# HISTONE MODIFICATIONS GUIDING HIV INTEGRATION

> **NIH NIH R21** · OHIO STATE UNIVERSITY · 2024 · $236,250

## Abstract

HISTONE MODIFICATIONS GUIDING HIV INTEGRATION
PROJECT SUMMARY / ABSTRACT
Human immunodeficiency virus (HIV-1) is the causative agent of acquired immunodeficiency syndrome (AIDS)
with ~36.7 million people currently infected worldwide. Integration of the viral genome establishes an irreversible
insertion of the proviral sequence into the host chromatin. The integrated genome ensures effective HIV gene
expression and ultimately virus production or the establishment of latency where the provirus remains dormant
for an extended time. Retroviral integration is mediated by the viral integrase (IN) protein that is bound to the
direct-repeated ends of the viral DNA genome, along with additional cellular and viral co-factors that direct
integration to host chromatin sites. The overarching goal of this proposal is to understand how viral integration
is targeted to chromatin by histone post translational modifications (PTMs), and how cellular factors that tightly
control the localization of these PTMs influence target site choice.
LEDGF/p75 is a key cellular transcription co-activator that binds to HIV-1 IN via a C-terminal integrase binding
domain (IBD). The N-terminus of LEDGF/p75 contains a PWWP domain that is expected to recognize histone
methylated lysine PTMs. Bimodal tethering of the HIV-1 integration complex (intasome) to a transcription-related
histone PTM has been proposed to account for the observed ~76% of chromosomal integrations that occur in
actively transcribed genes. LEDGF/p75 purportedly targets HIV-1 to nucleosomes containing trimethylation of
histone H3 lysine 36 residues (H3K36me3). However, H3K36me3 is most often found at the 3’ ends of
transcribed genes, whereas HIV-1 integrates more frequently toward the 5’ ends of genes.
Bioinformatic correlations of HIV-1 integration sites with histone PTMs is limited by the data available in the
Encyclopedia of DNA Elements (ENCODE) database. Notably absent from ENCODE are genomic maps of the
H3K36me2 PTM in any cell type. We performed a ChIP-Seq analysis of H3K36me2 and determined that it was
commonly found near the 5’ transcription start site of genes. Moreover, we found that HIV-1 integration sites
correlate better with the location of H3K36me2 than H3K36me3. We propose to examine the role of H3K36me2
and H3K36me3 with two Specific Aims. Aim 1 will expand the current understanding of H3K36 methylation and
its connection to HIV-1 integration efficiency and site selection in vivo. Aim 2 will probe the influence of
H3K36me2 and H3K36me3 on HIV-1 integration in vitro. Our approaches will include technologically advanced
mass spectrometry, integration site mapping, and single molecule fluorescence microscopy. The results of these
studies will clearly determine the role of H3K36me2 and H3K36me3 during HIV-1 integration.

## Key facts

- **NIH application ID:** 10906005
- **Project number:** 5R21AI174874-02
- **Recipient organization:** OHIO STATE UNIVERSITY
- **Principal Investigator:** Ross C. Larue
- **Activity code:** R21 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2024
- **Award amount:** $236,250
- **Award type:** 5
- **Project period:** 2023-08-11 → 2026-07-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10906005

## Citation

> US National Institutes of Health, RePORTER application 10906005, HISTONE MODIFICATIONS GUIDING HIV INTEGRATION (5R21AI174874-02). Retrieved via AI Analytics 2026-05-22 from https://api.ai-analytics.org/grant/nih/10906005. Licensed CC0.

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