Abstract The longevity of persons living with HIV (PLWH) has been prolonged with the use of antiretroviral therapy (ART). Age-related complications, especially cognitive deficits, rise as PLWH live longer. Even in the post-ART era, neurocognitive deficits remain prevalent in PLWH. HIV-associated neurocognitive disorder (HAND) and co- occurring alcohol use disorder (AUD) can exacerbate these deficits. HAND persists despite the widespread implementation of ART, and as PLWH age on ART regimens, the risk of age-related comorbidities such as Alzheimer's disease (AD) may increase. Previously, we showed that chronic binge alcohol (CBA) administration prior to and during simian immunodeficiency virus (SIV) infection in rhesus macaques unmasks learning deficits in operant learning and memory tasks. Furthermore, exploratory analysis of CBA-induced differential expression of hippocampal genes revealed a dysregulation of genes involved in inflammation, immune responses, and neurotrophic support. Various mechanisms including neuroinflammation induced by HIV proteins (e.g., Tat, gp120, Nef), excitotoxicity, oxidative stress, and exposure to ART could contribute to the deposition of beta- amyloid (Aβ) and phosphorylated-tau (p-tau) proteins associated with AD. Importantly, neuron-derived extracellular vesicles (NDEVs) from AD subjects may serve as a readily accessible AD biomarker as they contain increased levels of soluble Aβ1-42, amyloid precursor protein, and hyperphosphorylated tau. Pathogenic substances and genetic cargo packaged in NDEVs can also interact with local microglia leading to further pathophysiological changes. Alcohol increases NDEV biogenesis and increases specific subsets of microRNAs and protein content in NDEVs. This application will identify whether NDEVs derived from CBA-administered, SIV-infected animals contain protein cargo indicative of AD pathology. Our overarching hypothesis is that CBA and prolonged exposure to SIV/ART in rhesus macaques additively produce neuroadaptations and associated biomarkers that may increase the risk for AD.

Narrative Lifestyle factors in people living with HIV may increase risk for Alzheimer’s disease (AD)-associated neuropathology. SIV-infected Rhesus macaques will be used to examine the impact of chronic binge alcohol exposure on AD-associated neuropathology.