A comparison of herpes simplex virus type 1 and varicella-zoster virus latency and reactivation

Abstract

Herpes simplex virus type 1 (HSV-1; human herpesvirus 1) and varicella-zoster virus (VZV; human herpesvirus 3) are human neurotropic alphaherpesviruses that cause lifelong infections in ganglia. Following primary infection and establishment of latency, HSV-1 reactivation typically results in herpes labialis (cold sores), but can occur frequently elsewhere on the body at the site of primary infection (e.g. whitlow), particularly at the genitals. Rarely, HSV-1 reactivation can cause encephalitis; however, a third of the cases of HSV-1 encephalitis are associated with HSV-1 primary infection. Primary VZV infection causes varicella (chickenpox) following which latent virus may reactivate decades later to produce herpes zoster (shingles), as well as an increasingly recognized number of subacute, acute and chronic neurological conditions. Following primary infection, both viruses establish a latent infection in neuronal cells in human peripheral ganglia. However, the detailed mechanisms of viral latency and reactivation have yet to be unravelled. In both cases latent viral DNA exists in an 'end-less' state where the ends of the virus genome are joined to form structures consistent with unit length episomes and concatemers, from which viral gene transcription is restricted. In latently infected ganglia, the most abundantly detected HSV-1 RNAs are the spliced products originating from the primary latency associated transcript (LAT). This primary LAT is an 8.3 kb unstable transcript from which two stable (1.5 and 2.0 kb) introns are spliced. Transcripts mapping to 12 VZV genes have been detected in human ganglia removed at autopsy; however, it is difficult to ascribe these as transcripts present during latent infection as early-stage virus reactivation may have transpired in the post-mortem time period in the ganglia. Nonetheless, low-level transcription of VZV ORF63 has been repeatedly detected in multiple ganglia removed as close to death as possible. There is increasing evidence that HSV-1 and VZV latency is epigenetically regulated. In vitro models that permit pathway analysis and identification of both epigenetic modulations and global transcriptional mechanisms of HSV-1 and VZV latency hold much promise for our future understanding in this complex area. This review summarizes the molecular biology of HSV-1 and VZV latency and reactivation, and also presents future directions for study. Received 5 January 2015Accepted 18 March 2015 IntroductionHerpes simplex virus type 1 (HSV-1; human herpesvirus 1) and varicella-zoster virus (VZV; human herpesvirus 3) are human neurotropic alphaherpesviruses usually acquired early in life. Primary HSV-1 infection is usually localized and may be asymptomatic, although it can produce a more widespread systemic infection in neonates and immunocompromised adults, whilst primary VZV infection is systemic and results in childhood varicella (chickenpox). During primary infection, both viruses gain access to neurons most likely through retrograde transport from the site of cutaneous lesion...

Occupancy of RNA Polymerase II Phosphorylated on Serine 5 (RNAP S5 P ) and RNAP S2 P on Varicella-Zoster Virus Genes 9, 51, and 66 Is Independent of Transcript Abundance and Polymerase Location within the Gene

“…During HSV-1 reactivation, these chromatin boundary elements are released from the virus DNA (32,33). Since the release of CTCF from the virus genome is an attractive mechanism connecting external stress to HSV-1 reactivation (34,35) and the critical CCCTC-binding sites are separated by at least 3,300 nt (31), the HSV-1 DNA fragment size is not a critical aspect of these ChIP analyses. However, determination of the efficiency of virus DNA fragmentation is critical when locating transcription factors on the virus genome where promoters are closely linked to the genes that they control.…”

Issues in the Treatment of Neurological Conditions Caused by Reactivation of Varicella Zoster Virus (VZV)

“…Within 9 h of death, only VZV gene 63 is transcribed [5]. However, the consistent detection by several groups of other VZV transcripts (VZV open reading frames 4, 21, 29, 62, 63 and 66) after this time may possibly reflect agonal attempts at VZV reactivation [6][7][8][9]. Decades later, as cell-mediated immunity to VZV declines with advancing age or when humans are immunosuppressed by disease or drug therapy, VZV reactivates to cause herpes zoster (Bshingles^), a painful dermatomally distributed vesicular eruption [1][2][3].…”

Varicella and herpes zoster vaccine development: lessons learned

“…During latency, the VZV genome is maintained in a nonintegrated circular concatemeric form, with a very restricted pattern of viral gene expression [3]. The absence of an animal model of VZV natural history has hampered understanding of the precise pattern of gene expression during latency, although low-level transcription of the immediate early gene ORF 63 has been repeatedly detected in human ganglia from autopsy samples taken as close to death as possible [15]. Recent evidence suggests that latency of both VZV and herpes simplex virus type-1 may be epigenetically regulated [15].…”

“…The absence of an animal model of VZV natural history has hampered understanding of the precise pattern of gene expression during latency, although low-level transcription of the immediate early gene ORF 63 has been repeatedly detected in human ganglia from autopsy samples taken as close to death as possible [15]. Recent evidence suggests that latency of both VZV and herpes simplex virus type-1 may be epigenetically regulated [15]. VZV-specific memory T cells, with a mixed central and effector phenotype, are important for maintaining VZV latency, with immunity boosted periodically by endogenous (subclinical) reactivation and exogenous reexposure to VZV [16].…”