# Targeting early instigators of vascular inflammation to prevent and/or delay vascular aging in chronic treated HIV

> **NIH NIH R01** · UT SOUTHWESTERN MEDICAL CENTER · 2022 · $335,399

## Abstract

PROJECT SUMMARY ABSTRACT
Increased comorbidities associated with aging such as atherosclerotic cardiovascular disease (CVD) is an
emerging problem in HIV-1 infection despite potent antiretroviral therapy (ART). The SARS-CoV-2 pandemic
emphasizes the urgent need to determine pathways that can be targeted by novel treatments. High-density
lipoproteins (HDLs) are the most powerful negative predictors of CVD. Apolipoprotein A-I (apoA-I), the major
protein of HDL, is responsible for the much of the anti-inflammatory properties of HDL. These effects can be
mimicked by apoA-I peptides such as 4F that are promising therapy for CVD and have antiviral properties. Our
goal is to examine whether statins have additive effects with apoA-I mimetics to attenuate key instigators of
early vascular aging and lung tissue dysfunction in chronic treated HIV-1 infection and SARS-CoV-2 infection.
In the setting of the main award, we will isolate monocytes (Aim 1), gut tissue explants (Aim 2) and endothelial
cells (ECs) (Aim 3) from middle aged(MA)/older (O) (40-70 years old) HIV-infected ART-treated patients with
suppressed viremia and subclinical CVD who receive (Group A) or not (Group B) statins. We will determine
self-amplifying molecular pathways that involve the crosstalk between bioactive lipids, macrophages, epithelial
and EC isolated from group A versus group B. In sub-aim 2 of each Aim we will expose (or not) in vitro blood
monocytes, enterocytes, gut M/M, gut and whole blood ECs to physiologically relevant 4F concentrations in the
setting of ex vivo assays of proatherogenic cellular dysfunction. In each aim, we will also include blocking ex
vivo experiments and an exploratory approach to elucidate novel mechanisms of HIV-1 related CVD.
In the setting of the Supplement award, in Aim 1 of this proposal and using an air-liquid interface (ALI) culture
of primary airway epithelial cells, and cell lines in combination with viral and immune assays, we will determine
the mechanisms how the combination of 4F with atorvastatin attenuates aberrant activation of proinflammatory
pathways as a novel mechanism that drives viral replication and associated inflammatory responses in SARS-
CoV-2 infected lung cells. Given that vascular dysfunction is a possible mechanism of chronic post-infectious
sequalae of COVID-19, in Aim 2 of this proposal and using an established ex vivo model of vascular
dysfunction and immune cells from COVID-19 patients, we will determine whether 4F and atorvastatin
attenuate aberrant activation of the proinflammatory pathway in macrophages from COVID-19 patients that
interact ex vivo with endothelial cells to drive proinflammatory proatherogenic responses.
Our independent aims will complement each other and will advance the use of the combination of apoA-I
mimetic peptides and statins as novel therapy for HIV and COVID-19. This work is innovative, interdisciplinary,
public health-oriented, and directly addresses the goals of this funding opportunity.

## Key facts

- **NIH application ID:** 11000727
- **Project number:** 7R01AG059502-06
- **Recipient organization:** UT SOUTHWESTERN MEDICAL CENTER
- **Principal Investigator:** Theodoros Kelesidis
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2022
- **Award amount:** $335,399
- **Award type:** 7
- **Project period:** 2018-09-30 → 2025-05-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/11000727

## Citation

> US National Institutes of Health, RePORTER application 11000727, Targeting early instigators of vascular inflammation to prevent and/or delay vascular aging in chronic treated HIV (7R01AG059502-06). Retrieved via AI Analytics 2026-06-11 from https://api.ai-analytics.org/grant/nih/11000727. Licensed CC0.

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