# Histone decrotonylation uniquely regulates HIV latency

> **NIH NIH R01** · UNIV OF NORTH CAROLINA CHAPEL HILL · 2024 · $747,553

## Abstract

The latent infection of human immunodeficiency type 1 virus (HIV) is the major hurdle to the eradication of HIV.
A better understanding of the molecular basis of HIV latency is essential for the development of proper strategies
to attack such stable HIV reservoirs. HIV latency is largely controlled by epigenetic regulations surrounding the
chromatin proximal to the HIV promoter, i.e. HIV long terminal repeats (LTR). However, our understanding of
epigenetic regulation of HIV transcription remains incomplete. This is evidenced by the fact that an effective
reduction of HIV reservoirs has not been achieved in people with HIV (PWH) by the inhibition of histone
deacetylase alone or in combination with other latency reversal reagents.
We recently found that HIV transcription 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.
Crotonylation induction also enhanced latency reversal elicited by the activation of NF-κB signaling pathway.
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, which
are independent of histone acetylation. Furthermore, unlike the inhibitory role of acetylation reader BRD4 in HIV
transcription, the crotonylation reader ENL is essential for HIV latency reversal elicited by the induction of histone
crotonylation. Of interest, the opposite may also hold. For example, although crotonylation is reversed by the
same enzymes regulating deacetylation to induce latency (e.g. HDACs), decrotonylation-efficient but
deacetylation-deficient HDAC3 directly suppresses the Tat transactivation of HIV. Lastly, we discovered several
selective HDCR inhibitors (HDCRi) that prefer to induce histone crotonylation over acetylation in both T cells and
brain myeloid cells. These selective HDCR inhibitors did not dock into the deacetylation enzymatic pocket at the
HDAC3 crystal structure predicted by Google AlphaFold. Instead, they docked just outside the enzymatic pocket,
distinct from the nonspecific HDACi SAHA. Of note, one such HDCRi prevented HIV entry to latency.
The overall objective of this application is to determine the molecular mechanism of histone decrotonylation
underlying HIV latency. We hypothesize that distinct from histone deacetylation, decrotonylation plays an
important role in the establishment of HIV latency, and this can be applied to our current efforts to control HIV
latency by preventing HIV entry into latency. Our goals will be achieved through 3 specific aims, directed at the
following premises:
Aim 1: Crotonylation is distinct from acetylation to regulate HIV transcription.
Aim 2: Decrotonylation uniquely regulates HIV latency.
Aim 3: Pharmacologic modulating decrotonylation prevents the establishment of HIV latency.

## Key facts

- **NIH application ID:** 11008685
- **Project number:** 1R01AI186609-01
- **Recipient organization:** UNIV OF NORTH CAROLINA CHAPEL HILL
- **Principal Investigator:** Guochun Jiang
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2024
- **Award amount:** $747,553
- **Award type:** 1
- **Project period:** 2024-06-10 → 2029-04-30

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/11008685

## Citation

> US National Institutes of Health, RePORTER application 11008685, Histone decrotonylation uniquely regulates HIV latency (1R01AI186609-01). Retrieved via AI Analytics 2026-05-24 from https://api.ai-analytics.org/grant/nih/11008685. Licensed CC0.

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