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(1)反式激活蛋白(Tat)是病毒复制的重要因子,正性转录延伸因子b(P-TEFb)是Tat反式激活HIV-1转录所必需的特异性宿主细胞因子,其活性与HIV-1的转录密切相关。(2)在细胞内,无活性7SK snRNP复合体是功能性有活性P-TEFb的贮存和来源。在特定条件下,7SK snRNP复合体发生解离并释放出P-TEFb,从而刺激转录延伸。可以说,P-TEFb的活性受到严格的调控,维持着一种动态的平衡。(3)同时,P-TEFb还存在于一个具有超高转录活性的超级延伸复合体(SEC)中。Tat能将含有两个延伸因子P-TEFb和ELL2的SEC复合体募集至HIV-1长末端结构域(LTR),然后众多因子协同作用有效地增强HIV-1的转录作用。(4)溴区包含蛋白4(Brd4)像Tat一样,将P-TEFb募集至众多细胞基因的启动子区域,促进转录。Brd4也可激活基础水平的HIV-1转录,却对依赖Tat的HIV-1转录具有抑制作用,因为Brd4和Tat竞争性地与P-TEFb结合。(5)鉴于Brd4对Tat依赖性HIV-1转录的抑制作用,寻找能够抑制Brd4的小分子药物,激活HIV-1潜伏,结合高效抗逆转录病毒治疗(HAART),使得彻底根除HIV-1变成可能。Brd4的抑制剂JQ1就是这样的一种小分子,并且已被证明可以在多种细胞模型中激活HIV-1潜伏。
(1) Transactivator (Tat) is an important factor in viral replication. P-TEFb is a specific host cytokine necessary for trans transactivation of HIV-1 by Tat. Its activity is correlated with HIV -1 transcription is closely related. (2) Intracellularly, the inactive 7SK snRNP complex is the storage and source of functionally active P-TEFb. Under certain conditions, the 7SK snRNP complex dissociates and releases P-TEFb, stimulating transcriptional elongation. It can be said that P-TEFb activity is strictly regulated, maintaining a dynamic balance. (3) In the meantime, P-TEFb is also present in a super-extended complex (SEC) with ultra-high transcriptional activity. Tat can recruit the SEC complex containing two elongation factors, P-TEFb and ELL2, to the long terminal domain of HIV-1 (LTR) and then many factors synergistically act to enhance the transcription of HIV-1. (4) Bromine-Containing Protein 4 (Brd4) Like Tat, P-TEFb is recruited to the promoter region of numerous cellular genes to promote transcription. Brd4 also activates underlying levels of HIV-1 transcription but inhibits Tat-dependent HIV-1 transcription because Brd4 and Tat competitively bind to P-TEFb. (5) In view of the inhibitory effect of Brd4 on Tat-dependent HIV-1 transcription, looking for small molecule drugs that can inhibit Brd4, activating latent HIV-1 and binding HAART, As possible. JQ1, an inhibitor of Brd4, is one such small molecule that has been shown to activate HIV-1 in a variety of cell models.