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.

中文翻译：

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HIV潜伏期被ACSS2驱动的组蛋白巴豆酰化逆转

稳定的病毒库阻碍了HIV-1（HIV）的根除。病毒潜伏期受表观遗传调控。虽然已经描述了在HIV长末端重复序列（LTR）上组蛋白乙酰化和甲基化的影响，但我们对前病毒后生情况的了解还不完整。我们报告说，以前无法识别的HIV LTR表观遗传修饰，组蛋白巴豆酰化，是HIV潜伏期的调节器。通过提高生产巴豆酰辅酶A的酶酰基辅酶A合成酶短链家族成员2（ACSS2）的表达来诱导组蛋白巴豆酰化，从而实现了潜伏HIV的重新激活。通过增加组蛋白乙酰化和减少组蛋白甲基化，这对HIV LTR的局部染色质进行了重新编程。ACSS2的药理抑制或siRNA抑制可减少组蛋白巴豆酰化诱导的HIV复制和再激活。ACSS2诱导与蛋白激酶C激动剂（PEP005）或组蛋白脱乙酰基酶抑制剂（伏立诺他）结合在一起，在重新激活潜在HIV方面具有高度协同作用。在艾滋病病毒感染的非人灵长类动物的SIV感染模型中，在体内肠道粘膜中明显诱导了ACSS2的表达，这与脂肪酸代谢的改变有关。我们的研究将HIV / SIV感染引起的脂肪酸酶ACSS2与HIV潜伏期联系起来，并将组蛋白赖氨酸巴豆酰化确定为HIV转录的新型表观遗传调控因子，可将其作为消除HIV的靶标。ACSS2诱导与蛋白激酶C激动剂（PEP005）或组蛋白脱乙酰基酶抑制剂（伏立诺他）结合在一起，在重新激活潜在HIV方面具有高度协同作用。在艾滋病病毒感染的非人灵长类动物的SIV感染模型中，在体内肠道粘膜中明显诱导了ACSS2的表达，这与脂肪酸代谢的改变有关。我们的研究将HIV / SIV感染引起的脂肪酸酶ACSS2与HIV潜伏期联系起来，并将组蛋白赖氨酸巴豆酰化确定为HIV转录的新型表观遗传调控因子，可将其作为消除HIV的靶标。ACSS2诱导与蛋白激酶C激动剂（PEP005）或组蛋白脱乙酰基酶抑制剂（伏立诺他）结合在一起，在重新激活潜在HIV方面具有高度协同作用。在艾滋病病毒感染的非人灵长类动物的SIV感染模型中，在体内肠道粘膜中明显诱导了ACSS2的表达，这与脂肪酸代谢的改变有关。我们的研究将HIV / SIV感染引起的脂肪酸酶ACSS2与HIV潜伏期联系起来，并将组蛋白赖氨酸巴豆酰化确定为HIV转录的新型表观遗传调控因子，可将其作为消除HIV的靶标。