DESCRIPTION: The long term objectives of this project are to understand the role of virus-specific immunity in the pathogenesis of HIV-1 infection. The major hypothesis to be tested is that strong virus specific cytotoxic T lymphocyte (CTL)responses are important for limiting viral replication and disease progression. Our studies will focus on a cohort of 144 individuals with hemophilia, followed since 1983, 85% of whom have been infected with HIV-1. In this cohort we have identified HIV-1 infected long term non-progressors (LTNP), slow progressors and progressors. Currently, in 1997, 72 individuals remain alive and continue to be followed in the cohort. Immunological and virological studies will be carried out on repository samples of sequential plasma and peripheral blood mononuclear cells collected prospectively since 1983-84 when the project began. We propose to perform the following during the next grant period: (1) a targeted analysis of Gag- and Nef- specific CTL activity as it relates to disease progression, (2) an evaluation of CTL reactivity to epitopes in Nef in individuals with non-progressive infection, (3) an analysis of Nef- specific reactivity in relation to the allelic variation of viral Nef over time in these long term non-progressors, (4) a characterization of the breadth of CTL activity as it relates to disease progression, and (5) Finally, to develop CTL assays which utilize target cells and viral isolates more relevant to in vivo infected cells. These studies should further our understanding of HIV-1 specific cell-mediated immunity and provide new information which will be useful in the development of an effective vaccine for the prevention of HIV-1 infection.