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.

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Journal Nature Communications
Depledge, D.P. (Daniel P.), Ouwendijk, W.J.D, Sadaoka, T. (Tomohiko), Braspenning, S.E. (Shirley E.), Mori, Y. (Yasuko), Cohrs, R.J, … Breuer, J. (Judith). (2018). A spliced latency-associated VZV transcript maps antisense to the viral transactivator gene. Nature Communications, 9(1). doi:10.1038/s41467-018-03569-2