Despite recent progress in our understanding of HIV pathogenesis, the immunologic mechanisms responsible for controlling viral replication in vivo remain poorly understood. A wide variety of HIV-specific humoral and cellular immune responses have been described, including cytotoxic T lymphocyte (CTL) responses and neutralizing antibody responses. However, efforts to correlate these responses with control of viremia have been generally, though not invariably, unsuccessful. A recent report suggested that control of HIV viremia, either in HIV-infected long-term nonprogressors or in subjects treated with highly active antiretroviral therapy, was associated with the development of strong HIV-specific proliferative response. Although this report supports the provocative hypothesis that induction of strong virus-specific helper responses may play a role in controlling viremia, there are many unresolved questions raised by these results, many of which will be difficult to address in human clinical studies. We therefore propose to use the rhesus macaque model to further explore the role of CD4+ T cell help in host immune responses to SIV. Specifically, we plan to: 1. To characterize in detail the SIV-specific T helper response during infection with pathogenic and attenuated SIV strains 2. To identify SIV- specific T helper epitopes and their restricting alleles 3. To examine SIV-specific T helper responses following treatment of SIV-infected macaques with the potent antiretroviral agent PMPA. 4. To determine the relationship between CD4+ T helper responses and control of viral replication following discontinuation of antiretroviral therapy 5. To determine the ability of immunization to boost CD4+ T cell responses in PMPA-treated animals and to modify host control of viral replication following discontinuation of PMPA. These studies should provide valuable information regarding the conditions under which antiretroviral therapy may restore SIV-specific CD4+ T helper responses and on the relationship of these responses to the ability of the host to contain SIV replication. G

National Institute of Health (NIH)
National Institute of Allergy and Infectious Diseases (NIAID)
Research Project (R01)
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Special Emphasis Panel (ZRG1-AARR-1 (03))
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Bradac, James A
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Harvard University
Veterinary Sciences
Schools of Medicine
United States
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