Lymphoid cells in the presence of HIV may be induced into apoptosis by CD4 molecular binding with HIV-derived gp120, or by interactions of Fas and TNF receptors on target cells, with corresponding Fas ligand and TNF molecules from effector cells. Another apoptotic pathway i through the generation of toxic levels of Nitric Oxide by immune cells. Therefore, the interface between HIV infection and apoptosis is a very timely, and fundamentally important topic in HIV research. While some highly cytotoxic viruses induce cell death by apoptosis, others like HIV may prevent or regulate it to maintain persistent infections in nature. The purpose of the proposed research work is to achieve in vitro restoration of apoptosis in apoptosis-resistant cells chronically infected with HIV (Jurkat-derived clone J1.1) by manipulating rel4evant cellular events involved in lethal pathways. The nature of apoptosis resistance in J1.1 cells will be studied by evaluating the kinetics of several biochemical and molecular events following apoptosis induction.
Specific aims of this work include the characterization of cellular pathways for apoptosis in sensitive and resistant cells stimulated with three different apoptosis inducers (anti-Fas, TNF and SIN-1), by sequentially evaluating their alterations in apoptosis early events (Bcl-2, caspase 8 expression) in expression of HIV-derived proteins which regulate apoptosis early events (Bcl-2, caspase 8 expression) in expression of HIV-derived proteins which regulate apoptosis (gp120m Tat, Vpr), and in apoptosis late events (expression of caspases 3, 6 and 7 and cyclin-dependent kinases and telomere length dynamics). The hypothesis that inhibition of telomerase or exogenous exposure to tat protein activated apoptosis in HIV- chronically infected cells will then be tested. The characterization of this in vitro model could provide a simple system for testing drugs that may effect apoptosis in AIDS. it would also allow the development of strategies to selectively destroy latently infected cells for a better control of HIV-infection.
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