The Loss of Binary: Pushing the Herpesvirus Latency Paradigm

Abstract

Purpose of Review Herpesvirus latency has been viewed as a binary state where replication is either on or off. During latency, gene expression is thought to be restricted to non-coding RNAs or very few proteins so that the virus avoids detection by the immune system. However, a number of recent studies across herpesvirus families call into question the existence of a binary switch for latency, and suggest that latency is far more dynamic than originally presumed. These studies are the focus of this review. Recent Findings Highly sensitive and global approaches to investigate viral gene expression in the context of latency have revealed low level viral transcripts, and in some cases protein, from each of the three kinetic gene classes during the latent alpha and beta herpesvirus infection either in vitro or in vivo. Further, low level, asymptomatic virus shedding persists following acute infection. Together, these findings have raised questions about how silent the latent infection truly is. Summary Emerging evidence suggests that viral gene expression associated with latent states may be broader and more dynamic than originally presumed during herpesvirus latency. This is an important possibility to consider in understanding the molecular programs associated with the establishment, maintenance and reactivation of herpesvirus latency. Here, we review these findings and detail how they contribute to the emergence of a biphasic model of reactivation.

Chromatin Profiles of Chromosomally Integrated Human Herpesvirus-6A

“…Although previous studies have linked low levels of viral transcripts to herpesvirus latency (Collins-McMillen and Goodrum, 2017), our RNA-seq analysis demonstrates that viral associated transcripts were not detected from the integrated HHV-6A genome in both iciHHV-6A and 293-HHV-6A cells. A previous study described four HHV-6B latency-associated transcripts (LATs) in latently infected cells (Kondo et al, 2002); however, these LATs were barely detectable in a more sensitive assay and showed maximal expression during the establishment of latency, and just before the onset of reactivation both in vivo and in vitro (Kondo et al, 2003).…”

“…For alphaherpesviruses, HSV latency is associated with the expression of LATs in some latently infected neurons; however, LAT equivalent transcripts are not expressed in varicella zoster virus (VZV) latency (Kinchington et al, 2012), although a recently discovered latency transcript antisense of ORF61 has been reported (Depledge et al, 2018). Varying degrees of evidence on LATs in both natural HCMV infection and experimental latency models have been reported (Cheng et al, 2017; Shnayder et al, 2018), suggesting that herpesvirus latency may be more complex and dynamic than previously assumed (Goodrum, 2016; Collins-McMillen and Goodrum, 2017).…”

Viral gene drive in herpesviruses

“…Herpesviruses establish life-long persistent infections in humans and animals. In immunocompetent hosts, they remain in a latent sate in the nucleus of infected cells indefinitely and only reactivate sporadically 1,31 . Given the low level of viral replication under these conditions, a gene drive would not be expected to spread in a predominantly latent infection.…”

A Presumed Etiology of Kawasaki Disease Based on Epidemiological Comparison With Infectious or Immune-Mediated Diseases

“…ES may have no differences in age predilection, possibly sero-prevalence rate, and clinical manifestations across populations around the world and have occurred throughout every year with no seasonal variations (26, 27). Herpes virus groups become latent in the host after the initial infection as shown in herpes zoster, herpes labialis, and reactivation of cytomegalovirus and Epstein-Barr virus (EBV) in depressed immune state of the host (28). It was reported that EBV infection or herpes virus 6 infection was related to certain clinical manifestations in KD such as otorrhea or BCG inoculation site inflammation (29, 30).…”