The histone methyltransferase SETD2 regulates HIV expression and latency

Understanding the mechanisms that drive HIV expression and latency is a key goal for achieving an HIV cure. Here we investigate the role of the SETD2 histone methyltransferase, which deposits H3K36 trimethylation (H3K36me3), in HIV infection. We show that prevention of H3K36me3 by a potent and selec...

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Published in:	PLoS pathogens Vol. 20; no. 6; p. e1012281
Main Authors:	Bussey-Sutton, Cameron R, Ward, Airlie, Fox, Joshua A, Turner, Anne-Marie W, Peterson, Jackson J, Emery, Ann, Longoria, Arturo R, Gomez-Martinez, Ismael, Jones, Corbin, Hepperla, Austin, Margolis, David M, Strahl, Brian D, Browne, Edward P
Format:	Journal Article
Language:	English
Published:	United States Public Library of Science 01-06-2024 Public Library of Science (PLoS)
Subjects:	Acquired immune deficiency syndrome AIDS Biology and Life Sciences Care and treatment CD4 antigen CD4-Positive T-Lymphocytes - metabolism CD4-Positive T-Lymphocytes - virology Chromatin Cloning CRISPR Development and progression Enzymes Flow cytometry Gene expression Gene Expression Regulation, Viral Genetic aspects Histone deacetylase Histone methyltransferase Histone-Lysine N-Methyltransferase - genetics Histone-Lysine N-Methyltransferase - metabolism Histones HIV HIV infection HIV Infections - genetics HIV Infections - metabolism HIV Infections - virology HIV-1 - genetics HIV-1 - physiology Human immunodeficiency virus Humans Infections Infectious diseases Inhibitors Integration Latency Latent infection Lymphocytes Lymphocytes T Medicine and Health Sciences Methylation Methyltransferases Polycomb group proteins Post-transcription Proteins Research and Analysis Methods Ribonucleic acid RNA RNA polymerase Transcriptomics Virus latency Virus Latency - physiology Virus research United States
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Summary:	Understanding the mechanisms that drive HIV expression and latency is a key goal for achieving an HIV cure. Here we investigate the role of the SETD2 histone methyltransferase, which deposits H3K36 trimethylation (H3K36me3), in HIV infection. We show that prevention of H3K36me3 by a potent and selective inhibitor of SETD2 (EPZ-719) leads to reduced post-integration viral gene expression and accelerated emergence of latently infected cells. CRISPR/Cas9-mediated knockout of SETD2 in primary CD4 T cells confirmed the role of SETD2 in HIV expression. Transcriptomic profiling of EPZ-719-exposed HIV-infected cells identified numerous pathways impacted by EPZ-719. Notably, depletion of H3K36me3 prior to infection did not prevent HIV integration but resulted in a shift of integration sites from highly transcribed genes to quiescent chromatin regions and to polycomb repressed regions. We also observed that SETD2 inhibition did not apparently affect HIV RNA levels, indicating a post-transcriptional mechanism affecting HIV expression. Viral RNA splicing was modestly reduced in the presence of EPZ-719. Intriguingly, EPZ-719 exposure enhanced responsiveness of latent HIV to the HDAC inhibitor vorinostat, suggesting that H3K36me3 can contribute to a repressive chromatin state at the HIV locus. These results identify SETD2 and H3K36me3 as novel regulators of HIV integration, expression and latency.
Bibliography:	new_version ObjectType-Article-1 SourceType-Scholarly Journals-1 ObjectType-Feature-2 content type line 23 BDS is a co-founder and BOD member of EpiCypher and received financial compensation from this company.
ISSN:	1553-7374 1553-7366 1553-7374
DOI:	10.1371/journal.ppat.1012281