HIV Heterogeneity. Effects of HIV Proteins

HIV Heterogeneity. Another feature of HIV that might be important in causing disease is its genetic and biological heterogeneity. HIV isolates from a single individual, and especially from different individuals, demonstrate a high degree of genetic divergence. Over time new HIV variants emerge within individuals, and as many as 27 different but related HIVs have been cloned from a single person. Although the source of the diversity is unknown, the infidelity of the HIV reverse transcriptase most likely plays a role.

Corresponding to the high degree of genetic diversity is a high degree of biological diversity. Different HIV isolates vary widely in their abilities to grow in primary macrophages and lymphocytes and in a variety of established cell lines. While virtually all isolates grow in peripheral blood mononuclear cells to varying degrees, some cannot establish productive infections in macrophages or established cell lines in culture. And while some isolates have fast kinetics, grow to high titers, are highly cytopathic, and down-modulate surface CD4 expression, others have slower kinetics, grow to lower titers, and have little effect on cell viability and surface CD4 expression.

This heterogeneity can be important in the pathogenic features of different HIV strains. For example, highly cytopathic fast-replicating strains have been found to be associated with advanced stages of disease.

Many regions of genetic variation are localized to specific domains within gpl20 (Fig. 6). Subtle changes in the structure or amino acid composition of the envelope protein complex may alter the ability of the virus to bind to a cellular receptor or fuse with the cell. Changes in other parts of the viral genome could also alter the ability of the virus to replicate in cells of various tissues. Such modifications could result in new variants that can infect and cause disease in different tissues.

FIGURE 6. Conserved and variable regions in the external envelope glycoprotein. Numbered regions are conserved among most HIV strains

Viruses with distinct cellular tropisms have been isolated from different tissues within an infected individual. Brain isolates, for example, frequently replicate to high titers in macrophages, but rarely infect established T cell lines. In contrast, blood isolates from the same individual often replicate well in established T cell lines and are very cytopathic. How these viruses evolve is unknown, but conceivably mutant viruses arise over time within infected individuals and show differing abilities to replicate in various tissues.

The genetic variation in the envelope region also has important consequences on the ability of HIV strains to be neutralized by antibodies. Subtle changes in the envelope protein complex could prevent antibodies from binding the envelope protein and inactivating HIV. Thus, by continually changing its envelope protein, HIV could keep ahead of neutralizing antibodies. Indeed, most infected individuals make antibodies against HIV, yet the antibodies often do not neutralize the viruses isolated from that individual.

Moreover, under some experimental conditions, antibodies have been found that enhance virus production in macrophages, lymphocytes, and even fibroblasts. It has been suggested that Fc or complement receptor binding of antibody-coated virus could facilitate entry of the virus into these cells. Clearly, the extreme genetic diversity of the envelope protein and the difficulties in raising neutralizing antibodies are major challenges for vaccine development.

Effects of HIV Proteins.Cell destruction or malfunction as a result of direct infection with HIV is not the only way that HIV can cause disease. Several theories have suggested that the envelope glycoprotein alone can lead to pathology. As mentioned in Section III,A,2, free gpl20 can directly bind CD4⁺ cells and render them targets for immune attack. Similarly, gpl20 complexed to antibodies can nonspecifically bind to some circulating cells and tag them for immune clearance. The latter mechanism could contribute to the severe destruction of platelets frequently seen in some HIV-infected individuals.

Circulating gpl20 can also directly affect cellular processes. For example, adding gpl20 to lymphocyte cultures can blunt the mitogenic response to lectins, and in high concentration gpl20 is toxic to cells. gpl20 has also been reported to inhibit the activity of IL-2, possibly by competitive interference, because a small region of gpl20 is homologous to IL-2.