# Diastolic dysfunction in HIV infection

> **NIH NIH R56** · UNIVERSITY OF NEBRASKA MEDICAL CENTER · 2020 · $586,400

## Abstract

Abstract:
 More than 25% of middle-aged people living with HIV-1 infection (PLWH) have early onset myocardial
diseases including diastolic dysfunction (DD), harbingers for symptomatic heart failure, dyspnea, pulmonary
abnormalities, frequent hospitalizations, and sudden cardiac death.8-16 To date, the molecular causes for the
myocardial dysfunction in PLWH remain poorly understood. This paucity of information and a lack of treatment
options have prompted the OAR to list “Strategies to Prevent and Treat HIV-Associated Heart Diseases” as
areas of high priority for HIV research. We hypothesize that “early onset myocardial dysfunction in PLWH is
arising from accumulation of cytotoxic glycolysis metabolite, methylglyoxal (MG) as a result of
persistent cardiac inflammation.” This hypothesis is based on several lines of new evidence recently obtained
in our laboratories. First, HIV-1 infected humanized NOD/Scid-IL2Rg-/-(NSG) mice reconstituted with human
immune system (Hu-NSG) develop a progressive cardiomyopathy akin to that seen in patients. Second, cART
lowers plasma HIV-1 viremia but does not lower cardiac inflammation indicated by upregulation of the
inflammation-biomarker, vascular adhesion protein-1 (VAP-1). Third, the cytotoxic glycolysis by-product MG,
accumulated in hearts of HIV-1 infected Hu-NSG mice with/without cART due to inflammation-induced
downregulation of MG-degrading enzyme glyoxalase-1 (Glo1). Elevated MG form MG-H1 adduct on proteins.
Fourth, increased VAP-1 and MG-H1, and reduced Glo1 were found in autopsied ventricular tissues from HIV-1
patients, indicating clinical relevance of our findings. Fifth, administration of an engineered adeno-associated
virus that uses the promoter of an inflammation-induced protein, endothelin-1 (AAV2/9-Endo-Glo1) to express
Glo1 in hearts of Hu-NSG mice, attenuate coronary microvascular leakage, ischemia, fibrosis and myocardial
dysfunction, establishing a cause-effect relationship between MG accumulation and myocardial dysfunction. This
multi-PI project brings together the expertise of Drs. Keshore R. Bidasee (M-PI, heart failure) and Santhi Gorantla
(M-PI, humanized mice and HIV-1 infection) and build on these findings to (1) delineate the pathobiological
trajectories responsible for HIV-1 associated cardiac dysfunction in Hu-NSG mice in the absence and presence
of cART; (2) delineate molecular mechanisms responsible for elevation of cardiac inflammation in cART-treated
HIV-infected Hu-NSG mice and validate the findings in autopsied tissues from HIV-1 infected patients, and (3)
investigate whether attenuating MG accumulation in HIV-infected and cART-treated Hu-NSG mice will blunt
myocardial dysfunction. Accomplishments of these aims will not only define for the first time a novel link between
inflammation and myocardial dysfunction in the setting of HIV-1 infection, but the data could pave the way for
the development of urgently needed therapeutics to mitigate early onset myocardial dysfunction i...

## Key facts

- **NIH application ID:** 10250637
- **Project number:** 1R56HL151602-01A1
- **Recipient organization:** UNIVERSITY OF NEBRASKA MEDICAL CENTER
- **Principal Investigator:** KESHORE R BIDASEE
- **Activity code:** R56 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2020
- **Award amount:** $586,400
- **Award type:** 1
- **Project period:** 2020-09-17 → 2023-08-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10250637

## Citation

> US National Institutes of Health, RePORTER application 10250637, Diastolic dysfunction in HIV infection (1R56HL151602-01A1). Retrieved via AI Analytics 2026-06-01 from https://api.ai-analytics.org/grant/nih/10250637. Licensed CC0.

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