Immune Responses to HIV

HIV-specific humoral and cell-mediated immune responses develop after infection but generally provide limited protection. The early response to HIV infection is, in fact, similar in many ways to the immune response to other viruses and serves to clear most of the virus present in the blood and in circulating T cells. Nonetheless, it is clear that these immune responses fail to eradicate all virus, and the infection eventually overwhelms the immune system in most individuals. Despite the poor effectiveness of immune responses to the virus, it is important to characterize them for three reasons. First, the immune responses may be detrimental to the host, for example, by stimulating the uptake of opsonized virus into uninfected cells by Fc receptor-mediated endocytosis or by eradication of CD4+ T cells expressing viral antigens by CD8+ CTLs. Second, antibodies against HIV are diagnostic markers of HIV infection that are widely used for screening purposes. Third, the design of effective vaccines for immunization against HIV requires knowledge of the types of immune responses that are most likely to be protective (the "correlates of protection").

Many innate immune responses against HIV have been described. These include antimicrobial peptides (defensins), NK cells, dendritic cells (particularly plasma-cytoid dendritic cells producing type I interferons), and the complement system. The role of these responses in combating the infection is not established.

The initial adaptive immune response to HIV infection is characterized by expansion of CD8+ T cells specific for HIV peptides. As many as 10% or more of circulating CD8+ T cells may be specific for HIV during the early stages of infection. These CTLs control infection in the acute phase (see Fig. 20-8) but ultimately prove ineffective because of the emergence of viral escape mutants (variants with mutated antigens). CD4+ T cells also respond to the virus, and these CD4+ T cells may contribute to viral control in a number of ways. An effective CD4+ T cell response is required as a source of help for the generation of CD8+ memory T cells, but CD4+ T cells have also been shown to mediate cytolytic responses against HIV-infected cells, perhaps using Fas ligand to target Fas on infected CD4+ T cells.

The importance of CTL responses in HIV control is underscored by the evolution of the virus under immune pressure, resulting in viral isolates that have lost their original CTL epitopes. The evolution of the virus also results in the loss of epitopes recognized by CD4+ T cells, indicating that both CD8+ and CD4+ cells contribute to host defense against the virus.

Antibody responses to a variety of HIV antigens are detectable within 6 to 9 weeks after infection. The most immunogenic HIV molecules that elicit antibody responses appear to be the envelope glycoproteins, and high titers of anti-gp120 and anti-gp41 antibodies are present in most HIV-infected individuals. Other anti-HIV antibodies found frequently in patients' sera include antibodies to p24, reverse transcriptase, and gag and pol products (see Fig. 20-8). The effect of these antibodies on the clinical course of HIV infection is uncertain. The early antibodies are not neutralizing and are generally poor inhibitors of viral infectivity or cytopathic effects. Neutralizing antibodies against gp120 develop 2 to 3 months after primary infection, but even these antibodies cannot cope with a virus that is able to rapidly change the most immunodominant epitopes of its envelope glycoproteins.

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