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-associated superoxide release and subsequent redox-based inflammatory signaling in glial cells, thereby driving toxic brain inflammation. Based on this 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 signaling 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.
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| Gupta, Sunita; Knight, Alecia G; Losso, Boriss Y et al. (2012) Brain injury caused by HIV protease inhibitors: role of lipodystrophy and insulin resistance. Antiviral Res 95:19-29 |
| Bruce-Keller, Annadora J; Gupta, Sunita; Knight, Alecia G et al. (2011) Cognitive impairment in humanized APP×PS1 mice is linked to A?(1-42) and NOX activation. Neurobiol Dis 44:317-26 |
| Bruce-Keller, Annadora J; White, Christy L; Gupta, Sunita et al. (2010) NOX activity in brain aging: exacerbation by high fat diet. Free Radic Biol Med 49:22-30 |
| Bruce-Keller, Annadora J; Gupta, Sunita; Parrino, Taryn E et al. (2010) NOX activity is increased in mild cognitive impairment. Antioxid Redox Signal 12:1371-82 |
| Pistell, Paul J; Gupta, Sunita; Knight, Alecia G et al. (2010) Metabolic and neurologic consequences of chronic lopinavir/ritonavir administration to C57BL/6 mice. Antiviral Res 88:334-42 |
| Pistell, Paul J; Morrison, Christopher D; Gupta, Sunita et al. (2010) Cognitive impairment following high fat diet consumption is associated with brain inflammation. J Neuroimmunol 219:25-32 |
| Gupta, Sunita; Knight, Alecia G; Gupta, Shruti et al. (2010) HIV-Tat elicits microglial glutamate release: role of NAPDH oxidase and the cystine-glutamate antiporter. Neurosci Lett 485:233-6 |
| Turchan-Cholewo, Jadwiga; Dimayuga, Vanessa M; Gupta, Sunita et al. (2009) NADPH oxidase drives cytokine and neurotoxin release from microglia and macrophages in response to HIV-Tat. Antioxid Redox Signal 11:193-204 |
| Turchan-Cholewo, Jadwiga; Dimayuga, Filomena O; Gupta, Sunita et al. (2009) Morphine and HIV-Tat increase microglial-free radical production and oxidative stress: possible role in cytokine regulation. J Neurochem 108:202-15 |
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