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.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.