Varicella-zoster virus VLT-ORF63 fusion transcript induces broad viral gene expression during reactivation from neuronal latency.

Werner J D Ouwendijk, Daniel P Depledge, Labchan Rajbhandari, Tihana Lenac Rovis, Stipan Jonjic, Judith Breuer, Arun Venkatesan, Georges M G M Verjans, Tomohiko Sadaoka

Nature communications 2020 Dec 10

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Varicella-zoster virus (VZV) establishes lifelong neuronal latency in most humans world-wide, reactivating in one-third to cause herpes zoster and occasionally chronic pain. How VZV establishes, maintains and reactivates from latency is largely unknown. VZV transcription during latency is restricted to the latency-associated transcript (VLT) and RNA 63 (encoding ORF63) in naturally VZV-infected human trigeminal ganglia (TG). While significantly more abundant, VLT levels positively correlated with RNA 63 suggesting co-regulated transcription during latency. Here, we identify VLT-ORF63 fusion transcripts and confirm VLT-ORF63, but not RNA 63, expression in human TG neurons. During in vitro latency, VLT is transcribed, whereas VLT-ORF63 expression is induced by reactivation stimuli. One isoform of VLT-ORF63, encoding a fusion protein combining VLT and ORF63 proteins, induces broad viral gene transcription. Collectively, our findings show that VZV expresses a unique set of VLT-ORF63 transcripts, potentially involved in the transition from latency to lytic VZV infection.

Citation

Werner J D Ouwendijk, Daniel P Depledge, Labchan Rajbhandari, Tihana Lenac Rovis, Stipan Jonjic, Judith Breuer, Arun Venkatesan, Georges M G M Verjans, Tomohiko Sadaoka. Varicella-zoster virus VLT-ORF63 fusion transcript induces broad viral gene expression during reactivation from neuronal latency. Nature communications. 2020 Dec 10;11(1):6324