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Review
. 2018 Sep:522:81-91.
doi: 10.1016/j.virol.2018.07.011. Epub 2018 Jul 14.

Strength in diversity: Understanding the pathways to herpes simplex virus reactivation

Jon B Suzich  1 , Anna R Cliffe  2
Affiliations
Review

Strength in diversity: Understanding the pathways to herpes simplex virus reactivation

Jon B Suzich et al. Virology. 2018 Sep.

Abstract

Herpes simplex virus (HSV) establishes a latent infection in peripheral neurons and can periodically reactivate to cause disease. Reactivation can be triggered by a variety of stimuli that activate different cellular processes to result in increased HSV lytic gene expression and production of infectious virus. The use of model systems has contributed significantly to our understanding of how reactivation of the virus is triggered by different physiological stimuli that are correlated with recrudescence of human disease. Furthermore, these models have led to the identification of both common and distinct mechanisms of different HSV reactivation pathways. Here, we summarize how the use of these diverse model systems has led to a better understanding of the complexities of HSV reactivation, and we present potential models linking cellular signaling pathways to changes in viral gene expression.

Keywords: Axotomy; DLK; Epigenetics; Herpes simplex virus; NGF-deprivation; Reactivation.

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Figures

Figure 1.
Figure 1.. Model of HSV reactivation in response to NGF-deprivation.
(A) In primary neurons, sustained NGF-signaling through the TrkA receptor maintains latency via activation of PI3K/AKT. AKT activation maintains mTOR activity, while inhibiting the activation of DLK. JNK is constitutively active but does not mediate a stress response. Viral lytic promoters associate with repressive histones. (B) Following loss of NGF binding to TrkA, or inhibition of PI3K activity, HSV reactivates. Inhibition of AKT results in mTOR inhibition and redirection of JNK to a cell stress role via DLK. Decreased mTOR activity could result in decreased synthesis of proteins required to maintain latency and possibly activation of JNK. JNK is found enrichened on lytic gene promoters and there is an accompanying H3K9me3pS10 histone methyl/phospho switch.
Figure 2.
Figure 2.. Model of HSV reactivation in response to axotomy/explant.
Following axotomy, there is a rapid increase in intracellular calcium levels triggering a calcium wave that is propagated to the soma. This permits rapid cellular responses, including a global increase in histone acetylation due to the export of HDAC5, along with HDAC3, from the nucleus. This may explain the increased histone acetylation observed on HSV lytic promoters following explant. Increased intracellular calcium also activates adenylate cyclase and DLK, which activates JNK. JNK activity is required for explant induced reactivation. HCF-1 has been found to rapidly translocate to the nucleus and bind to HSV IE promoters. Viral gene expression is dependent on LSD-1 and JMJD2 histone K9 demethylase activity, which are presumably recruited along with Set1, by HCF-1.
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