Antiretroviral Therapy Administration Reduces Neuroinflammation Without Restoring Brain-Derived Neurotrophic Factor Signaling in Alcohol-Administered Simian Immunodeficiency Virus-Infected Macaques
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+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 SIVmac251infection until the study endpoint. At viral setpoint, a subset of CBA/SIV+ and SUC/SIV+ 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+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.
Lippincott, Williams & Wilkins
Maxi, John K.; Foret, Brittany L.; Amedee, Angela; McDaniel, Lee S.; Nelson, Steve; Simon, Liz; Edwards, Scott; and Molina, Patricia E., "Antiretroviral Therapy Administration Reduces Neuroinflammation Without Restoring Brain-Derived Neurotrophic Factor Signaling in Alcohol-Administered Simian Immunodeficiency Virus-Infected Macaques" (2021). School of Medicine Faculty Publications. 314.