Work

S20-1Alcohol interaction with HIV disease pathogenesis; translational approach to understanding mechanisms & comorbidities

Year: 2017

Type: article

Abstract: Chronic alcohol misuse has had a significant impact on the HIV epidemic through increased risky sexual behavior resulting from alcohol-induced cognitive and executive function impairments. With combined ART (cART), HIV infection has become a chronic disease, and alcohol use disorders (AUD) are common in persons living with HIV/AIDS (PLWHA). Increased survival resulting from cART has elevated the risk for HIV-associated comorbid conditions, including myopathy, insulin resistance, prediabetes, and lipodystrophy. We have used a longitudinal integrated physiological approach to examine how chronic binge alcohol (CBA) consumption affects disease progression, response to ART, and end organ pathophysiology in simian immunodeficiency virus (SIV) infected macaques. Our results show that CBA/SIV infected macaques have marked alcohol-induced alterations in mucosal immunity associated with increased viral infectivity and viral replication in tissue reservoirs; which in untreated macaques leads to a faster progression to end stage disease. Integration of whole body, tissue, and cell-based studies supports a working hypothesis in which chronic alcohol increases viral replication, T-cell turnover in gut mucosa, and alterations in gut microbiota that we believe contribute to gut leak of bacterial toxins. These produce chronic systemic immune activation that eventually lead to immune exhaustion and senescence and at the same time a chronic subclinical inflammation that associates with decreased growth factor/anabolic signaling and increased disease pathogenesis. Two comorbid conditions resulting from this state of chronic inflammation, oxidative stress and impaired growth factor signaling have been the focus of our studies; the first is cognitive impairment, and the second is metabolic dysregulation. CBA unmasks behavioral deficits in SIV-infected macaques and this is accompanied by an increased number of upregulated inflammatory genes and decreased growth factor signaling in the frontal cortex and basal ganglia of SIV-infected macaques. CBA-induced mechanisms underlying impaired metabolic regulation in SIV infection include increased skeletal muscle (SKM) inflammation, oxidative stress and fibrosis, decreased SKM oxidative phosphorylation capacity, and altered mitochondrial homeostasis; leading to whole body impairment in insulin response to glucose, and glucose disposal. This presentation will describe preclinical studies, salient findings and our translational approach to examining comorbid conditions in PLWHA with AUD.

Source: Alcohol and Alcoholism

DOI: 10.1093/alcalc/agx075.75