# Lipid raft therapy – a novel therapeutic approach for HIV-associated cardiometabolic co-morbidities

> **NIH NIH R01** · GEORGE WASHINGTON UNIVERSITY · 2024 · $627,036

## Abstract

Abstract
HIV infection is accompanied by a number of co-morbidities, with cardio-metabolic complications being among
the most prominent. Current antiretroviral therapy (ART) controls the HIV load and reverses immunodeficiency,
but does not eliminate HIV-associated co-morbidities. The mechanisms responsible for the persistence of cardio-
metabolic co-morbidities in ART-treated HIV-infected subjects with an undetectable virus load remain unknown,
preventing the development of therapeutic treatments. Our studies identified HIV protein Nef as the main
contributor to viral effects on cholesterol metabolism and potential cardiac phenotypes. Other recent reports from
several groups demonstrated that HIV-infected cells release extracellular vesicles (EVs) containing Nef, which
were found in the plasma of ~50% of ART-treated HIV-infected individuals with undetectable viral load. We
showed that Nef-containing EVs, but not EVs produced by cells infected with Nef-deficient HIV, triggered
perturbations of cellular cholesterol metabolism in uninfected macrophages, increased abundance and changed
the properties of lipid rafts in these cells, and led to potentiation of inflammatory responses. These findings led
us to a hypothesis that changes to lipid rafts induced by Nef EVs may underlie the mechanism of cardio-
metabolic co-morbidities of HIV disease, and therefore these co-morbidities can be treated by agents blocking
or reversing the Nef-induced changes of lipid rafts. We named this treatment approach “lipid raft therapy”. In the
proposed project we will test this hypothesis by pursuing the following Specific Aims. In Aim 1, we will
characterize the effects of Nef-containing EVs on the composition and structure of the lipid rafts and will relate
these changes to functional properties. We will also determine whether treatments blocking the effect of Nef EVs
on lipid rafts can reverse the Nef-induced functional effects. In Aim 2, we will investigate the association between
Nef EVs and cardio-metabolic co-morbidities and will test lipid raft-targeting treatment approaches in vivo. We
will use apoE-/- mice transgenic for HIV or infected with murine HIV (EcoHIV) to model HIV-associated
atherosclerosis and metabolic impairment. In Aim 3, we will determine whether levels of exNef in plasma of
people living with HIV (PLWH) correlate with markers of cardio-metabolic co-morbidities, whether blood
monocytes of PLWH exhibit lipid rafts changes, and whether these changes can be reversed ex vivo by the lipid
raft therapy tested in Aims 1 and 2. Together, these studies will describe a new mechanism of HIV-associated
co-morbidities and will investigate new therapeutic treatments targeting this mechanism, thus producing both a
basic science and a translational impact on the field.

## Key facts

- **NIH application ID:** 10817675
- **Project number:** 5R01HL158305-04
- **Recipient organization:** GEORGE WASHINGTON UNIVERSITY
- **Principal Investigator:** MICHAEL Ilya BUKRINSKY
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2024
- **Award amount:** $627,036
- **Award type:** 5
- **Project period:** 2021-04-09 → 2026-03-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10817675

## Citation

> US National Institutes of Health, RePORTER application 10817675, Lipid raft therapy – a novel therapeutic approach for HIV-associated cardiometabolic co-morbidities (5R01HL158305-04). Retrieved via AI Analytics 2026-05-23 from https://api.ai-analytics.org/grant/nih/10817675. Licensed CC0.

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