Transcriptional repression of human immunodeficiency virus type 1 by AP-4
Transcriptional repression of human immunodeficiency virus type 1 by AP-4
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DOI：
10.1074/jbc.m511773200
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发表时间：
2006-05-05
影响因子：
4.8
通讯作者：
Okamoto, T
中科院分区：
文献类型：
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作者：
Imai, K;Okamoto, T
阐明潜伏感染细胞中人类免疫缺陷病毒 1 型 (HIV-1) 原病毒的转录沉默机制对于了解 HIV-1 感染的病理生理学和开发新疗法至关重要。在这里，我们证明 AP-4 负责 HIV-1 的转录抑制。我们发现，病毒长末端重复序列 (LTR) 内的 AP-4 位点在大多数 HIV-1 亚型中都非常保守，并且 AP-4 通过招募组蛋白脱乙酰酶 (HDAC) 1 以及将 TATA 结合蛋白掩蔽到 TATA 盒来抑制 HIV-1 基因表达。 AP-4 介导的转录抑制可被 HDAC 抑制剂 Tricostatin A 抑制，甚至可以在远离 TATA 盒的位置发挥作用。此外，AP-4 在体内和体外均与 HDAC1 相互作用。此外，染色质免疫沉淀分析表明，AP-4和HDAC1存在于潜伏感染的ACH2和U1细胞的HIV-1 LTR启动子中，并且在TNF-α刺激HIV-1复制时，它们从启动子上解离，同时与乙酰化组蛋白H3、TBP和RNA聚合酶II结合。此外，当 AP-4 被 siRNA 敲低时，在用全长 HIV-1 克隆转染的细胞中，HIV-1 的产生大大增加。这些结果表明，AP-4 可能负责潜伏的 HIV-1 原病毒的转录静止，并为传统抗 HIV 药物与 HDAC 抑制剂联合治疗在加速病毒感染者体内清除 HIV-1 方面的功效提供了分子基础。
Elucidation of the mechanism of transcriptional silencing of human immunodeficiency virus type 1 (HIV-1) provirus in latently infected cells is crucial to understand the pathophysiology of HIV-1 infection and to develop novel therapies. Here we demonstrate that AP-4 is responsible for the transcriptional repression of HIV-1. We found that AP-4 site within the viral long terminal repeat (LTR) is well conserved in the majority of HIV-1 subtypes and that AP-4 represses HIV-1 gene expression by recruiting histone deacetylase ( HDAC) 1 as well as by masking TATA-binding protein to TATA box. AP-4-mediated transcriptional repression was inhibited by an HDAC inhibitor, tricostatin A, and could be exerted even at distant locations from the TATA box. In addition, AP-4 interacted with HDAC1 both in vivo and in vitro. Moreover, chromatin immuno-precipitation assays have revealed that AP-4 and HDAC1 are present in the HIV-1 LTR promoter in latently infected ACH2 and U1 cells, and they are dissociated from the promoter concomitantly with the association of acetylated histone H3, TBP, and RNA polymerase II upon TNF-alpha stimulation of HIV-1 replication. Furthermore, when AP-4 is knocked down by siRNA, HIV-1 production was greatly augmented in cells transfected with a full-length HIV-1 clone. These results suggest that AP-4 may be responsible for transcriptional quiescence of latent HIV-1 provirus and give a molecular basis to the reported efficacy of combination therapy of conventional anti-HIV drugs with an HDAC inhibitor in accelerating the clearance of HIV-1 from individuals infected with the virus.