The histone methyltransferase SETD2 regulates HIV expression and latency

• Published in: PLoS pathogens 2024-06, Vol.20 (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: Article
• Language: English
• 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
• ISSN: 1553-7374; 1553-7366; 1553-7374
• DOI: 10.1371/journal.ppat.1012281

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.