A spliced latency-associated VZV transcript maps antisense to the viral transactivator gene 61

Daniel P Depledge,Randall J Cohrs,Werner J D Ouwendijk,Judith Breuer,Shirley E Braspenning,Georges M G M Verjans,Tomohiko Sadaoka,Yasuko Mori

doi:10.1038/s41467-018-03569-2

Daniel P Depledge, Randall J Cohrs + Show 6 more

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https://doi.org/10.1038/s41467-018-03569-2

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Varicella-zoster virus (VZV), an alphaherpesvirus, establishes lifelong latent infection in the neurons of >90% humans worldwide, reactivating in one-third to cause shingles, debilitating pain and stroke. How VZV maintains latency remains unclear. Here, using ultra-deep virus-enriched RNA sequencing of latently infected human trigeminal ganglia (TG), we demonstrate the consistent expression of a spliced VZV mRNA, antisense to VZV open reading frame 61 (ORF61). The spliced VZV latency-associated transcript (VLT) is expressed in human TG neurons and encodes a protein with late kinetics in productively infected cells in vitro and in shingles skin lesions. Whereas multiple alternatively spliced VLT isoforms (VLTly) are expressed during lytic infection, a single unique VLT isoform, which specifically suppresses ORF61 gene expression in co-transfected cells, predominates in latently VZV-infected human TG. The discovery of VLT links VZV with the other better characterized human and animal neurotropic alphaherpesviruses and provides insights into VZV latency.

Highlights

Varicella-zoster virus (VZV), an alphaherpesvirus, establishes lifelong latent infection in the neurons of >90% humans worldwide, reactivating in one-third to cause shingles, debilitating pain and stroke
We have identified a unique spliced VZV transcript, VZV latency-associated transcript (VLT), which is consistently expressed in latently VZV-infected human trigeminal ganglia (TG)
The VLT locus, including splice donor/acceptor sites and pVLT coding sequence, is highly conserved between wildtype and vaccine strains of VZV (Supplementary Table 4)

Summary

Introduction

Varicella-zoster virus (VZV), an alphaherpesvirus, establishes lifelong latent infection in the neurons of >90% humans worldwide, reactivating in one-third to cause shingles, debilitating pain and stroke. RNA-Seq of unenriched RNA libraries from two latently VZV and HSV-1 co-infected human TGs (donors 1 and 2, Supplementary Tables 1 and 2), enriched for polyadenylated transcripts or ribosomal RNA-depleted total RNA VZV transcripts (Fig. 2b and Supplementary Fig. 6) or miRNAs were detected in human TGs. Distinct VLT mRNA isoforms expressed during lytic infection.

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