extensive death of CD4 T cells in the GALT that are killed by viral cytopathic effects (macrophages and dendritic cells appear more resistant to lysis by replicating virus). The depletion of immune cells in the gut might compound the rapid production of virus in the GALT by fostering increased immunecell activation due to barrier breakdown and translocation of constituents of the microbiota. Because of the high viral titers and preponderance of R5 strains during the acute phase of infection, the risk of viral transmission to uninfected contacts during this time is especially high.
The acute phase and its high viremia reside in virtually all patients once an adaptive immune response is established (see Fig. 13.33). Cytolytic CD8 T cells specific for viral antigens develop and kill HIVinfected cells, and virusspecific antibodies become detectable in the serum of those infected (seroconversion). The development of a CTL response results in early control of the virus, resulting in a sharp drop in viral titers and a rebound of CD4 Tcell counts. The level of virus that persists in blood plasma at this stage of infection, referred to as the viral set point, is usually a good indicator of future disease progression. At this point, the disease transitions to a clinically latent, or asymptomatic, phase marked by low viremia and slowly declining CD4 Tcell numbers, typically over several years. During this time the virus continues to actively replicate, but it is held in check, principally by HIVspecific CD8 T cells and antibodies.
Under strong selective pressure brought by the antiviral immune response, there is selection for HIV escape mutants that are no longer detected by adaptive immune cells. This gives rise to many different viral variants in a single infected person and to even broader variation within the population as a whole. Late in infection, in approximately 50% of cases, the dominant viral type switches from R5 to X4 variants that infect T cells via CXCR4 coreceptors. This is followed by a rapid decline in CD4 Tcell count and progression to AIDS. The exact mechanism by which this shift in viral tropism leads to accelerated loss of CD4 T cells is unknown. On balance, then, R5 variants appear critical for transmission of the virus from infected to uninfected individuals, whereas X4 variants that emerge under selective pressure exerted by the antiviral immune response contribute to the progression of disease within an infected individual.
13-30 A genetic deficiency of the co-receptor CCR5 confers resistance to HIV infection.
Evidence for the importance of CCR5 in transmission of HIV infection has come from studies of individuals with a high risk of exposure to HIV1 who remain seronegative. Lymphocytes and macrophages from these people are resistant to HIV infection in cultures inoculated with HIV. The resistance of these individuals to HIV infection is explained by discovery that they are homozygous for a nonfunctional variant of CCR5 called Δ32, caused by a 32basepair deletion from the coding region that leads to a frameshift mutation and a truncated protein. The frequency of this mutant allele in Caucasians is high at 0.09 (that is, about 10% of the population are heterozygous carriers of the allele and about 1% are homozygous). The mutant allele has not been found in Japanese or in black Africans from Western or Central Africa. Whether heterozygous deficiency of CCR5 provides some protection against infection by HIV is controversial, but it appears to contribute to a modest, if any, reduction in progression rates. In addition to the structural polymorphism of the gene, variations in the promoter region of the CCR5 gene have been associated with different rates of disease progression. The high incidence of the CCR5Δ32  allele in Caucasians predating the HIV pandemic suggests selection for this variant in a past epidemic. Both smallpox and bubonic plague have been put forward as possible selective agents, but this is as yet unproven.
13-31 An immune response controls but does not eliminate HIV.