Development of an AIDS vaccine

AIDS was initially described in the U.S. in 1981, although sporadic cases probably occurred for at least two decades prior to this. By 1983, the causative agent, now termed HIV, was identified. HIV is a member of the lentivirus subfamily of retroviruses. It is a spherical, enveloped particle, 100-150 nm in diameter, and contains RNA as its genetic material (Figure 13.13).

The viral surface protein, gp 120, is capable of binding to a specific site on the CD4 molecule, found on the surface of susceptible cells (Table 13.10). Some CD4 negative cells may (rarely) also become infected, indicating the existence of an entry mechanism independent of CD4.

Table 13.10 Some cell types whose susceptibility to infection by HIV is believed to be due to the presence of the CD4 antigen on their surface

T-helper lymphocytes

Blood monocytes

Tissue macrophages

Dendritic cells of skin and lymph nodes

Brain microglia

Infection of CD4+ cells commences via interaction between gp 120 and the CD4 glycoprotein, which effectively acts as the viral receptor. Entry of the virus into the cell, which appears to require some additional cellular components, occurs via endocytosis and/or fusion of the viral and cellular membranes. The gp 41 transmembrane protein plays an essential role in this process.

Once released into the cell, the viral RNA is transcribed (by the associated viral reverse transcriptase) into double-stranded DNA. The retroviral DNA can then integrate into the host cell genome (or, in some instances, remain unintegrated). In resting cells, transcription of viral genes usually does not occur to any significant extent. However, commencement of active cellular growth/differentiation usually also triggers expression of proviral genes and, hence, synthesis of new viral particles. Aggressive expression of viral genes usually leads to cell death. Some cells, however (particularly macrophages), often permit chronic low-level viral synthesis and release without cell death.

Entry of the virus into the human subject is generally accompanied by initial viral replication, lasting a few weeks. High-level viraemia (presence of viral particles in the blood) is noted and p24 antigen can be detected in the blood. Clinical symptoms associated with the initial infection include an influenza-like illness, joint pains and general enlargement of the lymph nodes. This primary viraemia is brought under control within 3-4 weeks. This appears to be mediated largely by HIV-specific cytotoxic T-lymphocytes, indicating the likely importance of cell-mediated immunity in bringing the initial infection under control. Although HIV-specific antibodies are also produced at this stage, effective neutralizing antibodies are detected mainly after this initial stage of infection.

After this initial phase of infection subsides, the free viral load in the blood declines, often to almost undetectable levels. This latent phase may last for anything up to 10 years or more. During this phase, however, there does seem to be continuous synthesis and destruction of viral particles. This is accompanied by a high turnover rate of (CD4+) T-helper lymphocytes. The levels of these T-lymphocytes decline with time, as does antibody levels specific for viral proteins. The circulating viral load often increases as a result, and the depletion of T-helper cells compromises general immune function. As the immune system fails, classical symptoms of AIDS-related complex (ARC) and, finally, full-blown AIDS begin to develop.

In excess of 40 million individuals are now thought to be infected by HIV. In 2001 alone, it was estimated that 3 million people died from AIDS and a further 5 million became infected with the virus. Over 20 million people in total are now thought to have died from AIDS. The worst affected geographical region is the southern half of Africa (Table 13.11). Some 90 per cent of sufferers live in poorer world regions. So far, no effective therapy has been discovered, and the main hope of eradicating this disease lies with the development of safe, effective vaccines. The first such putative vaccine entered clinical trials in 1987; but, thus far, no effective vaccine has been developed.

Table 13.11 WHO estimated numbers of individuals infected with HIV by the end of 2005. Almost 75 per cent of these live in the southern half of Africa

World region Numbers infected

Sub-Saharan Africa 25.8 million

South and South East Asia 7.4 million

Latin America 1.8 million

North America 1.2 million

Eastern Europe and central Asia 1.6 million

North Africa and Middle East 0.51 million

Western and central Europe 0.72 million

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