Alphaherpesvirus Latency and Reactivation with a Focus on Herpes Simplex Virus

Abstract

We are at an interesting time in the understanding of alpha herpesvirus latency and reactivation and their implications to human disease. Conceptual advances have come from both animal and neuronal culture models. This review focuses on the concept that the tegument protein and viral transactivator VP16 plays a major role in the transition from latency to the lytic cycle. During acute infection, regulation of VP16 transactivation balances spread in the nervous system, establishment of latent infections and virulence. Reactivation is dependent on this transactivator to drive entry into the lytic cycle. In vivo de novo expression of VP16 protein is mediated by sequences conferring pre-immediate early transcription embedded in the normally leaky late promoter. In vitro, alternate mechanisms regulating VP16 expression in the context of latency have come from the SCG neuron culture model and include the concepts that (i) generalized transcriptional derepression of the caister.com/cimb 267 Curr. Issues Mol. Biol. Vol. 41 Latency and Reactivation Sawtell and Thompson viral genome and sequestration of VP16 in the cytoplasm for ~48 hours (Phase I) precedes and is required for VP16-dependent reactivation (Phase II); and (ii) a histone methyl/phospho switch during Phase I is required for Phase II reactivation. The challenge to the field is reconciling these data into a unified model of virus reactivation.The greatest enemy of knowledge is not ignorance, it is the illusion of knowledge.--Daniel J. Boorstin.The task of compiling this review was uncomfortably humbling, as if cataloging the stars in the universe. While not completely dark, our night sky is missing a multitude of studies which are among the many points of light contributing to our field. This article is a focused review in which we discuss from the vantage point of our expertise, just a handful of concepts that have or are emerging. A lookback at some of the pioneering work that grounds our field is also included.

Duck Plague Virus pUL48 Protein Activates the Immediate-Early Gene to Initiate the Transcription of the Virus Gene

“…Some studies have also fused VP16 TAD into plant transcriptional suppressors, using this technology to explore the inhibitory function and mechanism of transcriptional suppressors to strongly activate “silent genes” that are not normally expressed ( Aguilar et al, 2014 ; Fujiwara et al, 2014 ). Currently, more and more studies have shown that VP16 plays an important role in the reactivation of α herpesvirus from latency ( Sawtell and Thompson, 2016 , 2021 ). Ala replaced HSV-1 VP16 Ser375 to block the binding of VP16 to Oct-1, thus, inhibiting the transcriptional activation function of VP16.…”

Chromatin-mediated epigenetic regulation of HSV-1 transcription as a potential target in antiviral therapy

“…The latent genomes persist for life, however, resulting in a constant source for recrudescence of disease and infection spread. For a recent comprehensive review of latency, please see ( Sawtell and Thompson, 2020 ).…”

Host factors associated with either VP16 or VP16‐induced complex differentially affect HSV‐1 lytic infection

“…25 The transcriptional activator VP16 is involved in the regulation of both lytic infection and latency-reactivation in neurons. [26][27][28] VP16 promoters contain unique neuro-specific sequences that are essential for latency-reactivation in neurons because they can be activated by neuron-associated factor(s) independent of both IE products, such as ICP0 and ICP4, and viral DNA replication. 29,30 So far, the neuronassociated factors have not been extensively addressed, while the host factors affecting HSV-1 lytic infection via association with either VP16 or VP16-induced complex has been extensively characterised.…”