Alcohol, Gut derived inflammation, Disturbed Tryptophan Metabolism and CVD risk in People With HIV (GUT CVD HIV)

Vanderbilt University Medical Center, Nashville TN

Investigators

Abstract

People living with HIV (PWH) have elevated risks of cardiovascular disease (CVD) ranging from myocardial infarction to heart failure. Heavy alcohol use is a significant cardiovascular risk factor and is common among PWH. Since, heavy alcohol drinking and HIV-1 infection are independently associated with the increased risk of CVD, their interactive effects are likely to compound the risk and development of CVD. Indeed, work done by our group has documented that heavy alcohol use is associated with higher CVD and total mortality rates in PWH. However, there is limited understanding of the impact of interactive effects of heavy alcohol drinking and HIV-1 infection on the development of CVD risk in PWH. Our preliminary data and current evidence suggest that the gut derived inflammation and immune activation fuels the abnormal immunometabolism of Tryptophan (TRP) leading to increased TRP catabolism and the resultant biogenesis of inflammatory Kynurenine (KYN) pathway metabolites. These abnormal changes in TRP catabolism have been implicated in the pathophysiological process of CVD. Importantly, work done by our group and others have documented abnormal TRP catabolism in HIV infection and disease progression in PWH; however, its relationship with CVD risk and CVD incidence, particularly in the context of heavy alcohol use, remains largely unexplored. In relevance to the present studies, our preliminary data demonstrates that abnormal increase in KYN/TRP ratio is directly associated with a higher proportion of CD4+ senescent T cells that play a pathogenic role in the vascular inflammation in atherosclerotic diseases. Thus, our main hypothesis is that the interactive effects of alcohol and HIV-1 infection augment TRP catabolism with resultant increase in the biosynthesis of inflammatory KYN and KYN/TRP ratio that in turn significantly leads to the increase in CD4+ senescent T cells, vascular inflammation, and exacerbation of CVD in PWH. To test this hypothesis, the proposed study leverages two existing and extremely well-phenotyped cohorts from NIAAA funded studies on PWH with a history of heavy alcohol use - 1) Veterans Aging Cohort Study (VACS) Biomarker Cohort and 2) Microbiome, Metabolites, and Alcohol in HIV to reduce CVD Randomized Clinical Trial (META HIV CVD RCT) (P01AA029542 – Frieberg, Barve - MPI) with the following specific aims: Aim 1: Determine if the dysregulation of Tryptophan (TRP) catabolism and generation of inflammatory Kynurenine (KYN) pathway metabolites is associated with alcohol consumption and CVD in PWH. Aim 2: Determine the effect of abnormal Tryptophan (TRP) catabolism, increased Kynurenine (KYN) levels and KYN/TRP ratio on CD4+T cell subset distribution and induction of senescent T cells associated with CVD in PWH with a history of heavy alcohol use. Aim3: Assess the impact of probiotic administration on increased Tryptophan (TRP) catabolism and aberrant induction of senescent T cells associated with CVD in PWH with a history of heavy alcohol use.