In chronic alcohol-administered, SIV-infected macaques, differential brain region susceptibility to inflammatory, viral, neurotropic, and alcohol insults was associated with neurocognitive impairment. In the prefrontal cortex, suppression of growth factor signaling may be an important neuropathological mechanism, while inflammatory processes play a more important role in the caudate and hippocampus.

Objective: The present study examined interactions between simian immunodeficiency virus (SIV), chronic binge alcohol (CBA), and antiretroviral therapy (ART) on growth factor signaling, neuroinflammatory markers, viral loads (VL), and CD4 þ cell counts.Design: Adult male rhesus macaques were administered CBA (13-14 g ethanol (EtOH)/kg per week) or sucrose (SUC) 3 months prior to SIV mac251 infection until the study endpoint. At viral setpoint, a subset of CBA/SIVþ and SUC/SIVþ macaques were randomized to receive daily ART (9-[2-Phosphonyl-methoxypropyly]adenine [PMPA] 20 mg/kg, 2',3'-dideoxy-5-fluoro-3'-thiacytidine (FTC), 30 mg/kg). Frontal cortex (FC) and basal ganglia (BG) were collected for gene and protein expression.Methods: Relationships between brain and plasma VL or CD4 þ cell counts were determined using linear regression. Effects of SIV, CBA, and ART on markers of neuroinflammation and brain-derived neurotrophic factor (BDNF) signaling were determined by ANOVA and linear regression.Results: SIV increased FC and BG neuroinflammatory and glial cell gene expression (CX3CR1, B2M), and reduced FC protein kinase B phosphorylation. CBA decreased FC and BG tropomyosin receptor kinase B (TrkB) phosphorylation, and increased full-length TrkB (TrkB-FL) and SLC1A3 expression in FC and BG, respectively. ART suppressed plasma and brain VL, reduced neuroinflammatory gene expression in FC (IBA1, CX3CR1, and GFAP), and BG (CD74 and CD11ß), and did not restore FC or BG BDNF signaling deficits.Conclusions: Results show ART-mediated reduction in VL and neuroinflammatory gene expression, irrespective of CBA administration. ART did not attenuate SIV-and CBA-mediated BDNF signaling deficits, suggesting these deficits, despite effective neuroinflammation suppression, may explain CBA-and SIV-associated neurocognitive deficits. Therapeutics targeting growth factor signaling may be important adjuvants in treating HIV-associated neurocognitive decline.

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Chronic pain affects more than half of people living with HIV (PLWH), and the current pain management strategies, such as opioids, capsaicin, and gabapentin, remain inefficient in PLWH. Moreover, the pathogenesis of HIV‐associated pain remains widely unknown, hindering implementation of evidence‐based treatments. Alcohol and pain have a bidirectional relationship, where people consume alcohol to relieve pain, and unhealthy alcohol uses leads to chronic pain. Approximately 30% of PLWH develop alcohol use disorder; therefore, it is important to understand the effects of alcohol on pain in this population. Using a relevant preclinical model of HIV‐infection, the aim of the study was to determine if chronic binge alcohol (CBA)‐administration causes hyperalgesia in SIV‐infected macaques. We hypothesized that CBA‐administration causes hyperalgesia in rhesus macaques prior to infection, and these findings will be exacerbated during peak viremia in SIV infection. Rhesus macaques, four to six years old were administered CBA or isovolumetric water (VEH) through an intragastric catheter for 30 minutes, five days a week, with blood alcohol concentrations reaching 50–60 mM. Three months after the start of CBA administration, macaques were inoculated with SIVMac251 and 2.5 months later initiated on antiretroviral therapy. To assess thermal hyperalgesia, tail withdrawal test was used. Conscious macaques were restrained in chairs and their tails are placed in water baths at 40, 50, and 55C, and the latency to remove their tail (in seconds) determined. The test was performed three months after the initiation of CBA administration (24 hours after a CBA administration session), and repeated 2.5 months after SIV‐infection. Molecular analysis for proteins involved in pain circuitry will be determined in the spinal cord and periaqueductal gray. Our results indicate that three months of CBA administration causes hyperalgesia in rhesus macaques. Whether SIV infection exacerbates hyperalgesia, and if the molecular measures correlates to behavioral measures warrants further investigation. These data provide mechanistic insight into how unhealthy alcohol use affects hyperalgesia in HIV infection, and will provide a scientific basis for pain management strategies in this population. Support or Funding Information NIH/NIAAA P60 AA009803 and 5T32AA007577‐19

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