# The role of extracellular vesicle-associated MicroRNAs in HIV-associated atherosclerosis

> **NIH NIH R01** · UNIVERSITY OF MIAMI SCHOOL OF MEDICINE · 2024 · $383,750

## Abstract

People living with HIV (PLWH) have a significantly higher risk of cardiovascular diseases (CVD) compared
to their HIV negative counterparts. However, the underlying mechanisms that drive this increased CVD risk
remain elusive. Extracellular vesicles (EVs)/exosomes are released by all cells and widely distributed in
plasma, urine, and other biological fluids. EVs contain diverse bioactive molecules, including mRNAs,
microRNAs (miRs), proteins, and lipids, which can be transferred to target cells altering their functionality.
The cargo of EVs reflects the pathophysiological states of the host cells. It is conceivable that the latent HIV
reservoir established during early infection, long-term exposure to antiretroviral therapy (ART), and chronic
immune activation/inflammation (referred to as HIV positivity for grant writing purpose) may impact host
cells, particularly those in the peripheral blood, altering the release and the cargo of plasma EVs. These EVs
in turn may serve as information vehicles for cell-to-cell communication, affecting cells of the arterial wall,
including endothelial cells (ECs) and smooth muscle cells (SMCs), as well as endothelial progenitor cells
(EPCs) in the bone marrow, promoting atherogenesis. To test this hypothesis, we fractionated plasma from
PLWH on ART with undetectable viral load into plasma EVs (HIVposEVs) and plasma-depleted of EVs
(HIVplasmadepEVs) and injected these fractions into atherogenic apoE-/- mice. Remarkably, HIVposEVs, but not
HIVplasmadepEVs, increased atherosclerosis plaque burden compared to EVs isolated from HIV negative
subjects (HIVnegEVs) and PBS. These changes were accompanied by increased senescence and apoptosis
of ECs and SMCs in the arterial wall and impaired viability and functionality of bone marrow EPCs. These
exciting data support the hypothesis that circulating EVs from PLWH reconstitute the effects of HIV positivity
(without active HIV infection) on atherosclerosis. RNA-seq in HIVposEVs and HIVnegEVs revealed differential miR
profiles. The target genes of EV-miRs overrepresented in PLWH are enriched in cardiovascular pathology
pathways. We have engineered tailored EVs (TEVs) that are loaded with the antagomirs for let-7b-5p and
miR103a-2, two candidate EV-miRs overrepresented in HIVposEVs by transducing mesenchymal stromal cells.
These TEVs counteracted the effects of HIVposEVs on the accelerated senescence of EPCs, whereas let-7b-
5p overexpressing EVs recapitulated, in part, the effects of HIVposEVs. Furthermore, EPCs overexpressing
HMGA2 (a top let-7b-5p target gene) lacking the 3'UTR (resistant to miR regulation) showed protection
similar to miRZip-let-7b TEVs against HIVposEVs-induced senescence. In this proposal, we will determine if
TEVs engineered to modulate key HIVposEVs-associated miRs counteract the effects of the chronic
inflammation and immune activation, ART, and latent HIV reservoir associated with HIV positivity on
atherosclerosis development. In addition, we will fu...

## Key facts

- **NIH application ID:** 10757745
- **Project number:** 5R01HL162579-02
- **Recipient organization:** UNIVERSITY OF MIAMI SCHOOL OF MEDICINE
- **Principal Investigator:** CHUNMING DONG
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2024
- **Award amount:** $383,750
- **Award type:** 5
- **Project period:** 2023-01-01 → 2027-12-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10757745

## Citation

> US National Institutes of Health, RePORTER application 10757745, The role of extracellular vesicle-associated MicroRNAs in HIV-associated atherosclerosis (5R01HL162579-02). Retrieved via AI Analytics 2026-05-24 from https://api.ai-analytics.org/grant/nih/10757745. Licensed CC0.

---

*[NIH grants dataset](/datasets/nih-grants) · CC0 1.0*