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Chromatin control of herpes simplex virus lytic and latent infection

Key Points

  • Herpes simplex virus (HSV) undergoes a productive infection of epithelial cells at mucosal surfaces and spreads to sensory neurons, where it can undergo a latent infection. From latently infected cells, HSV can later reactivate to cause a recurrent infection in the epithelium.

  • During lytic infection, histones associate with HSV lytic genes at early times but are reduced by 4–6 hours post-infection. The histones that are associated with HSV DNA bear post-translational modifications that are markers for euchromatin or active chromatin.

  • HSV gene products, including the virion-associated protein VP16, the immediate–early infected cell protein 0 (ICP0) and the early ICP8, are required for the reduced level of histones that are associated with HSV lytic genes and the euchromatic modifications on the histones.

  • During latent infection, HSV lytic genes are associated with heterochromatin.

  • The HSV latency-associated transcript promotes the formation of heterochromatin on the HSV lytic genes and their transcriptional silencing during latent infection of sensory neurons.

  • We propose a chromatin switch model in which HSV gene products that are expressed in epithelial cells 'flip' the switch towards euchromatin in those cells, whereas gene products that are expressed in neuronal cells 'flip' the switch towards heterochromatin and silencing of lytic viral genes.

Abstract

Herpes simplex viruses (HSV) can undergo a lytic infection in epithelial cells and a latent infection in sensory neurons. During latency the virus persists until reactivation, which leads to recurrent productive infection and transmission to a new host. How does HSV undergo such different types of infection in different cell types? Recent research indicates that regulation of the assembly of chromatin on HSV DNA underlies the lytic versus latent decision of HSV. We propose a model for the decision to undergo a lytic or a latent infection in which HSV encodes gene products that modulate chromatin structure towards either euchromatin or heterochromatin, and we discuss the implications of this model for the development of therapeutics for HSV infections.

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Figure 1: Stages of herpes simplex virus infection.
Figure 2: Overview of the herpes simplex virus lytic infection cycle.
Figure 3: The fate of viral DNA.
Figure 4: Summary of potential mechanisms that might determine the outcome of viral infection of epithelial cells and neurons.
Figure 5: Schematic representation of the latency-associated transcriptional unit of the herpes simplex virus genome.

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Acknowledgements

Studies on HSV latent infection in the authors' laboratory are supported by NIH grant P01 NS35138.

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Correspondence to David M. Knipe.

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Glossary

Epigenetic

Factors that affect gene action without changing nucleotide sequence. Epigenetic modifications function by changing the structure of chromatin, and are facilitated by DNA methylation and histone modification.

Nucleosome

A subunit of chromatin that is composed of DNA wrapped around a tetramer of histone proteins.

Anterograde transport

The direction of anterograde axonal transport is from the cell body to the synapses. By contrast, retrograde axonal transport is from the synapses to the cell body.

Trigeminal ganglia

The trigeminal ganglion is a sensory ganglion of the trigeminal nerve that occupies a cavity in the dura mater that covers the trigeminal impression near the apex of the petrous part of the temporal bone.

Nucleoside analogues

Nucleoside analogues are chemically similar enough to nucleosides to be incorporated into growing DNA strands, but different enough to ensure that the resultant DNA is non-functional.

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Knipe, D., Cliffe, A. Chromatin control of herpes simplex virus lytic and latent infection. Nat Rev Microbiol 6, 211–221 (2008). https://doi.org/10.1038/nrmicro1794

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