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.

Fig. 1. HSV and VZV genomes. The HSV and VZV ORFs are represented by blue arrows on the genome maps. The diamond-shaped red lines denote the origin of DNA replication. Both the genomes have a unique long U_L and a unique short U_S region flanked by repeat regions (R_L and R_S). The VZV genome is ∼30 kbp smaller than the HSV genome. The primary HSV-1 latency associated transcript (LAT) along with the two (nested) introns is shown.

Fig. 2. Proposed pattern of alphaherpesvirus reactivation. HSV-1 DNA in latently infected murine trigeminal ganglia or VZV in human trigeminal ganglia removed ≤ 9 h post-mortem is episomal from which transcription is limited (LAT for HSV-1 and ORF63 for VZV). Following explant of latently infected HSV-1 mouse ganglia or human trigeminal ganglia >9 h post-mortem (VZV), virus gene transcription undergoes generalized deregulation (animation) characterized by transcription of multiple virus genes (only HSV-1 genes quantified < 24 h post-reactivation are identified). Following animation, HSV-1 gene transcription undergoes a shift from generalized to organized transcription that orchestrates protein synthesis with DNA replication resulting in release of progeny infectious virus by 24 h for HSV-1. To date, VZV reactivation with release of infectious virus from human ganglia explants has not been demonstrated, but VZV DNA replication has been detected by quantitative PCR analysis of human ganglia explants (Azarkh et al., 2012). Lower-right graph: y-axis, HSV-1 DNA copy number (black line) and VZV DNA copy number (red line); x-axis, time the human ganglia explants were incubated in optimized culture medium; data represent mean ± sem for virus DNA quantification by real-time, TaqMan-based PCR. In these same human trigeminal explanted cultures, HSV-1 DNA replication is also seen (black line). Release of progeny infectious VZV has yet to be attained in explant cultures of human trigeminal ganglia; however, VZV DNA replication has been detected by 5 days in explanted human trigeminal ganglia cultures (red line). IE, Intermediate-early; E, early; L, late.