Chronic Binge Alcohol and SIV: Interacting Neuropathological Mechanisms

Lsu Health Sciences Center, New Orleans LA

Investigators

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Abstract

? DESCRIPTION (provided by applicant): Twice as many people living with HIV/AIDS (PLWHA) are heavy drinkers compared to the rest of the population. Both alcohol and HIV infection can damage the brain and produce cognitive deficits. However, it is not known if alcohol use by PLWHA results in greater brain damage than HIV infection alone. Neuroinflammation and loss of neurotrophic factors are potential mechanisms by which alcohol and HIV may interact to produce greater brain damage (synaptodendritic loss) than HIV alone. To investigate these mechanisms, we will utilize a non-human primate model of HIV infection, which is considered the optimal model to study HIV disease progression. We hypothesize that rhesus macaques receiving chronic binge alcohol (CBA) administration during simian immunodeficiency virus (SIV) infection will have greater neuroinflammation, suppression of neurotrophic factors, and greater synaptodendritic loss compared to SIV- infected rhesus macaques receiving isocaloric sucrose (SUC) administration. We will investigate neuroinflammation, neurotrophic factor expression, and synaptodendritic loss in the frontal cortex, striatum, and hippocampus - brain regions responsible for cognitive deficits seen in HIV-associated neurocognitive disorders. The first aim of this project is to investigate exacerbation of neuroinflammation and suppression of neurotrophic factor expression in CBA/SIV-infected macaques compared to SUC/SIV-infected macaques by gene and protein expression analysis. Aim two will determine synaptodendritic loss and neuronal apoptosis in the brains of SUC/SIV and CBA/SIV macaques by immunohistochemical and gene expression analysis. The third aim proposes to determine if anti-retroviral therapy (ART) will ameliorate neuroinflammation, neurotrophic factor suppression, and synaptodendritic loss in CBA/SIV-infected macaques. These aims will determine region-specific neuropathological changes occurring due to the interaction of CBA administration and SIV infection, and if ART ameliorates neuropathology. If successful, these findings will show neurological consequences of alcohol abuse and HIV co-morbidity, and inform treatment strategies to reduce brain damage in the large population of PLWHA using alcohol. To achieve the goal of developing the skills necessary for a career as an independent scientist, this Fellowship application will emphasize 1) development of expertise in the biomedical consequences of alcohol abuse, 2) quantitative analytical techniques such as QuantiGene Plex assay, western blotting, and immunohistochemistry, and 3) proper analyses, presentation and communication of data. The training plan consists of mentored research, formal coursework and workshops, and participation in LSUHSC Department of Physiology journal club, seminar series, and Perspectives in Alcohol Research.