Expression of Latent HIV Induced by the Potent HDAC Inhibitor Suberoylanilide Hydroxamic Acid
Expression of Latent HIV Induced by the Potent HDAC Inhibitor Suberoylanilide Hydroxamic Acid
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DOI：
10.1089/aid.2008.0191
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发表时间：
2009-02-01
影响因子：
1.5
通讯作者：
Margolis, David M.
中科院分区：
文献类型：
--
作者：
Archin, Nancie M.;Espeseth, Amy;Margolis, David M.
组蛋白去乙酰化酶（HDAC）作用于核小体结合的人类免疫缺陷病毒1型（HIV-1）启动子内的组蛋白以维持前病毒潜伏期。HDAC抑制导致启动子表达和HIV从潜伏期逃逸。我们评估了最近批准用于肿瘤学的强效抑制剂辛二酰苯胺异羟肟酸（SAHA;伏立诺他）对I类HDAC的选择性，诱导细胞系中HIV启动子表达和抗逆转录病毒治疗的病毒血症HIV感染患者的静息CD 4（+）T细胞产生病毒的能力。在J89中，一种Jurkat T细胞系感染了HIV基因组内编码增强型绿色荧光蛋白（EGFP）的单个HIV基因组，SAHA在染色质免疫沉淀（ChIP）测定中诱导HIV启动子核小体1的变化，与EGFP表达一致。在抗逆转录病毒治疗的HIV感染患者的静息CD 4（+）T细胞中，临床上可达到的SAHA暴露诱导病毒体外生长。这些结果表明，有效的，选择性HDAC抑制剂可以允许改善持续性前病毒HIV感染的靶向，并定义使用SAHA的体内研究的参数。
Histone deacetylases (HDACs) act on histones within the nucleosome-bound promoter of human immunodeficiency virus type 1 (HIV-1) to maintain proviral latency. HDAC inhibition leads to promoter expression and the escape of HIV from latency. We evaluated the ability of the potent inhibitor recently licensed for use in oncology, suberoylanilide hydroxamic acid (SAHA; Vorinostat), selective for Class I HDACs, to induce HIV promoter expression in cell lines and virus production from the resting CD4(+) T cells of antiretroviral-treated, aviremic HIV-infected patients. In J89, a Jurkat T cell line infected with a single HIV genome encoding the enhanced green fluorescence protein (EGFP) within the HIV genome, SAHA induced changes at nucleosome 1 of the HIV promoter in chromatin immunoprecipitation (ChIP) assays in concert with EGFP expression. In the resting CD4(+) T cells of antiretroviral-treated, aviremic HIV-infected patients clinically achievable exposures to SAHA induced virus outgrowth ex vivo. These results suggest that potent, selective HDAC inhibitors may allow improved targeting of persistent proviral HIV infection, and define parameters for in vivo studies using SAHA.