Alcohol and Metabolic Dysregulation in PWH: Mechanisms Underlying Risk for Comorbidities

LSUHSC CARC RC 2 Alcohol use, which is highly prevalent among people with HIV (PWH) is a moderating factor of risk for cardiometabolic comorbidities. Data from our New Orleans Alcohol HIV (NOAH) Study, a longitudinal study of in care PWH, and parallel studies in the chronic binge alcohol (CBA) administered non-human primates (NHP) show that alcohol increases the risk of metabolic dysregulation. Our data also show that alcohol-mediated mitochondrial bioenergetic dysfunction is an underlying mechanism of alcohol-disrupted cellular energy metabolism and tissue injury. These findings lead us to propose that interventions targeting mitochondrial bioenergetic function will help restore metabolic homeostasis and as a result decrease risk of cardiometabolic comorbidities in PWH. Previous data from the Comprehensive HIV/AIDS Alcohol Research Center (CARC) demonstrated alcohol-associated gut dysbiosis and barrier dysfunction among PWH enrolled in the NOAH Study. Additionally, preliminary data from CBA administered NHPs fed a high fat high sugar diet (a.k.a. Western Diet) show a shift in plasma metabolomic profile implicated in energy metabolism. Taken together, clinical, and preclinical data support our overall hypothesis that metabolomic profile shifts resulting from alcohol use and low diet quality together with mitochondrial bioenergetic dysregulation increase the risk for age-related cardiometabolic comorbidities among PWH. Two specific aims will test the hypotheses that 1) alcohol use in the context of a diet with low healthy eating index shifts the circulating metabolomic profile, lowering the threshold for age-related cardiometabolic comorbidities in PWH, and 2) alcohol-mediated bioenergetic dysregulation contributes to multi-organ neuro-immuno-metabolic dysfunction. Proposed studies will investigate the interaction of alcohol use and diet quality and their modifying effects on circulating metabolomic profiles. Moreover, we will test the effectiveness of metformin in improving mitochondrial bioenergetic function in skeletal muscle, liver, adipose, brain, and immune cells and ameliorating alcohol-associated tissue dysfunction. The proposed approach uses state-of-the-art techniques, combines in vivo with ex vivo studies, and leverages our established NHP model and the longitudinal NOAH cohort of in care PWH and HIV seronegative participants. The bidirectional translational studies will examine mechanisms with potential for targeted therapeutic and lifestyle interventions to alleviate alcohol-associated metabolomic and bioenergetic dysregulation and ameliorate cardiometabolic comorbidities in PWH with alcohol use.