Histone decrotonylation plays a distinct role in HIV latency

  • Sci Adv. 2026 Apr 10;12(15):eaec0149. doi: 10.1126/sciadv.aec0149.
Xiaoyi Li  1  2 ,  Dajiang Li  1  2 ,  Yuyang Tang  1  2 ,  Marie Nearing  3 ,  Benjamin Varco-Merth  4 ,  Hongjie Chen  1  2 ,  Davey Smith  5 ,  Sara Gianella  5 ,  Nancie M Archin  1  2 ,  Afam A Okoye  4 ,  Satya Dandekar  3 ,  David M Margolis  1  2  6 ,  Venkat R Chirasani  7  8 ,  Ryan H Gumpper  9 ,  Guochun Jiang  1  2  7
Affiliations
  • 1. UNC HIV Cure Center, University of North Carolina, Chapel Hill, NC 27599, USA.
  • 2. Institute of Global Health & Infectious Diseases, University of North Carolina, Chapel Hill, NC 27599, USA.
  • 3. Department of Medical Microbiology and Immunology, University of California, Davis, CA 95616, USA.
  • 4. Vaccine & Gene Therapy Institute and Oregon National Primate Research Center, Oregon Health and Science University, Beaverton, OR 97006, USA.
  • 5. Department of Medicine, University of California, San Diego, CA 92093, USA.
  • 6. Department of Microbiology and Immunology, University of North Carolina School of Medicine, University of North Carolina at Chapel Hill, Chapel Hill, NC 27516, USA.
  • 7. Department of Biochemistry and Biophysics, University of North Carolina, Chapel Hill, NC 27599, USA.
  • 8. R. L. Juliano Structural Bioinformatics Core, University of North Carolina, Chapel Hill, NC 27599, USA.
  • 9. UNC Eshelman School of Pharmacy, University of North Carolina, Chapel Hill, NC 27599, USA.
PMID: 41961925 DOI: 10.1126/sciadv.aec0149
Abstract

The role of epigenetic regulation in HIV latency remains incompletely understood. We show that histone deacetylase 3 (HDAC3) inhibits trans-activator of transcription (Tat)-mediated HIV transcription through histone decrotonylation (HDCR), independent of deacetylase activity. Chemical biology approaches identified selective HDCR inhibitors (HDCRis) that reverse HIV latency with minimal impact on Other histone acylations. Although HDAC2, HDAC3, and HDAC8 exhibit HDCR activity, genetic and chemical studies reveal that the HDCRi citarinostat is selective for HDAC3 and HDAC8. Molecular docking suggests that HDCRi binds outside the zinc-binding pocket, distinct from the classical HDAC Inhibitor vorinostat (SAHA, suberoylanilide hydroxamic acid). Key residues (arginine-265, arginine-301, glutamine-113, and aspartic acid-57) are essential for HDCR selectivity, as their mutation abolishes HDCR activity and increases histone crotonylation without altering Other acylation marks. Citarinostat increases histone crotonylation at the HIV long terminal repeat, robustly activating HIV transcription in cell lines, primary CD4+ T cells, and brain microglia from simian immunodeficiency virus-infected nonhuman primates and participants enrolled in the Last Gift rapid research autopsy cohort, highlighting HDCR as a promising therapeutic target for HIV latency.

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