# HIV-infected Macrophages Induce Endothelial Cell Dysfunction and Metabolic Reprogramming to Promote HIV-associated Pulmonary Arterial Hypertension

> **NIH NIH F30** · UNIVERSITY OF PITTSBURGH AT PITTSBURGH · 2021 · $51,036

## Abstract

Project Summary
Pulmonary arterial hypertension (PAH) is an enigmatic vascular disease characterized by pulmonary vascular
remodeling, an increased pulmonary vascular resistance, and subsequent right ventricular hypertrophy and
failure. There is an increased predisposition to PAH in HIV-infected populations, and as a historically neglected
vascular disease, the pathogenesis of HIV-induced PAH (HIV-PAH) remains largely unknown. My mentor's
laboratory has demonstrated that stiffening of the extracellular matrix induces the mechanosensitive
transcriptional co-activators YAP/TAZ, resulting in the upregulation of the microRNA (miR) cluster miR-130/301
and glutaminase (GLS1) in human pulmonary arterial endothelial cells (HPAECs). Furthermore, his lab has
demonstrated HPAEC metabolic reprogramming via a shift from oxidative phosphorylation to glycolysis in
support of neoplastic-like growth. The implications of this discovery are two-fold: increased miR-130/301
further promotes matrix remodeling, while upregulated GLS1 increases glutaminolysis—an anaplerotic reaction
that sustains proliferation. In addition, my mentor's laboratory has demonstrated that miR-21 is upregulated in
the plasma of HIV-PAH patients, and that miR-21 is linked to the miR-130/301 cluster to exert broad influence
in PAH. Of note, however, is that the YAP/TAZ-miR-130/301-GLS1 axis in GLS1 upregulation may not be the
entire mechanism by which increased metabolic demands are met, for HIV-infected cells of myeloid origin
actively secrete GLS1 into the extracellular environment, thereby increasing extracellular glutamate
concentration.
Taken together, I hypothesize that HIV-infected macrophages actively secrete both miR-21 and GLS1 to
promote vessel stiffening, glutaminolysis, and the pathogenesis of HIV-PAH.
This model will be tested by co-culturing HPAECs and human monocyte-derived macrophages (MDMs)
infected or uninfected with HIV. HPAEC dysfunction will be assessed via functional assays, and metabolic
reprogramming—that is a shift from oxidative phosphorylation to glycolysis with accompanying anaplerosis—
will be measured in both cell types for aberrations. GLS1 transmission will be assessed using lentiviral
transduction of a GLS1-tagged vector into MDMs, and upregulation of extracellular metabolites will be
analyzed using mass spectrometry. Lastly, the effects of viral characteristics will be evaluated using various
artificial strains and using MDMs isolated from HIV-positive patients. This proposal leverages unique
experimental techniques that will expand my technical repertoire, while simultaneously elucidating a novel
paradigm of HIV-PAH. The execution of the proposal in question will enhance my pre-doctoral training and
establish a niche for me as a physician-scientist in addressing the cardiopulmonary manifestations of chronic
HIV infection.

## Key facts

- **NIH application ID:** 10242753
- **Project number:** 5F30HL143879-04
- **Recipient organization:** UNIVERSITY OF PITTSBURGH AT PITTSBURGH
- **Principal Investigator:** Lloyd David Harvey
- **Activity code:** F30 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2021
- **Award amount:** $51,036
- **Award type:** 5
- **Project period:** 2018-09-01 → 2022-08-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10242753

## Citation

> US National Institutes of Health, RePORTER application 10242753, HIV-infected Macrophages Induce Endothelial Cell Dysfunction and Metabolic Reprogramming to Promote HIV-associated Pulmonary Arterial Hypertension (5F30HL143879-04). Retrieved via AI Analytics 2026-05-24 from https://api.ai-analytics.org/grant/nih/10242753. Licensed CC0.

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