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Review
. 2017 Jan 3;91(2):e01419-16.
doi: 10.1128/JVI.01419-16. Print 2017 Jan 15.

Restarting Lytic Gene Transcription at the Onset of Herpes Simplex Virus Reactivation

Anna R Cliffe  1 , Angus C Wilson  2
Affiliations
Review

Restarting Lytic Gene Transcription at the Onset of Herpes Simplex Virus Reactivation

Anna R Cliffe et al. J Virol. .

Abstract

Herpes simplex virus (HSV) establishes a latent reservoir in neurons of human peripheral nerves. In this quiescent state, the viral genome persists as a circular, histone-associated episome, and transcription of viral lytic cycle genes is largely suppressed through epigenetic processes. Periodically, latent virus undergoes reactivation whereby lytic genes are activated and viral replication occurs. In this Gem, we review recent evidence that mechanisms governing the initial transcription of lytic genes are distinct from those of de novo infection and directly link reactivation to neuronal stress response pathways. We also discuss evidence that lytic cycle gene expression can be uncoupled from the full reactivation program, arguing for a less sharply bimodal definition of latency.

Keywords: JNK signaling; episome; herpes simplex virus; heterochromatin; histone methylation; latency; neurotropic viruses; reactivation; transcriptional regulation.

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Figures

FIG 1
FIG 1
Stepwise reversal of host-mediated epigenetic silencing of the HSV latent genome. During latency, the histones associated with HSV lytic promoters, such as histone H3 trimethylation at lysine 27 (H3K27me3) and histone H3 di- and trimethylation at lysine 9 (H3K9me2/3), are enriched for epigenetic silencing modifications, resulting in a stable chromatin state refractory to transcription by RNA polymerase II. Activation of neuronal stress response pathways triggers DLK/JIP-3-mediated activation of JNK and phosphorylation of histone H3 serine 10 (H3pS10) adjacent to the H3K9me2/3 mark. This dual modification (the methyl-phospho switch) displaces repressive factors and renders the chromatin permissive for simultaneous transcription of the viral IE, E, and L gene mRNAs characteristic of phase I (animation). Viral regulatory factors, such as VP16, synthesized during phase I can then associate with the viral IE promoters and recruit cellular demethylases to remove heterochromatic marks along with histone acetyltransferases that promote hyperacetylation of the viral chromatin. This increases the transcriptional capabilities of viral genes, achieving sufficient levels to initiate HSV DNA replication and assembly of new infectious particles.
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References

    1. Bloom DC. 2016. Alphaherpesvirus latency: a dynamic state of transcription and reactivation. Adv Virus Res 94:53–80. doi:10.1016/bs.aivir.2015.10.001. - DOI - PubMed
    1. Perng GC, Jones C, Ciacci-Zanella J, Stone M, Henderson G, Yukht A, Slanina SM, Hofman FM, Ghiasi H, Nesburn AB, Wechsler SL. 2000. Virus-induced neuronal apoptosis blocked by the herpes simplex virus latency-associated transcript. Science 287:1500–1503. doi:10.1126/science.287.5457.1500. - DOI - PubMed
    1. Thompson RL, Sawtell NM. 2001. Herpes simplex virus type 1 latency-associated transcript gene promotes neuronal survival. J Virol 75:6660–6675. doi:10.1128/JVI.75.14.6660-6675.2001. - DOI - PMC - PubMed
    1. Leib DA, Bogard CL, Kosz-Vnenchak M, Hicks KA, Coen DM, Knipe DM, Schaffer PA. 1989. A deletion mutant of the latency-associated transcript of herpes simplex virus type 1 reactivates from the latent state with reduced frequency. J Virol 63:2893–2900. - PMC - PubMed
    1. Cliffe AR, Garber DA, Knipe DM. 2009. Transcription of the herpes simplex virus latency-associated transcript promotes the formation of facultative heterochromatin on lytic promoters. J Virol 83:8182–8190. doi:10.1128/JVI.00712-09. - DOI - PMC - PubMed