This application pertains to RFA MH-01-007, Neurocognitive, neuroimaging, and neuropsychiatric correlates of BEIV infection. HIV-associated dementia (HAD) is a common and disabling complication of IUV infection that occurs in 10-20 percent of patients with AIDS. Although HAD is associated with E[rV viral load, and inversely associated with CD4 count, the correlation is not high, and many patients with high viral loads and low CD4 counts do not become demented. Conversely, a substantial number of patients with normalized CD4 counts as a result of HAART therapy become demented. Over the last decade much experimental and clinical evidence has accumulated supporting the hypothesis that a virary driven induction of inflammatory mediators such as cytokines, chemokines, nitric oxide, and free radicals is responsible for neurodegeneration in HAD. Recent progress in the Human Genome Project has identified polymorphisms genes involved in mediating inflammatory reactions in the brain, which have been proposed on the basis of experimental observations to play a role in HAD. Our hypothesis is that inheritance of certain alleles of these polymorphic candidate genes is associated with the development of HAD. This proposal will study polymorphisms in seven candidate genes: APOE4, ILIA*2, IL-1B*2, ILIRN*2, TNF-2 A2M*2, and GSTM3*B. These polymorphisms have been chosen based on their linkage to other neurologic diseases believed to share pathophysiologic features with HAD, and a biologic plausibility of a role in neurodegeneration. Two populations of patients will be studied (1) A group of 231 patients who have died of AIDS, and were extensively characterized neuropathologically by one of the collaborators (Dr. Bums) and (2) A prospectively collected group of patients with late-stage HIV disease whose clinical, virological, and immunological profiles have been determined and tissue banked in the National NeuroAlDS Tissue Consortium (NNTC). These studies, is if successful, will provide genetic evidence for a role of specific inflammatory mediators in HAD, and may identify novel targets for therapeutic intervention.
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