Tat, NADPH Oxidase, and HIV-Dementia

HIV dementia (HIVD) is a central nervous system complication of HIV viral infection that appears in as much as one fourth of AIDS patients. As HIV infection in the brain is relatively restricted, an unresolved issue in HIV research is how the low viral load in the brain causes such pronounced neuronal dysfunction. An intriguing possibility is that the deleterious effects of HIV infection in the brain are mediated by viral proteins, and a viral protein that has been repeatedly implicated in the pathogenesis of HIVD is the regulatory protein Tat. While it is not yet clear how Tat could cause the many manifestations of HIVD, recent data from our laboratory show that Tat is able to specifically increase.NADPH oxidase-assocaited superoxide release and subsequent redox-based inflammatory signaling in glial cells, thereby driving toxic brain inflammation. Based on these data, we propose that Tat perturbs brain function by increasing both blood brain barrier breech and neuronal injury, and that these distinct pathways are mediated by a single mechanism: Tat-mediated induction of NADPH oxidase. To test this hypothesis, we have designed in vitro and in vivo studies making use of 2 novel mouse models of Tat-neurotoxicity to model HIVD. Specific aim 1 will test the hypothesis that Tat is able to significantly induce oxidative burst activity and redox-based sognaling in astrocytes and microglial cells both in vitro and in vivo. Specific aim 2 will test the hypothesis that by directly triggering oxidative burst activity, Tat causes the release of matrix metalloproteinases and thus disrupts blood brain barrier integrity in mouse models of HIVD. Specific aim 3 will build upon these studies by testing the hypothesis that by increasing oxidative burst activity and redox signaling, Tat causes the release of neurotoxic inflammatory mediators (free radicals, excitotoxins and cytokines), culminating in neuronal injury and behavioral abnormalities in mice. Completion of these studies will result in a thorough understanding of the mechanisms of Tat-mediated neurotoxicity and could highlight a novel target for therapeutic intervention in HIVD.