Short chain fatty acids potently induce latent HIV-1 in T-cells by activating P-TEFb and multiple histone modifications.
Short chain fatty acids potently induce latent HIV-1 in T-cells by activating P-TEFb and multiple histone modifications.
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DOI：
10.1016/j.virol.2014.10.033
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发表时间：
2015-01-01
期刊：
影响因子：
3.7
通讯作者：
Ye, Fengchun
中科院分区：
文献类型：
--
作者：
Das, Biswajit;Dobrowolski, Curtis;Shahir, Abdel-Malek;Feng, Zhimin;Yu, Xiaolan;Sha, Jinfeng;Bissada, Nabil F.;Weinberg, Aaron;Karn, Jonathan;Ye, Fengchun
尽管进行了有效的治疗（HAART），但患有严重牙周炎的HIV患者的唾液和血浆中仍有高水平的残留病毒。来自牙周病原体的多种短链脂肪酸（SCFA）在Jurkat和原发性T细胞潜伏模型中重新激活HIV-1。SCFA不仅激活正转录延伸因子B（P-TEF B）（其是达特的必需细胞辅因子），而且还可以通过诱导组蛋白修饰来逆转染色质阻断。SCFA同时通过抑制1/2类组蛋白脱乙酰酶（HDAC）来增加组蛋白乙酰化，并通过下调3类HDAC沉默调节蛋白-1（SIRT 1）、组蛋白甲基转移酶Zeste同源物增强子2（EZH 2）和杂色抑制子3-9同源物1（SUV 39 H1）的表达来降低前病毒LTR处的抑制性组蛋白三甲基化。我们的研究结果提供了牙周病和增强的HIV-1复制之间的机制联系，并表明牙周病的治疗，或阻断SCFAs的活性，将对HIV患者有治疗益处。
HIV patients with severe periodontitis have high levels of residual virus in their saliva and plasma despite effective therapy (HAART). Multiple short chain fatty acids (SCFAs) from periodontal pathogens reactivate HIV-1 in both Jurkat and primary T-cell models of latency. SCFAs not only activate positive transcription elongation factor b (P-TEFb), which is an essential cellular cofactor for Tat, but can also reverse chromatin blocks by inducing histone modifications. SCFAs simultaneously increase histone acetylation by inhibiting class-1/2 histone deacetylases (HDACs) and decrease repressive histone tri-methylation at the proviral LTR by downregulating expression of the class-3 HDAC sirtuin-1 (SIRT1), and the histone methyltransferases enhancer of Zeste homolog 2 (EZH2) and suppressor of variegation 3–9 homolog 1 (SUV39H1). Our findings provide a mechanistic link between periodontal disease and enhanced HIV-1 replication, and suggest that treatment of periodontal disease, or blocking the activities of SCFAs, will have a therapeutic benefit for HIV patients.
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