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

ABSTRACT: 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.

ORGANISM(S): Homo sapiens Macaca mulatta

PROVIDER: GSE69685 | GEO | 2016/12/12

SECONDARY ACCESSION(S): PRJNA286203

REPOSITORIES: GEO

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Project description:The study describes miRNA expression in colon tissue following delta 9 tetrahydrocannabinol (Δ9-THC) administration to chronically SIV-infected rhesus macaques. To identify the underlying molecular mechanisms underlying its anti-inflammatory effects, we simultaneously profiled miRNA and mRNA expression in colon of chronically simian immunodeficiency virus (SIV)-infected rhesus macaques (RMs) administered either vehicle (VEH/SIV; n=9) or Δ9- tetrahydrocannabinol (THC; THC/SIV; n=8). Relative to controls, differentially expressed miRNAs were ~2 fold higher in VEH/SIV than THC/SIV RMs. Proinflammatory miR-130a, miR-222 and miR-29b, Lipopolysaccharide-responsive miR-146b-5p and SIV-induced miR-190b were significantly upregulated in VEH/SIV RMs. Compared to VEH/SIV RMs, 10 miRNAs were significantly upregulated in THC-SIV RMs, among which miR-204 was confirmed to directly target MMP8, an extracellular matrix-degrading collagenase that was significantly downregulated in THC/SIV RMs. Moreover, THC/SIV RMs failed to upregulate proinflammatory miR-21, miR-141 and miR-222 and alpha/beta defensins, suggesting attenuated intestinal inflammation. Further, THC/SIV RMs showed higher expression of tight junction proteins (occludin, claudin-3), anti-inflammatory MUC13, keratin-8 (stress protection), PROM1 (epithelial proliferation) and anti-HIV CCL5. Trichrome mason staining detected significant collagen deposition (fibrosis) in the paracortex and B cell follicular zones of axillary lymph nodes from all VEH/SIV but none of the THC/SIV RMs, thus demonstrating the ability of THC to prevent lymph node fibrosis, a serious irreversible consequence of HIV induced chronic inflammation. Furthermore, using flow cytometry, we showed that THC suppressed intestinal T cell proliferation/activation (Ki67/HLADR) and exhaustion (PD1) and increased the percentages of anti-inflammatory CD163+ macrophages. Finally, while THC did not affect CD4+ T cell levels, it significantly reduced CD8+ T cell percentages in blood at 150 and 180 days post SIV infection. These translational findings strongly support a role for differential miRNA/gene induction and T cell activation in THC-mediated suppression of intestinal inflammation in HIV/SIV and potentially other chronic inflammatory diseases of the intestine.

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

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