A Herpesviral Lytic Protein Regulates the Structure of Latent Viral Chromatin.

Donald M. Coen,Dongli Pan,Jean M. Pesola,David M. Knipe,Jennifer S. Lee,Michael J. Imperiale,Priya Raja

doi:10.1128/mbio.00633-16

Abstract

ABSTRACTLatent infections by viruses usually involve minimizing viral protein expression so that the host immune system cannot recognize the infected cell through the viral peptides presented on its cell surface. Herpes simplex virus (HSV), for example, is thought to express noncoding RNAs such as latency-associated transcripts (LATs) and microRNAs (miRNAs) as the only abundant viral gene products during latent infection. Here we describe analysis of HSV-1 mutant viruses, providing strong genetic evidence that HSV-infected cell protein 0 (ICP0) is expressed during establishment and/or maintenance of latent infection in murine sensory neurons in vivo. Studies of an ICP0 nonsense mutant virus showed that ICP0 promotes heterochromatin and latent and lytic transcription, arguing that ICP0 is expressed and functional. We propose that ICP0 promotes transcription of LATs during establishment or maintenance of HSV latent infection, much as it promotes lytic gene transcription. This report introduces the new concept that a lytic viral protein can be expressed during latent infection and can serve dual roles to regulate viral chromatin to optimize latent infection in addition to its role in epigenetic regulation during lytic infection. An additional implication of the results is that ICP0 might serve as a target for an antiviral therapeutic acting on lytic and latent infections.

Highlights

The herpesviruses are characterized by the ability to establish a latent infection, in which no infectious virus is found, following an acute infection in the host organism [1]
The promotion of viral gene expression involves the reversal of the cellular epigenetic silencing of the viral genome through the degradation of the PML, Sp100, Daxx, ATRX, and IFI16 proteins, the disruption of the CoREST-HDAC
Ganglia were scored as RNA positive for the indicated gene as described in Materials and Methods. b The Fisher’s exact test was used to analyze the fraction of trigeminal ganglia (TG) with detectable expression of viral lytic transcripts during latent infection in n212 versus n212R samples

Summary

Introduction

The herpesviruses are characterized by the ability to establish a latent infection, in which no infectious virus is found, following an acute infection in the host organism [1]. Viral lytic promoters are associated with chromatin characterized by constitutive H3K9me and facultative H3K27me heterochromatin modifications, while the LAT promoter is associated with bivalent chromatin characterized by both euchromatin and heterochromatin modifications, without any role for DNA methylation [15, 16, 25,26,27]. This has led to the hypothesis that an epigenetic switch initiates the transition of the viral genome from lytic to latent infection

Methods

Results

Conclusion