Antiretroviral Therapy Impacts Autophagy in Astrocytes, and May Contribute to HIV Associated Neurocognitive Disorders

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Project Summary/Abstract This proposal presents a 4 year research career development program focused on the study of macroautophagy (autophagy) in the context of HIV associated neurocognitive disorders (HAND) to increase the understanding of HAND pathogenesis with the goal of identifying targets for treatment of HAND. The candidate is currently an Instructor of Infectious Diseases and of Pathology at Montefiore Medical Center/Albert Einstein College of Medicine. The proposal builds on the candidate’s previous HIV research and clinical experiences by integrating two new domains of expertise, overseen by her mentors, Dr. Berman and Dr. Cuervo. The proposed experiments and didactic work will provide Dr. Cheney with the skill sets to enable her transition to independence as a Principal Investigator at the crossroads of neuroHIV and macroautophagy. A significant number of people with HIV (PWH) develop HAND despite control of viremia with antiretroviral therapy (ART). Efforts to treat HAND are hindered by an incomplete understanding of the factors underlying its development. Data suggest that dysregulated autophagy may contribute to HAND, but much remains to be understood, specifically in astrocytes. It is essential to maintain astrocyte homeostasis because they are major support cells of the brain, performing many vital functions for the CNS. As astrocytes rely on autophagy for homeostasis, it is particularly important to understand dysregulated astrocyte autophagy as it may contribute to HAND. The foundation for this proposal is based on our published data demonstrating an inhibitory effect on autophagy in primary human astrocytes resulting from treatment with a commonly prescribed regimen of Tenofovir, Emtricitabine and Raltegravir (ART). The aims of this proposal are to: 1. Characterize ART induced changes in autophagy in human astrocytes, 2. Characterize selective autophagy in human astrocytes treated with ART, and 3. Define changes in astrocyte-specific functions as a result of ART treatment, and correlate with changes in autophagy. These aims will expand the understanding of HAND development in PWH in the ART era, with the ultimate objective of identifying therapeutic targets with which to mitigate HAND.