ART administration reduces neuroinflammation without restoring BDNF signaling in alcohol-administered SIV-infected macaques.

Objective This 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 counts. Design Adult male rhesus macaques were administered CBA (13-14 g EtOH/kg/week) or sucrose (SUC) three months prior to SIVmac251 infection until study endpoint. At viral setpoint, a subset of CBA/SIV+ and SUC/SIV+ macaques were randomized to receive daily ART (PMPA 20 mg/kg, 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 counts were determined using linear regression. Effects of SIV, CBA, and ART on markers of neuroinflammation and brain-derived neurotropic factor (BDNF) signaling were determined by ANOVA and linear regression. Results SIV increased FC and BG neuroinflammatory and glial cell gene expression (CX3CR1, B2 M), and reduced FC AKT phosphorylation. CBA decreased FC and BG TrkB phosphorylation, and increased 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 CD11s), 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.