD4+T cells causes immunodeficiency*

Untreated HIV-1 infection is associated with a gradual loss of peripheral CD4<sup>+</sup> T cells. Loss of CD4<sup>+</sup> T cells and systemic immune activation are the major hallmarks of HIV infection [9]. There are two major phases of HIV disease, acute and chronic infection. Acute infection is associated with gradual loss of CD4<sup>+</sup> T cells in the mucosal tissue [10] while chronic infection is characterized by immune activation which is associated with massive production of proinflammatory cytokines [11]. This subsequently leads to decrease in peripheral CD4<sup>+</sup> T cells and profound immunodeficiency.

The major mechanism of CD4<sup>+</sup> T cell depletion in HIV patients is due to apoptosis, in which the number of apoptotic cells exceed the number of HIV-infected cells [12]. Other causes

of CD4+ T cell depletion include impairment of *de novo* production of T lymphocytes by the thymus [9], induction of syncytium formation, alteration of membrane permeability, mitochondrial dysfunction as well as killing by HIV-specific CD8+ T cells due to immune activation [9].
