Enhanced Susceptibility of the Frontal Cortex to Overlapping Effects of Alcohol, SIV, and Antiretroviral Therap

Persons living with HIV/AIDS (PLWHA) are more likely to be heavy drinkers. Alcohol consumption by PLWHA contributes to exacerbation of HIV comorbidities, including HIV-associated Neurocognitive Disorder (HAND). The mechanisms by which alcohol contributes to greater cognitive deficits in PLWHA, and their modulation by anti-retroviral therapy (ART), remain unknown. The studies presented herein utilized a non-human primate (NHP) model of chronic binge alcohol (CBA) administration and simian immunodeficiency virus (SIV) infection with and without ART to determine potential mechanisms by which these treatments may produce cognitive impairment. Exploratory studies using microarray analysis of hippocampal tissue identified inflammation and neurogenesis as likely mechanisms by which CBA contributes to cognitive deficits in SIV-infected macaques. Subsequent studies determined the relationship of inflammatory cytokine and growth factor genes microtubule-associated protein 2 (MAP2), which is inversely correlated with cognitive impairment, in brain regions associated with HAND. Growth factor genes were strongly associated with MAP2 in the frontal cortex and inflammatory cytokine genes were strongly associated with MAP2 in the basal ganglia. The relevance of these associations was verified in NHPs receiving ART. The results indicated SIV infection was associated with greater inflammatory gene expression in the basal ganglia and reduced growth factor signaling in the frontal cortex. CBA administration was associated with reduced growth factor signaling in both the frontal cortex and basal ganglia. ART reduced inflammatory gene expression in both the frontal cortex and basal ganglia, but did not ameliorate CBA-associated suppression of growth factor signaling. Taken together, these results show that the frontal cortex is most susceptible to the combined insults of CBA and SIV because of the inability of ART to ameliorate CBA- and SIV-associated suppression of growth factor signaling in the frontal cortex. These results are consistent with the increased prevalence of frontal cortex associated cognitive deficits in PLWHA in the era of widespread ART and lead to the prediction that restoration or activation of growth factor signaling may be beneficial as complementary therapy with ART in PLWHA.