Fig. 5.37 Thestructureofthehumanimmunodeficiencyvirus(HIV)-1virion.Theviralparticleiscoveredbyalipidbilayerderivedfromthehostcellandstuddedwithviralglycoproteinsgp41andgp120.gp120 Lipid bilayer p24 capsid Protease Integrase RNA Reverse transcriptase antibody response against HIV-1 is targeted against its envelope, such variability poses problems for the development of a single-antigen vaccine. Based on genetic variation, HIV-1 can be divided into three subgroups, designated M (major), O (outlier), and N (neither M nor O). Group M viruses are the most common form worldwide, and they are further divided into several subtypes, or clades, designated A through K. Various subtypes differ in their geographic distribution; for example, subtype B is the most common form in western Europe and the United States, whereas subtype E is the most common clade in Thailand. Currently, clade C is the fastest spreading clade worldwide, being present in India, Ethiopia, and Southern Africa.
While HIV can infect many tissues, the two major targets of HIV infection are the immune system and the central nervous system. The effects of HIV infection on each of these two systems are discussed separately.
Profound immune deficiency, primarily affecting cell-mediated immunity, is the hallmark of AIDS. This results chiefly from infection and subsequent loss of CD4+ T cells as well as impaired function of surviving helper T cells and other immune cells. We first describe the mechanisms involved in viral entry into T cells and macrophages and the replicative cycle of the virus within cells. This is followed by a more detailed review of the interaction between HIV and its cellular targets.
Life Cycle of HIV
The life cycle of HIV consists of infection of cells, integration of the provirus into the host cell genome, activation of viral replication, and production and release of infectious virus (
Fig. 5.38 ). The molecules and mechanisms of each of these steps are understood in considerable detail.
HIV infects cells by using the CD4 molecule as a receptor and various chemokine receptors as coreceptors (see
Fig.
5.38 ). Binding of HIV gp120 to CD4 is essential for infection and accounts for the tropism of the virus for CD4+ T cells and for CD4+ monocytes/macrophages and DCs. However, binding to CD4 is not sufficient for infection, as HIV gp120 also must bind to other cell surface molecules (coreceptors) for entry into the cell. Chemokine receptors, particularly CCR5 and CXCR4, serve this role. HIV isolates can be distinguished by their use of these coreceptors: R5 strains use CCR5, X4 strains use CXCR4, and some strains (R5X4) are dual-tropic. R5 strains preferentially infect cells of the monocyte/macrophage lineage and are thus referred to as M-tropic, whereas X4 strains are T-tropic, preferentially infecting T cells, but these distinctions are not absolute.
Polymorphisms in the gene encoding CCR5 are associated with altered susceptibility to HIV infection. About 1% of white Americans inherit two mutated copies of the CCR5 gene and are resistant to R5 HIV isolates. About 20% of individuals are heterozygous for this protective CCR5 allele; these individuals are not protected from AIDS, but the onset of their disease after infection is delayed. Only rare homozygotes for the mutation have been found in African and East Asian populations.