Inhibition of the Super Elongation Complex Suppresses Herpes Simplex Virus Immediate Early Gene Expression, Lytic Infection, and Reactivation from Latency
Inhibition of the Super Elongation Complex Suppresses Herpes Simplex Virus Immediate Early Gene Expression, Lytic Infection, and Reactivation from Latency
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DOI：
10.1128/mbio.01216-20
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发表时间：
2020-05-01
期刊：
影响因子：
6.4
通讯作者：
Kristie, Thomas M.
中科院分区：
文献类型：
--
作者：
Alfonso-Dunn, Roberto;Arbuckle, Jesse H.;Kristie, Thomas M.
单纯疱疹病毒（HSV）即时早期（1E）基因转录的诱导促进了裂解性感染的启动和感觉神经元潜伏期的再激活。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。HCF-1细胞共激活因子通过与转录因子、染色质调节复合物和转录延伸组分（包括活性超延伸复合物/P-TEFb (SEC-P-TEFb)）的相互作用，在多个阶段驱动IE表达中发挥核心作用。在这里，我们证明SEC在裂解性感染的起始和潜伏期的再激活过程中占据HSV IE基因的启动子。SEC的特异性抑制剂抑制病毒IE表达并阻断HSV感染的传播。值得注意的是，这些抑制剂还可以阻断感觉神经节潜伏期病毒再激活的启动。SEC抑制剂对IE基因表达的有效抑制表明，在HSV IE基因转录中，转录伸长是一个决定性的限速阶段，并且SEC在病毒生命周期的两个阶段中都在推动生产伸长方面起着关键作用。最重要的是，这支持了一个模型，即信号介导的SEC-P-TEFb水平的诱导可以促进静止潜伏基因组群体的再激活。HSV感染可引起从复发性病变到重大眼部疾病的各种病理。裂解性感染的启动和感觉神经元潜伏期的再激活依赖于病毒即时早期基因的诱导表达。这些基因的转录在多个水平上受到控制，包括对病毒基因组染色质状态的调节以及转录因子和辅激活因子的适当募集。在开始转录后，IE基因受到一个关键的调控阶段，其中转录延伸率由超延伸复合物的活性控制。抑制SEC可阻断裂解性感染和感觉神经元潜伏期的再激活。除了提供对控制病毒感染和再激活机制的见解外，关键成分的抑制剂（如SEC）可能代表新的抗病毒药物。
Induction of herpes simplex virus (HSV) immediate early (1E) 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.IMPORTANCE HSV infections can cause pathologies ranging from recurrent lesions to significant ocular disease. Initiation of lytic infection and reactivation from latency in sensory neurons are dependent on the induced expression of the viral immediate early genes. Transcription of these genes is controlled at multiple levels, including modulation of the chromatin state of the viral genome and appropriate recruitment of transcription factors and coactivators. Following initiation of transcription, IE genes are subject to a key regulatory stage in which transcriptional elongation rates are controlled by the activity of the super elongation complex. Inhibition of the SEC blocks both lytic infection and reactivation from latency in sensory neurons. In addition to providing insights into the mechanisms controlling viral infection and reactivation, inhibitors of critical components such as the SEC may represent novel antivirals.