# Epigenetic Reprogramming in HIV-Associated Cardio-Vascular Disease

> **NIH NIH R01** · GEORGE WASHINGTON UNIVERSITY · 2021 · $777,389

## Abstract

Abstract
HIV infection is associated with increased risk for atherosclerosis and cardio-vascular disease (CVD). This risk
does not subside even when HIV load is suppressed to undetectable levels by combined anti-retroviral therapy
(cART). Reasons for persistent risk of CVD in cART-treated subjects are not fully understood. Although cART
metabolic effects may drive some of this excess risk, this cannot be the only or the main reason, since new
generation of anti-retroviral drugs have reduced metabolic side-effects, and cART-naïve HIV-infected subjects
also have increased atherosclerotic CVD risk. We, and others, have shown that some of the virus-mediated
CVD risk may involve dysregulation of high density lipoprotein structure and reverse cholesterol transport
function. Another contributing factor is persistent activation of the innate immune system, presumably due to
disruption of the gut barrier and bacterial leakage. However, it remains unclear why these factors do not
subside after HIV replication had been brought down to undetectable levels by cART. We hypothesize that
HIV-associated atherosclerosis is caused by a two-hit mechanism: HIV replication during the early, untreated
phase of infection induces innate memory in myeloid cells increasing their responsiveness to TLR ligands,
which persists after cART initiation, so that even low levels of bacterial translocation through the incompletely
recovered gut mucosa lead to persistent inflammation and CVD. This hypothesis is based on published
literature showing trained innate immunity after exposure of monocytes to fungal cell wall β-glucans, and on
our preliminary evidence that HIV Nef drives trained immunity of human monocytes. Here, we propose to test
this hypothesis using blood and endoscopic samples from an interventional trial conducted by one of the
PD/PIs of this proposal (aim 1). In this trial, an HIV-positive cohort on stable cART is randomized to placebo or
teduglutide, a glucagon-like peptide 2 (GLP-2) analog that increases the tightness of gut epithelial barrier and
reduces intestinal leakage. We will use advanced epigenomic, transcriptomic and cell biology methods applied
to monocytes from these subjects to test if activation of the innate immune memory program is associated with
arterial inflammation and coronary atherosclerotic disease, and whether GLP-2 treatment reverses trained
memory. In aim 2 we will complement the human cohort studies with experiments in mouse models to
determine specific viral and host factors driving the long lasting innate immune memory, and identify their
mechanisms of action. Proposed studies will provide mechanistic insight into causes of CVD risk in HIV-
infected subjects and will likely inform future therapeutic and preventative strategies to reduce CVD in this
population.

## Key facts

- **NIH application ID:** 10169497
- **Project number:** 5R01HL140977-04
- **Recipient organization:** GEORGE WASHINGTON UNIVERSITY
- **Principal Investigator:** MICHAEL Ilya BUKRINSKY
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2021
- **Award amount:** $777,389
- **Award type:** 5
- **Project period:** 2018-08-15 → 2023-05-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10169497

## Citation

> US National Institutes of Health, RePORTER application 10169497, Epigenetic Reprogramming in HIV-Associated Cardio-Vascular Disease (5R01HL140977-04). Retrieved via AI Analytics 2026-05-25 from https://api.ai-analytics.org/grant/nih/10169497. Licensed CC0.

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