# Cell-derived extracellular vesicle mediated epigenetic silencing of HIV in the brain

> **NIH NIH R01** · GEORGE MASON UNIVERSITY · 2024 · $602,343

## Abstract

Project Summary
Extracellular vesicle mediated epigenetic silencing of HIV in the brain
Human Immunodeficiency Virus type 1 (HIV) is a lentivirus that causes a persistent viral infection and
results in the demise of immune regulatory cells. Clearance of HIV infection by the immune system is
inefficient, and integration of provirus into the genome of host cells provides a means for long-term
persistence and latency which require lifelong anti-retroviral therapy. Moreover, it is becoming apparent
that HIV-infected monocyte/macrophages represent a sanctuary for HIV-1 in central nervous system
(CNS), where they appear to contribute to HIV-associated neurological disorders (HAND). A
methodology that can specifically target and epigenetically silence HIV provirus within virus infected
microglial cells in the brain could be one means by which to develop a functional cure and possibly a
treatment for HAND. We recently developed a zinc finger epigenetic repressor that can epigenetically
silence HIV in the brain when delivered by extracellular vesicles (EVs) intravenously. We propose here
to contrast this recombinant zinc finger approach EV approach with a small hairpin RNA (shRNA) EV
approach, which is also targeted to the LTR to epigenetically silence HIV transcription. The premise of
this proposal is that cellular-derived EVs can be used to deliver novel anti-HIV zinc finger or LTR
targeted transcriptional modulating shRNAs to the brain and epigenetically silence HIV. We propose 3
aims here to test the hypothesis that cellular derived receptor targeted EVs containing anti-HIV zinc
finger and the LTR directed shRNA, both regulators of HIV transcription that utilize endogenous cellular
epigenetic silencing mechanisms (3-5, 14), can spread systemically in vivo and stably silence HIV
transcription. We will test this hypothesis here in vivo using a modular extracellular vesicle (EV) delivery
approach, whereby by neural stem cells (NSC) will be engineered such that they constitutively generate
anti-HIV EVs capable of cell directed stable epigenetic silencing of HIV. If successful the approach
outlined here may not only result in the epigenetic silencing of HIV in the brain but also help usher in a
new generation of EV-RNA therapies that can operate seamlessly with endogenous cellular
mechanisms to target epigenetic regulation of gene transcription.

## Key facts

- **NIH application ID:** 10897902
- **Project number:** 5R01MH134389-02
- **Recipient organization:** GEORGE MASON UNIVERSITY
- **Principal Investigator:** Fatah Kashanchi
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2024
- **Award amount:** $602,343
- **Award type:** 5
- **Project period:** 2023-08-02 → 2028-05-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10897902

## Citation

> US National Institutes of Health, RePORTER application 10897902, Cell-derived extracellular vesicle mediated epigenetic silencing of HIV in the brain (5R01MH134389-02). Retrieved via AI Analytics 2026-05-24 from https://api.ai-analytics.org/grant/nih/10897902. Licensed CC0.

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