# Mechanisms of HIV-associated Hypertension

> **NIH NIH R01** · AUGUSTA UNIVERSITY · 2024 · $641,960

## Abstract

PROJECT SUMMARY
Over the last few decades, the advent of combination antiretroviral therapy has led to a profound suppression of
HIV replication and dramatically increased life expectancy in people with HIV (PWH). As a consequence, the
spectrum of diseases related to HIV has shifted from opportunistic AIDS-related disorders towards a premature
aging phenotype including an early onset of cardiovascular disease (CVD). CVD is now the leading cause of
death in PWH, however, the etiopathology of the accelerated development of hypertension, the leading risk
factor for CVD, has yet to be determined. Herein, we will test whether HIV derived proteins, which remain in
circulation despite cART and well-controlled viremia, contribute to the development of hypertension. We provide
novel exciting preliminary data in the Tg26 mouse model of HIV supporting a role for T cell-derived HIV proteins
and inflammation in vascular dysfunction, sympatho-activation, and hypertension. We demonstrate that
expression of HIV-derived proteins in Tg26 mice increases circulating Interleukin-1α (IL-1α), impairs
endothelium-dependent relaxation, increases sympathetic activity, and induces hypertension in male and female
mice. Remarkably, we show that transplant of bone marrow from Tg26 to wild-type (WT) mice recapitulates the
cardiovascular phenotype of intact Tg26 mice. Moreover, inhibition of T lymphocytes (T cells) activation restores
blood pressure (BP) and sympatho-activation and improves endothelial function in Tg26 mice. Conversely,
exposure of WT aortic rings to Tg26 T cells in a novel “T cells-vessel” co-culture system impairs endothelial
function and incubation with an anti-IL-1α antibody abrogates Tg26 T cell-mediated endothelial dysfunction. We
also show that endothelial dysfunction involves increased expression of the NADPH oxidase homologue Nox1
and that deficiency in Nox1 protects against Tg26-induced hypertension and endothelial dysfunction. Strikingly,
we provide very preliminary evidence of higher IL-1α transcriptional levels in CD4+ T cells from PWH and show
that aorta specimens discarded from PWH exhibit higher Nox1 expression than that from HIV- individuals. In
addition, exposure of human aorta specimen to Tg26 T cells media elevates Nox1 expression. Finally, we report
that infusion of the viral protein Tat in mice impairs endothelial function via Nox1-dependent mechanism.
Together, these exciting and novel findings inform the core hypothesis of this proposal: HIV Tat protein derived
from CD4+ T cells induces hypertension via IL-1α and Nox1 dependent mechanisms. We will test this hypothesis
in three aims. In aim 1, we will test whether HIV-associated hypertension involves CD4+ T cell-mediated, IL-1α-induced endothelial dysfunction and sympatho-activation. In aim 2 we will investigate whether IL-1α accelerates
vascular aging and promotes hypertension through Nox1 and senescence-mediated endothelial dysfunction,
while aim 3 will test the hypothesis that HIV-deri...

## Key facts

- **NIH application ID:** 10945172
- **Project number:** 1R01HL175471-01
- **Recipient organization:** AUGUSTA UNIVERSITY
- **Principal Investigator:** Eric J Belin de Chantemele
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2024
- **Award amount:** $641,960
- **Award type:** 1
- **Project period:** 2024-09-01 → 2028-08-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10945172

## Citation

> US National Institutes of Health, RePORTER application 10945172, Mechanisms of HIV-associated Hypertension (1R01HL175471-01). Retrieved via AI Analytics 2026-05-25 from https://api.ai-analytics.org/grant/nih/10945172. Licensed CC0.

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