This application proposes the creation of a """"""""National Cooperative Drug Discovery Group for the Treatment of HIV infection"""""""" (NCDDG-HIV) under the direction of Dr. Leon G. Epstein at the University of Rochester. The overall goal of the proposed NCDG-HIV is to elucidate t he critical mechanisms involved in HIV-1-induced oxidative stress (in neurons) and NFkB activation (in microglia and brain endothelial cells) in order to identify potential therapeutic targets and compounds that impact on these processes. Based on data from their laboratories, the investigators propose that HIV-1-infected macrophages and immune activated microglia release proinflammatory substances including tumor necrosis factor (TNF- alpha), platelet activating factor (PAF), arachidonic acid (AA), and toxic viral products (gp120, Tat) which in turn cause both (1) oxidative stress in neurons, resulting in dendritic damage and, ultimately, death by apoptosis and (2) persistent activation of the cellular transcription factor NFkB. The investigators goal is to identify compounds that share the properties of blocking NFkB activation, inhibiting HIV-1 replication in microglia, blocking the release of neurotoxic products from HIV-1- infected and immune-activated microglia, and protecting neurons from death via oxidative stress leading to apoptosis.
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