Despite the detection of both humoral and cellular virus-specific immune responses in HIV-1-infected persons, the components of protective immunity have not been defined. Cytotoxic T lymphocytes (CTL) have been shown to play an important role in eliminating viruses in a number of animal models of viral infection, and are hypothesized to play a vitral role in containing HIV-1 replication and disease progression. An extremely vigorous class I restricted CTL response has been detected in HIV-1 infection, although the specific epitopes targeted appear to vary considerably from person to person. The factors which contribute to disease progression in the setting of this vigorous CTL response are not known, nor are the factors which permit rapid progression in some individuals and delayed progression in other. Both sequence variation leading to immune escape as well as clonal CTL expansion followed by clonal exhaustion have been proposed to play a role. Central to a better understanding of HIV-1 disease pathogenesis is an understanding of bother the effector cells which mediate the vigorous CTL activity in infected persons, as well as the relevance of the specific target epitopes recognized by the CTL response. We propose to further define the role of HIV-1-specific CTL in disease pathogenesis by evaluating the CTL response in persons who exhibit no evidence of disease progression after prolonged periods of infection, and by using T cell receptor (TCR) sequence analysis as a means to define and track specific clonal CTL responses. Effector cells of this response will be further characterized with regard to the release of inflammatory cytokines following encounter with target antigen, which may have direct immunomodulatory effects. Because our preliminary data indicate that the CTL response to a given epitope may represent monoclonal or oligoclonal expansion of CTL, we will also attempt to broaden the CTL repertoire to given epitopes in infected persons in vitro. Specifically, we propose to: a) Characterize the HIV-1-specific CTL responses in long-term non-progressors compared to controls, including the minimum optimal CTL epitopes recognized, the precursor frequency of HIV-1- specific CTL directed at these epitopes, and sequence variation within these epitopes; b) Determine the breadth and duration of HIV-1-specific CTL responses to individual epitopes by using TCR sequence analysis to evaluate specific clonal responses, and determine the range of TCR gene usage to a given epitope; c) Determine the ability of HIV-1-specific CTL to release immunoregulatory cytokines; and d) Develop techniques to broaden the CTL repertoire in infected persons, using dendritic cells pulsed with optimal peptides to generate in vitro immune responses. These studies should provide a better understanding of the role of CTL as a host defense, and will provide important information for interventions designed to augment CTL activity.

National Institute of Health (NIH)
National Institute of Allergy and Infectious Diseases (NIAID)
Method to Extend Research in Time (MERIT) Award (R37)
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Special Emphasis Panel (NSS)
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Plaeger, Susan F
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Massachusetts General Hospital
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