Chronic Binge Alcohol Administration Dysregulates Expression of Hippocampal Genes Involved in Immune Function, Neurotransmission and Neurogenesis in Simian Immunodeficiency Virus-Infected Macaques

HIV-associated neurocognitive disorder is prevalent despite wide-spread use of effective anti-retroviral therapy (ART). Alcohol use disorders (AUDs) exacerbate neurocognitive dysfunction in HIV+ patients. Previously we have shown that chronic binge alcohol administration (CBA, 13 – 14 g EtOH/kg/wk) starting 3 months prior to simian immunodeficiency virus (SIV) infection in rhesus macaques unmasks behavioral deficits. The underlying mechanisms of neurocognitive alterations due to alcohol and SIV are not known. The aim of this study was to explore the alterations in hippocampal gene expression of CBA administered, SIV-infected (CBA/SIV+; N=2) macaques and isocaloric sucrose administered, SIV-infected (SUC/SIV+; N=2) macaques in contrast to uninfected (SIV-; N=2) macaques. Transcriptomes of hippocampal samples dissected from brains obtained at necropsy (16 months post-SIV inoculation) were analyzed using Illumina Custom algorithm to determine differentially expressed genes (p-value filter of ≤ 0.05; either ≥ 1.3 fold change or ≤ 0.76 fold change) between SUC/SIV+ and SIV-, CBA/SIV+ and SIV-, and CBA/SIV+ and SUC/SIV+. We used Gene Codis to determine enrichment of specific Gene Ontology Biological Processes from both the SUC/SIV+ and CBA/SIV+ gene lists. Gene Codis analysis revealed over-representation of genes involved in neurodevelopment, neurotransmission, interferon-signaling, and antigen presentation in the CBA/SIV+ group. Further analysis of differentially expressed genes between SIV- and CBA/SIV+ showed predominantly up-regulation of immune function genes and down-regulation of nervous system development and synaptic transmission genes in CBA/SIV+ animals. These findings provide insight into the potential mechanisms by which CBA may enhance neurobehavioral deficits. Rhesus macaques from three experimental groups; SIV- (N=2), sucrose SIV infected (SUC/SIV+; N=2), and CBA SIV infected (CBA/SIV+; N=2) were used in the study. Animals were 4-6 years of age at the beginning of the study. Following three months of CBA administration, animals were inoculated intravenously with 10,000 times the ID50 of SIVmac251, which was provided by Preston Marx (TNPRC). Alcohol or sucrose administration continued throughout the study. Sixteen months post-SIV inoculation animals were euthanized. Hippocampal RNA from necropsy time point was used in the study.