Over the past several years it has become increasingly clear that further advances in HIV drugs and vaccine development will be highly dependent on deepening the understanding of virus-host interactions. It has been hypothesized that virus specific effector mechanisms play a major role in limiting replication of HIV in vivo, and thus serve as an important determinant in defining the rate of clinical and immunologic progression of HIV infection. This concept serves as the major premise which underlies the rationale for immune based therapies for HIV infection. In addition, a recently completed statistical analysis of the initial placebo controlled study of zidovudine has raised the possibility that partial reconstitution of HIV specific immune responses might result in secondary antiviral effects which might further contribute to the efficacy of antiretroviral agents. As clinical trials become increasingly complex, it will be critical that they be designed and conducted with a full understanding of concepts of HIV pathogenesis. Such an approach the execution of clinical trials will result in a more effective use of increasingly limited resources available for clinical investigation, and will provide an additional venue for the testing of hypotheses related to HIV pathogenesis. Our group has a particular interest in the cell mediated immune response to HIV. In this project we propose to apply our interest and expertise in this area to clinical trials of both immune based therapies, and studies of antiretroviral chemotherapy. It is our expectation that these studies will provide important insights into the feasibility of therapeutic approaches which seek to enhance virus specific immune responses, and into possible indirect mechanisms by which antiretroviral agents might mediate beneficial clinical effects.
Specific Aims for this proposal are: 1. To examine the effects of antiretroviral and immune-based therapies on HIV-specific cell-mediated immunity (CMI). 2. To determine extent to which the survival benefit conferred by antiretroviral agents that cannot be explained by changes in CD4+ cell counts alone might be attributable to changes in HIV-specific CMI. 3. To serve as a reference laboratory for the performance and standardization of assays for HIV-specific cell-mediated immune responses in immune-based clinical trials undertaken at other ACTG sites.
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