In HSV-1, the LAT Enhancer Drives Pre-IE VP16 Transcription to Initiate Reactivation

Herpes Simplex Virus 1 (HSV-1) is a significant lifelong human pathogen that infects 70% of adults worldwide. HSV-1 establishes a persistent latent infection in the peripheral nervous system where the virus can periodically reactivate in response to environmental stressors. These reactivation events result in recurrence of corneal infections that can lead to corneal blindness. It is becoming clear that CTCF insulators play a key role in the maintenance of gene silencing in DNA viruses that can establish latency. CTCF insulators are essential regulators of chromatin structure and play vital regulatory roles in transcriptional control of DNA viruses by organizing chromatin architecture during both latent and lytic stages of virus lifecycles. Here we have identified and functionally characterized a novel CTCF insulator, located at the transactivating gene VP16. We provide evidence that this insulator is involved in silencing VP16 during latent infection, while eviction of insulator protein coincides with increased VP16 gene expression during reactivation. To our knowledge, these are the first data that show that CTCF insulators is a key regulatory element in the exit from latency in a VP16-dependent manner and has important implications in understanding the heterogeneity of HSV-1 reactivation in different populations of neurons.