# Novel Epigenetic Marks for HIV Latency Entry and Reversal

> **NIH NIH R21** · UNIV OF NORTH CAROLINA CHAPEL HILL · 2024 · $194,375

## Abstract

Novel Epigenetic Marks for HIV Latency Entry and Reversal
The latent HIV reservoirs in human immunodeficiency type 1 virus (HIV) infection poses a major challenge to the
eradication of HIV. A better understanding of the molecular mechanisms of HIV transcription is essential for
developing proper strategies to attack the latent HIV reservoirs. HIV transcription and latency are fundamentally
controlled by epigenetic regulations surrounding the chromatin proximal to HIV promoter. However, our
understanding of epigenetic regulation of HIV transcription is still incomplete. This is demonstrated by the fact
that an effective reduction of the HIV reservoir has not been achieved in HIV+ patients by the inhibition of histone
deacetylase alone or in combination with killing strategies.
We recently found that HIV was activated from latency when crotonylation is induced. This was associated with
enhanced histone crotonylation and acetylation, but reduced histone methylation at the HIV LTR. When histone
crotonylation is inhibited, latency reversal was blocked. Crotonylation induction greatly enhanced latency
reversal elicited by the activation of noncanonical NF-κB (ncNF-κB) signaling, which was mediated via the
enhancing induction of p100 cleavage into p52, one of the essential steps during ncNF-κB activation.
Transcription of HIV appears to be regulated by a network of crotonylation interactome which orchestrates an
efficient HIV transcription. These preliminary observations indicate that crotonylation- a novel and previously
unrecognized protein modification - is directly involved in HIV transcription. Of interest, the opposite may also
hold, and when crotonylation is reversed, HIV may be enforced into latency. Importantly, while crotonylation is
controlled by the same enzymes stimulating acetylation to activate gene transcription (e.g., p300), crotonylation
and its downstream signaling are regulated by distinct mechanisms. Similarly, although crotonylation is reversed
by the same enzymes regulating deacetylation to induce latency (e.g., HDACs), the mechanism of
decrotonylation signaling is different from deacetylation.
The overall objective of this R21 application is to determine the molecular mechanisms of crotonylation that
underlie the direct activation of HIV transcription and how the regulation of protein decrotonylation facilitates HIV
into latency. We hypothesize that, distinct from acetylation, protein crotonylation plays a direct role in
HIV transcription, and this can be applied to our current efforts to eliminate HIV latency, and perhaps to
future efforts to enforce HIV into latency. Our goals will be achieved through 2 specific aims, directed at the
following premises:
Aim 1: Crotonylation is distinct from acetylation and directly induces HIV transcription by effects on
epigenetics and signaling.
Aim 2: Decrotonylation suppresses HIV transcription to enforce HIV latency by direct effects at the HIV
LTR and on the cellular milieu, which is inde...

## Key facts

- **NIH application ID:** 10885922
- **Project number:** 5R21AI167709-02
- **Recipient organization:** UNIV OF NORTH CAROLINA CHAPEL HILL
- **Principal Investigator:** Guochun Jiang
- **Activity code:** R21 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2024
- **Award amount:** $194,375
- **Award type:** 5
- **Project period:** 2023-07-11 → 2025-06-30

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10885922

## Citation

> US National Institutes of Health, RePORTER application 10885922, Novel Epigenetic Marks for HIV Latency Entry and Reversal (5R21AI167709-02). Retrieved via AI Analytics 2026-05-24 from https://api.ai-analytics.org/grant/nih/10885922. Licensed CC0.

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