Inhibition of the Super Elongation Complex Suppresses Herpes Simplex Virus Immediate Early Gene Expression, Lytic Infection, and Reactivation from Latency

• Published in: mBio Vol. 11; no. 3
• Main Authors: Alfonso-Dunn, Roberto, Arbuckle, Jesse H., Vogel, Jodi L., Kristie, Thomas M.
• Format: Journal Article
• Language: English
• Published: United States American Society for Microbiology 09.06.2020
• Subjects: AFF4; Animals; Antiviral Agents - pharmacology; Cell Line; Chlorocebus aethiops; Fibroblasts - virology; Gene Expression; Genes, Immediate-Early; HCF-1; herpes simplex virus; Herpesvirus 1, Human - drug effects; Herpesvirus 1, Human - genetics; Herpesvirus 1, Human - physiology; Host-Microbe Biology; HSV reactivation; Humans; Immediate-Early Proteins - genetics; latency; Lung - cytology; transcription elongation; Transcriptional Elongation Factors - antagonists & inhibitors; Transcriptional Elongation Factors - genetics; Vero Cells; Virus Latency - drug effects; Virus Latency - genetics; Virus Replication - drug effects; herpes simplex virus; transcription elongation; HSV reactivation; transcription; super elongation complex; latency; HCF-1; AFF4
• ISSN: 2161-2129; 2150-7511; 2150-7511
• DOI: 10.1128/mBio.01216-20

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. 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 s uper e longation c omplex/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.