Abstract
Alcohol use disorders (AUD) exacerbate neurocognitive dysfunction in Human Immunodeficiency Virus (HIV+) patients. We have shown that chronic binge alcohol (CBA) administration (13–14 g EtOH/kg/wk) prior to and during simian immunodeficiency virus (SIV) infection in rhesus macaques unmasks learning deficits in operant learning and memory tasks. The underlying mechanisms of neurocognitive alterations due to alcohol and SIV are not known. This exploratory study examined the CBA-induced differential expression of hippocampal genes in SIV-infected (CBA/SIV+; n = 2) macaques in contrast to those of sucrose administered, SIV-infected (SUC/SIV+; n = 2) macaques. Transcriptomes of hippocampal samples dissected from brains obtained at necropsy (16 months post-SIV inoculation) were analyzed to determine differentially expressed genes. MetaCore from Thomson Reuters revealed enrichment of genes involved in inflammation, immune responses, and neurodevelopment. Functional relevance of these alterations was examined in vitro by exposing murine neural progenitor cells (NPCs) to ethanol (EtOH) and HIV trans-activator of transcription (Tat) protein. EtOH impaired NPC differentiation as indicated by decreased βIII tubulin expression. These findings suggest a role for neuroinflammation and neurogenesis in CBA/SIV neuropathogenesis and warrant further investigation of their potential contribution to CBA-mediated neurobehavioral deficits.
Highlights
The lifetime history of alcohol use disorder (AUD) in persons living with HumanImmunodeficiency Virus/Acquired Immune Deficiency Syndrome (HIV/AIDS) (PLWHA) is 55%, compared to 12%–29% in the general population [1,2]
The cerebrospinal fluid (CSF) viral loads in both chronic binge alcohol (CBA)/simian immunodeficiency virus (SIV)+ animals were higher than the CSF viral loads from SUC/SIV+ animals (Table 1)
We examined the hippocampal gene expression profile of CBA/SIV+ macaques using microarray
Summary
The lifetime history of alcohol use disorder (AUD) in persons living with HumanImmunodeficiency Virus/Acquired Immune Deficiency Syndrome (HIV/AIDS) (PLWHA) is 55%, compared to 12%–29% in the general population [1,2]. AUD in PLWHA accelerates disease progression and contributes to comorbid pathologies, including cognitive dysfunction, termed HIV-associated neurocognitive disorder (HAND) [3,4,5]. This disorder occurs in up to 50% of PLWHA and is diagnosed when impairment is present in two or more cognitive domains (e.g., learning and memory, executive functioning, speed of information processing, motor skills, language) [6,7]. Studies from our laboratory have demonstrated that chronic binge alcohol (CBA) administration in non-antiretroviral treated, simian immunodeficiency virus (SIV)-infected macaques increases viral load at set-point, increases muscle wasting, accelerates time to end-stage disease, and unmasks cognitive impairment as determined by an operant learning and memory task [8,9,10,11,12]. These types of operant tasks are associated with hippocampal function, an area of the brain shown to be negatively affected by both alcohol and HIV [13,14,15]
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