Elucidating the role of the gut reservoir and inflammation in driving cardiovascular disease among persons living with HIV

PROJECT SUMMARY/ABSTRACT Cardiovascular disease (CVD) accounts for significant morbidity and mortality among persons living with HIV (PWH) on antiretroviral therapy (ART). Compared to HIV-seronegative individuals, PWH experience higher risk of acute myocardial infarction, sudden cardiac death, and progression of subclinical carotid atherosclerosis. Chronic inflammation plays a crucial role in increased CVD risk among PWH, as indicated by elevated soluble and cellular biomarkers of inflammation, endothelial dysfunction, and hypercoagulation. A major contributor to this inflammation is the minimal restoration of CD4+ T cells in gut lamina propria and disturbed CD4+ T cell homeostasis which results in immune dysregulation, compromised gut barrier integrity, and microbial translocation. We showed that rectal tissue HIV RNA persists after 12 weeks of ART despite sustained undetectable plasma viral loads and that this residual virus was replication-competent. Additionally, rectal HIV RNA was associated with increased biomarkers of systemic inflammation, including TNF-𝛂, D- Dimer, and interleukin-6. Using an integrated multi-OMICS approach including transcriptomal profiling, metabolomics, pathogen sequencing, and high-density cytokine profiling and flow cytometry, we recently identified cellular and molecular pathways that regulate immune reconstitution and HIV persistence in two independent cohorts of ART-treated PWH. Using a similar multi-OMICs approach and complementary expertise in HIV reservoirs and comorbidities, basic virology/immunology, and cardiovascular clinical/translational research, we propose to define how rectal HIV persistence promotes mucosal immune dysregulation and bacterial translocation to drive inflammation and subclinical cardiovascular disease, providing a framework to identify new therapeutic targets. Three aims are proposed: 1) Assess association between markers of rectal tissue persistence and systemic inflammation and immune activation; 2) Assess association between markers of rectal tissue persistence and prevalence/progression of subclinical CVD; and 3) Define mechanisms by which HIV rectal persistence promotes mucosal immune dysregulation, bacterial translocation, and systemic inflammation to increase CVD risk. To accomplish this, virally-suppressed PWH on ART (n=100) recruited from the Atlanta MACS/WIHS Combined Cohort Study and Emory CFAR clinical sites will undergo longitudinal cardiovascular imaging, vascular function assessments, and paired sampling of blood and rectal tissue to measure: 1) viral persistence; 2) systemic inflammation/immune activation; 3) gut gene signatures; and 4) circulating microbiome and metabolome. This study will elucidate how the gut reservoir promotes mucosal immune dysregulation, bacterial translocation, and systemic inflammation leading to comorbid CVD so that preventative and/or therapeutic intervention targets can be identified.