Induction of herpes simplex virus (HSV) immediate early (IE) gene transcription promotes the initiation of lytic infection and reactivation from latency in sensory neurons. IE genes are transcribed by the cellular RNA polymerase II (RNAPII) and regulated by multiple transcription factors and coactivators. The HCF-1 cellular coactivator plays a central role in driving IE expression at multiple stages through interactions with transcription factors, chromatin modulation complexes, and transcription elongation components, including the active super elongation complex/P-TEFb (SEC-P-TEFb). Here, we demonstrate that the SEC occupies the promoters of HSV IE genes during the initiation of lytic infection and during reactivation from latency. Specific inhibitors of the SEC suppress viral IE expression and block the spread of HSV infection. Significantly, these inhibitors also block the initiation of viral reactivation from latency in sensory ganglia. The potent suppression of IE gene expression by SEC inhibitors indicates that transcriptional elongation represents a determining rate-limiting stage in HSV IE gene transcription and that the SEC plays a critical role in driving productive elongation during both phases of the viral life cycle. Most importantly, this supports the model that signal-mediated induction of SEC-P-TEFb levels can promote reactivation of a population of poised latent genomes.

中文翻译：

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超伸长复合物的抑制抑制单纯疱疹病毒立即早期基因表达，溶菌感染和潜伏期重新激活。

单纯疱疹病毒（HSV）立即早期（IE）基因转录的诱导促进了感官神经元的裂解感染和潜伏期的重新激活。IE基因由细胞RNA聚合酶II（RNAPII）转录并受多种转录因子和共激活因子调控。的HCF-1共活化剂的细胞中起着通过与转录因子，染色质调制复合物，和转录延伸组件，包括有源交互驱动IE表达在多个阶段中心作用小号UPER ë longation Çomplex / P-TEFb（SEC-P-TEFb）。在这里，我们证明了SEC在裂解感染的启动过程中以及潜伏期的重新激活过程中都占据了HSV IE基因的启动子。SEC的特定抑制剂可抑制病毒IE表达并阻止HSV感染的扩散。重要的是，这些抑制剂还阻止了感觉神经节潜伏期引起的病毒再激活。SEC抑制剂对IE基因表达的有效抑制表明，转录延伸代表HSV IE基因转录中的决定性限速阶段，并且SEC在病毒生命周期的两个阶段均在驱动生产性延伸中起关键作用。最重要的是，这支持了该模型，即信号介导的SEC-P-TEFb水平的诱导可以促进平衡的潜伏基因组种群的重新激活。