Expression of latent human immunodeficiency type 1 is induced by novel and selective histone deacetylase inhibitors.
Expression of latent human immunodeficiency type 1 is induced by novel and selective histone deacetylase inhibitors.
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DOI：
10.1097/qad.0b013e32832ec1dc
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发表时间：
2009-09-10
期刊：
影响因子：
--
通讯作者：
Margolis DM
中科院分区：
文献类型：
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作者：
Archin NM;Keedy KS;Espeseth A;Dang H;Hazuda DJ;Margolis DM
组蛋白脱乙酰酶 (HDAC) 家族介导染色质重塑和基因表达抑制。 HDAC 对 HIV-1 长末端重复序列 (LTR) 内的组蛋白进行去乙酰化在潜伏期的维持中发挥着关键作用，而 LTR 周围组蛋白的乙酰化则与前病毒表达和 HIV 逃离潜伏期相关。全局 HDAC 抑制可能会对宿主基因表达产生不利影响，导致细胞毒性。对 HDAC 具有选择性、维持 LTR 抑制的强效抑制剂可能是理想的抗潜伏期疗法。我们研究了选择性 HDAC 抑制剂在潜伏期细胞系模型和从抗逆转录病毒治疗 (ART) 无病毒血症患者中分离的静息 CD4+ T 细胞中去抑制 HIV-1 LTR 的能力。我们发现抑制 I 类 HDAC 会增加 LTR 处组蛋白的乙酰化，但 LTR 染色质不受 II 类 HDAC 抑制剂的影响。在潜伏感染的细胞系中，针对 I 类 HDAC 的选择性抑制剂是比针对 II 类 HDAC 的抑制剂更有效的 LTR 激活剂。 I 类 HDAC 抑制剂是无病毒血症患者静息 CD4+ T 细胞中病毒生长的极其有效的诱导剂，而 HIV 很少能从暴露于 II 类 HDAC 抑制剂的患者细胞中恢复。作为针对持续性 HIV 感染的临床策略的一部分，有必要进一步开发选择性 HDAC 抑制剂。
A family of histone deacetylases (HDACs) mediates chromatin remodeling, and repression of gene expression. Deacetylation of histones within the HIV-1 long terminal repeat (LTR) by HDACs plays a key role in the maintenance of latency, whereas acetylation of histones about the LTR is linked to proviral expression and escape of HIV from latency. Global HDAC inhibition may adversely affect host gene expression, leading to cellular toxicities. Potent inhibitors selective for HDACs that maintain LTR repression could be ideal antilatency therapeutics. We investigated the ability of selective HDAC inhibitors to de-repress the HIV-1 LTR in both a cell line model of latency and in resting CD4+ T cells isolated from patients who were aviremic on antiretroviral therapy (ART). We found that inhibition of class I HDACs increased acetylation of histones at the LTR, but that LTR chromatin was unaffected by class II HDAC inhibitors. In a latently infected cell line, inhibitors selective for class I HDACs were more efficient activators of the LTR than inhibitors that target class II HDACs. Class I HDAC inhibitors were strikingly efficient inducers of virus outgrowth from resting CD4+ T cells of aviremic patients, whereas HIV was rarely recovered from patient’s cells exposed to class II HDAC inhibitors. Further development of selective HDAC inhibitors as part of a clinical strategy to target persistent HIV infection is warranted.