Alcohol, Immunosenescence, & Senodynamics in People with HIV

Lsu Health Sciences Center, New Orleans LA

Investigators

Linked publications & trials

Abstract

LSUHSC CARC RC4 People with HIV (PWH) who achieve viral suppression have a near normal lifespan. However, the precocious onset of geriatric comorbidities has emerged as the new face of the HIV endemic. Alcohol use is highly prevalent in PWH and is associated with many of these comorbidities. We have reported that alcohol use over the lifespan in PWH correlates with frailty and biological age in cross-sectional analyses of participants in the New Orleans Alcohol Use in HIV (NOAH) Study. Our translational studies have focused on senescent T cells as a mechanism underlying alcohol’s impact on frailty. Senescent T cells are enriched in the CD8+CD28- population. Functionally, they are hyporesponsive to novel antigens and display a Senescence-Associated Secretory Phenotype (SASP), producing pro-inflammatory mediators that promote organ dysfunction in the context of biological aging. Important findings from RC4 regarding alcohol’s effects on T cells in PWH include: [i] Alcohol use increases the prevalence of activated senescent (CD8+CD28-CD38+) T cells; [ii] Intestinal dysbiosis mediates alcohol-induced increases in these T cells; [iii] Alcohol induces changes in intestinal and plasma metabolites; [iv] Alcohol increases glycolysis, impairs oxidative phosphorylation and mitochondrial repair, and promotes a pro-inflammatory phenotype in T cells; [v] Alcohol-linked circulating proinflammatory mediators correlate with activated senescent T cells; and [vi] Senescent T cells display alcohol-exaggerated caspase 1 activation. We hypothesize that caspase 1 activation contributes to the functional consequences of alcohol exposure on senescent CD8+ T cells. Our vision is that understanding these mechanisms will uncover therapeutic targets and inform approaches to mitigate the accelerated biological aging and frailty associated with alcohol use in PWH. Our studies will identify mechanisms contributing to alcoholassociated T cell senescence in PWH. Because our preliminary data generated in collaboration with RC2 show that metformin attenuates alcohol-induced increases in senescent T cells, we will test the senoprotective effects of metformin in the chronic-binge alcohol simian immunodeficiency virus (CBA/SIV) non-human primate (NHP) model and in the NOAH Study participants, employing a bidirectional, mechanistic translational approach. Metformin is a fundamental therapeutic for type 2 diabetes that targets multiple pathways associated with biological aging and has shown promise as a geroprotective in preclinical models. Two Specific Aims are proposed: Specific Aim 1: To identify bioenergetic mechanisms by which alcohol increases senescent CD8+ T cells; Specific Aim 2: To identify alcohol-mediated mechanisms that contribute to senescent CD8+ T cell production of pro-inflammatory mediators (SASP) in PWH. This project will provide an enhanced understanding of the mechanisms by which alcohol use promotes a senescent immunophenotype in PWH. Our data will inform novel approaches to mitigating the geriatric comorbidities in PWH that use alcohol.