%0 Journal Article
%T HIV latency is reversed by ACSS2-driven histone crotonylation
%A David M. Margolis
%A Dennis J. Hartigan-O¡¯Connor
%A Don Nguyen
%A Gema M¨¦ndez-Lagares
%A George R. Thompson III
%A Guochun Jiang
%A Joseph K. Wong
%A Maher M. Elsheikh
%A Nancie M. Archin
%A Satya Dekar
%A Steven A. Yukl
%A Yuyang Tang
%J The Journal of Clinical Investigation
%D 2018
%R 10.1172/JCI98071
%X 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¨Cproducing 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¨Cinduced 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¨Cinduced 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
%U https://www.jci.org/articles/view/98071