An inverse correlation is found between the strength of CD4 Tcell proliferative responses to HIV antigen and viral load. In addition, the type of effector CD4 Tcell response mounted against the virus appears important. There is an inverse correlation with viral load and control of acute infection in patients whose CD4 T cells express greater TH1 type activity, including production of IFNγ and granzyme B. Moreover, CD4 T cells from patients who do not progress to AIDS long after infection by HIV show strong antiviral proliferative responses. Finally, early treatment of acutely infected individuals with antiretroviral drugs is associated with a recovery in CD4 proliferative responses to HIV antigens. If antiretroviral therapy is stopped, the CD4 responses persist in some of these people and are associated with reduced levels of viremia. However, infection continues to persist in these patients and immunological control of the infection will ultimately fail. If CD4 Tcell responses are essential for the control of HIV infection, then the fact that HIV is tropic for these cells and kills them may explain the inability of the host immune response to control the infection in the long term.
Antibodies against HIV proteins are generated early in the course of infection, but, like T cells, are ultimately unable to clear the virus. As for viral Tcell epitopes, the virus shows a high capacity for generating escape mutants under the selective pressure of the antibody response. Two aspects of the antibody response appear to be important: (1) generating neutralizing antibodies against gp120 and gp41 envelope viral antigens in order to block viral attachment or entry into CD4positive target cells, and (2) generating nonneutralizing antibodies that target infected cells for antibodydependent cellular cytotoxicity (ADCC). Although neutralizing antibodies are eventually produced in nearly all who are HIVinfected, the relative inaccessibility of viral epitopes that bind CD4 and chemokine coreceptors hampers the development of such antibodies for a prolonged period (typically months); this buys the virus time to generate escape mutants before the neutralizing antibodies can be produced. Indeed, the generation of socalled broadly neutralizing antibodies, which can block infection by multiple viral strains, is typically found in those with high viral titers, emphasizing the fact that these antibodies cannot significantly modify established disease. Analyses of effective neutralizing antibodies to HIV indicate that they have undergone extensive somatic hypermutation that is rarely induced before the first year following infection. Nevertheless, the passive administration of some antibodies against HIV can protect experimental animals from mucosal infection by HIV, offering hope that an effective vaccine might be developed that could prevent new infections.
In contrast to neutralizing antibodies, which develop late in infection and appear to play a modest role in restraining viral replication, there is growing evidence that nonneutralizing antibodies that recruit ADCC by NK cells, macrophages, and neutrophils develop early in infections and are important in restraining viral replication in concert with the actions of cytolytic CD8 T cells. Again, however, the high rate of mutability of the virus allows it to stay a step ahead and persist. The mutations that occur as HIV replicates can allow resulting virus variants to escape recognition by CTLs or antibodies, and are important in contributing to the longterm failure of the immune system to contain the infection. An immune response is often dominated by T or B cells specific for particular epitopes—immunodominant epitopes—and mutations in immunodominant HIV peptides presented by MHC class I molecules have been found, as have mutations in the epitopes targeted by neutralizing and nonneutralizing antibodies. Mutant peptides have been found to inhibit T cells responsive to the wildtype epitope, thus allowing both the mutant and wildtype viruses to survive.