The Fas antigen is a member of the Tumor Necrosis Factor (TNF) Receptor family that transduces signals resulting in apoptotic cell death. In HIV infection, recent data suggest that both CD4+ and CD8+ T-cells are depleted through poorly understood mechanisms involving apoptosis. A role for Fas in this process has been hypothesized. The mechanisms by which Fas induces cell death remain enigmatic. Recently, however, two intracellular proteins have been identified that interact with the cytosolic domain of Fas, including MORT-1/FADD and RIP, a kinase. Both of these proteins bind to a conserved domain in Fas that is required for induction of apoptosis (the death domain) and trigger apoptosis when over-expressed in cells. Regulation of Fas-induced apoptosis in T-cells is complex, with activated T-cells fluctuating between Fas-sensitive and Fas-resistant states. Peripheral T-cells from HIV-infected persons contain abnormally high proportions of Fas-sensitive T-cells. During attempts to understand mechanisms of Fas-signaling, the PI identified a protein tyrosine phosphatase (PTPase), which he termed Fas-Associated Phosphatase-1 (FAP-1), that binds to a negative regulatory region in the cytosolic domain of Fas and that blocks Fas-induced apoptosis. The PI now proposes to explore the expression and function of FAP-1 in T-cells from normal and HIV-infected persons. Among the specific questions that will be addressed are: (1) Does the regulation of FAP-1 expression in peripheral T-cells from normal and HIV-infected individuals correlate with sensitivity and resistance to Fas-mediated apoptosis in vitro?; (2) What effect does FAP-1 have on apoptosis in induced by anti-CD3, anti-CD4, SEB, or gp120/anti-gp120 antibodies in HIV-Tat-sensitized T cells?; and (3) How does FAP-1 modulate the biochemical Fas-initiated signal transduction events that lead to apoptosis in T-cells? These latter studies will include investigation of the functional and physical interactions of FAP-1 with the other Fas-binding proteins, MORT-1/FADD and RIP. Taken together, the results of these studies will contribute to an improved understanding of the cytotoxic mechanism by which Fas regulates apoptosis of T-cells in normalcy and HIV infection.
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