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

> **NIH NIH R01** · EMORY UNIVERSITY · 2023 · $745,702

## Abstract

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.

## Key facts

- **NIH application ID:** 10670393
- **Project number:** 5R01HL166004-02
- **Recipient organization:** EMORY UNIVERSITY
- **Principal Investigator:** Christina Gavegnano
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2023
- **Award amount:** $745,702
- **Award type:** 5
- **Project period:** 2022-07-22 → 2026-06-30

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10670393

## Citation

> US National Institutes of Health, RePORTER application 10670393, Elucidating the role of the gut reservoir and inflammation in driving cardiovascular disease among persons living with HIV (5R01HL166004-02). Retrieved via AI Analytics 2026-05-26 from https://api.ai-analytics.org/grant/nih/10670393. Licensed CC0.

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