Inhibition of HIV-Induced Apoptosis by Host Target Genes

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DESCRIPTION (provided by applicant): Ground-breaking research in basic biology has led to an understanding of some of the pathogenic mechanisms of HIV-1 infection. Surprisingly, an unanswered question remains the mechanism(s) by which HIV-1 kills T-cells. We hypothesize that productive infection does not kill all infected cells. Furthermore, we hypothesize that HIV-1 and host cellular targets are both actively involved in regulation of apoptosis during HIV-1 infection. The goal of the proposed investigation is to identify differential gene expression in apoptotic and non-apoptotic HIV-1 infected cells, and to identify and characterize novel or unstudied host cell-specific targets that inhibit apoptosis in infected cells. In preliminary studies, we have identified a set of candidate gene products associated with survival of HIV-1 infected T-cells. The expression level of candidate genes (for example, our novel gene, HALP) will be examined in cells infected with various HIV-1 strains and primary isolates. The role of candidate genes will be evaluated by establishing stable cell lines, or by transducing HIV-infected cells using plasmid or retroviral expression vectors. Transductants expressing HALP or other candidate genes will be evaluated for viability, in the face of productive HIV-1 infection. We hypothesize that constitutive or inducible expression of HALP inhibits apoptosis of HIV-infected T-cells, via the hypoxia-inducible factor-1 (HIF-1) and regulation of reactive oxygen species (ROS). Future goals will include in-depth definition of candidate gene function and development of drugs targeting infected cell viability. It is anticipated that these studies will yield new insights into the pathogenesis of AIDS, identify potential cellular targets that regulate HIV-1 infection, and suggest novel therapeutic approaches for treatment of HIV-infected individuals.