# Impact of HIV Infection on Myocardial Cell Homeostasis

> **NIH NIH R01** · UNIVERSITY OF CENTRAL FLORIDA · 2021 · $502,855

## Abstract

SUMMARY
Antiretroviral therapy (ART) has significantly reduced HIV-1/AIDS-related mortality and transformed HIV
infection into a chronic disease. Cardiomyopathy remains one of the leading causes of co-morbidity and heart
failure in HIV-1/AIDS. However, the underlying mechanism(s) of HIV-induced cardiotoxicity and heart failure
remain largely unknown. Due to a lack of HIV productive infection in cardiomyocytes, it is believed that indirect
pathways involving viral and cellular factors with toxic effects are involved in HIV-induced cardiomyopathy.
Among viral proteins, Nef, which is released by infected cells such as macrophages and T-cells and is taken
up by neighboring cells, is a possible HIV-1 toxic factor. Nef possesses several interesting capacities that
compromise multiple cellular processes including autophagy, apoptosis and viability. Our preliminary data
demonstrate that Nef protein accumulates in the cardiomyocytes of HIV-infected patients and SIV-infected
macaques even on ART, thus demonstrating the clinical relevance of studying Nef expression in
cardiomyocytes. Accordingly, our preliminary data show that exposure of cardiomyocytes to Nef causes
dysregulation of autophagy and triggers apoptosis. Mechanistically, our data indicate that Nef inhibits the
terminal step of autophagy through inhibition of Beclin 1 and Rab7 localization and function. Further, we found
that Nef dysregulates mitochondrial turnover, generation of ROS and decreases mitochondrial membrane
potential. This leads to compromised mitochondrial function causing aberrations in cellular bioenergetic
pathways. Additionally, we found that Nef reduces cellular NAD+ level, an important metabolite for cellular
function and regulates cellular autophagy. Based on these observations, we hypothesize that HIV-1 Nef protein
perturbs protein quality control (PQC) in cardiomyocytes by dysregulating autophagy and causes gradual cell
death and consequently cardiomyopathy by impacting several critical elements that control cell homeostasis.
Accordingly, our most recent results suggest that Nef induces ER-stress, as evidenced by upregulation of
several of its key regulators including GRP78. Additionally we found that ART treatment causes mitochondrial
abnormalities. In this application, we will examine our hypothesis by determining the role Nef and ART in
cardiac PQC and cellular function in primary cardiomyocytes (Aim 1). We will investigate the molecular
pathways of Nef-induced dysregulation of autophagy including the physical and functional interplay between
Nef and Beclin 1, Rab7 and several other regulatory proteins involved in PQC (Aim 2). We will assess if
stimulation of autophagy through NAD+ might offer a new pathway for suppressing Nef-induced pathology in
cardiomyocytes (Aim 3). To address these questions, we will perform our studies in vitro using primary
cardiomyocytes, validate in animal models and confirm in HIV+ clinical samples with ART. The outcome of
these studies will ...

## Key facts

- **NIH application ID:** 10169498
- **Project number:** 5R01HL141045-04
- **Recipient organization:** UNIVERSITY OF CENTRAL FLORIDA
- **Principal Investigator:** Manish Kumar Gupta
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2021
- **Award amount:** $502,855
- **Award type:** 5
- **Project period:** 2018-08-01 → 2024-05-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10169498

## Citation

> US National Institutes of Health, RePORTER application 10169498, Impact of HIV Infection on Myocardial Cell Homeostasis (5R01HL141045-04). Retrieved via AI Analytics 2026-05-22 from https://api.ai-analytics.org/grant/nih/10169498. Licensed CC0.

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