Making a Short Story Long: Regulation of P-TEFb and HIV-1 Transcriptional Elongation in CD4+ T Lymphocytes and Macrophages.
Making a Short Story Long: Regulation of P-TEFb and HIV-1 Transcriptional Elongation in CD4+ T Lymphocytes and Macrophages.
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DOI：
10.3390/biology1010094
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发表时间：
2012-06-15
期刊：
影响因子：
4.2
通讯作者：
Rice AP
中科院分区：
文献类型：
--
作者：
Ramakrishnan R;Chiang K;Liu H;Budhiraja S;Donahue H;Rice AP
整合的HIV-1前病毒的生产性转录受到抑制RNA聚合酶II延伸的细胞因子的限制。病毒达特蛋白通过将一般延伸因子P-TEFb募集到在新生病毒转录物的5'端形成的TAR RNA元件来克服这一点。P-TEFb存在于细胞中的多个复合物中，其核心由激酶Cdk 9和调节亚基Cyclin T1或Cyclin T2组成。达特直接结合细胞周期蛋白T1，从而靶向磷酸化RNA聚合酶II的CTD的细胞周期蛋白T1/P-TEFb复合物和抑制延伸的负因子，导致有效的转录延伸。P-TEFb在HIV-1-CD 4 + T淋巴细胞和单核细胞/巨噬细胞感染的细胞中受到严格调控。已经确定了许多抑制静息CD 4 + T淋巴细胞和单核细胞中P-TEFb的机制，包括抑制细胞周期蛋白T1蛋白表达和Cdk 9 T环中残基Thr 186去磷酸化的miRNA。这些抑制机制在T细胞活化和巨噬细胞分化时被克服，此时HIV-1复制的概率大大增加。本文将总结目前已知的机制，调节P-TEFb和这种调节如何影响HIV-1的复制和潜伏期。
Productive transcription of the integrated HIV-1 provirus is restricted by cellular factors that inhibit RNA polymerase II elongation. The viral Tat protein overcomes this by recruiting a general elongation factor, P-TEFb, to the TAR RNA element that forms at the 5’ end of nascent viral transcripts. P-TEFb exists in multiple complexes in cells, and its core consists of a kinase, Cdk9, and a regulatory subunit, either Cyclin T1 or Cyclin T2. Tat binds directly to Cyclin T1 and thereby targets the Cyclin T1/P-TEFb complex that phosphorylates the CTD of RNA polymerase II and the negative factors that inhibit elongation, resulting in efficient transcriptional elongation. P-TEFb is tightly regulated in cells infected by HIV-1—CD4+ T lymphocytes and monocytes/macrophages. A number of mechanisms have been identified that inhibit P-TEFb in resting CD4+ T lymphocytes and monocytes, including miRNAs that repress Cyclin T1 protein expression and dephosphorylation of residue Thr186 in the Cdk9 T-loop. These repressive mechanisms are overcome upon T cell activation and macrophage differentiation when the permissivity for HIV-1 replication is greatly increased. This review will summarize what is currently known about mechanisms that regulate P-TEFb and how this regulation impacts HIV-1 replication and latency.