Intranasal Tat: A Mouse Model for NeuroAIDS and Aging

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DESCRIPTION (provided by applicant): Even in the era of highly active antiretroviral therapy (HAART), individuals with HIV-1 infection continue to be at risk for developing HIV-l-associated dementia (HAD). Peripheral monocytes continue to be infected with HIV-1 on HAART and the brain continues to be a reservoir. Our laboratory utilizes an intranasal (IN) delivery system in the mouse to deliver peptides and growth factors directly to the brain. The IN delivery system provides noninvasive, rapid delivery to the central nervous system, eliminating the need for systemic delivery and thereby reducing unwanted systemic side effects. My Co-Investigator has new data to show that in vitro, HIV-1 Tat inhibits a major catabolizing enzyme, neprilysin, and increases amyloid beta (Abeta). It is our overall hypothesis that continued exposure of the brain to HIV-1 infection and its' protein Tat will cause an accelerated Abeta accumulation and to prove this, we will utilize the IN delivery of Tat to mice. Our specific aims are: 1) To deliver 1251-Tat to normal mice and establish its distribution, 2) To deliver Tat IN to normal mice and evaluate by immunohistochemistry the level of neuroinflammation and prevalence of Abeta and 3) To deliver Tat IN to APPSW mice and evaluate neuroinflammation and the prevalence of Abeta. Results from these studies could lead to a new model of NeuroAIDS and aging as well as a potential method of delivery of therapeutics to both decrease brain viral load and Abeta accumulation.