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J Clin Invest. 2018 Mar 1;128(3):1190-1198. doi: 10.1172/JCI98071. Epub 2018 Feb 19.

HIV latency is reversed by ACSS2-driven histone crotonylation.

Author information

1
Department of Medical Microbiology and Immunology, UCD, Davis, California, USA.
2
Department of Medicine, University of North Carolina at Chapel Hill, Chapel Hill, North Carolina, USA.
3
Department of Medicine, UCSF, and San Francisco Veterans Affairs Medical Center, San Francisco, California, USA.

Abstract

Eradication of HIV-1 (HIV) is hindered by stable viral reservoirs. Viral latency is epigenetically regulated. While the effects of histone acetylation and methylation at the HIV long-terminal repeat (LTR) have been described, our knowledge of the proviral epigenetic landscape is incomplete. We report that a previously unrecognized epigenetic modification of the HIV LTR, histone crotonylation, is a regulator of HIV latency. Reactivation of latent HIV was achieved following the induction of histone crotonylation through increased expression of the crotonyl-CoA-producing enzyme acyl-CoA synthetase short-chain family member 2 (ACSS2). This reprogrammed the local chromatin at the HIV LTR through increased histone acetylation and reduced histone methylation. Pharmacologic inhibition or siRNA knockdown of ACSS2 diminished histone crotonylation-induced HIV replication and reactivation. ACSS2 induction was highly synergistic in combination with either a protein kinase C agonist (PEP005) or a histone deacetylase inhibitor (vorinostat) in reactivating latent HIV. In the SIV-infected nonhuman primate model of AIDS, the expression of ACSS2 was significantly induced in intestinal mucosa in vivo, which correlated with altered fatty acid metabolism. Our study links the HIV/SIV infection-induced fatty acid enzyme ACSS2 to HIV latency and identifies histone lysine crotonylation as a novel epigenetic regulator for HIV transcription that can be targeted for HIV eradication.

KEYWORDS:

AIDS/HIV; Infectious disease; Transcription

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