TY - JOUR
T1 - Varicella-zoster virus VLT-ORF63 fusion transcript induces broad viral gene expression during reactivation from neuronal latency
AU - Ouwendijk, Werner J.D.
AU - Depledge, Daniel P.
AU - Rajbhandari, Labchan
AU - Lenac Rovis, Tihana
AU - Jonjic, Stipan
AU - Breuer, Judith
AU - Venkatesan, Arun
AU - Verjans, Georges M.G.M.
AU - Sadaoka, Tomohiko
N1 - Funding Information:
We are grateful to Yasuko Mori for use of laboratory equipment, Angus C. Wilson and Ian Mohr for critical reading of the manuscript. We thank Tamana Mehraban for technical assistance. This work was supported by the Takeda Science Foundation, Daiichi Sankyo Foundation of Life Science, Japan Society for the Promotion of Science (JSPS KAKENHI JP17K008858, JP16H06429, and JP16K21723) and the Ministry of Education, Culture, Sports, Science and Technology (MEXT KAKENHI JP17H05816) (T. S.). Research reported in this publication was also supported by the National Institute of Allergy and Infectious Diseases of the National Institutes of Health under Award Number R01AI151290 (W.J.D.O. and G.M.G.M.V.). The content is solely the responsibility of the authors and does not necessarily represent the official views of the National Institutes of Health. D.P.D. was supported in part by NIH grants (R01GM056927, R01AI073898, R01AI152543). A.V. is supported by the NIH NINDS (R21NS107991). J.B. receives funding from the UCL/UCLH NIHR Biomedical Research Centre. S.J. and T.L.R. are supported by “Strengthening the capacity of CerVirVac for research in virus immunology and vaccinology”, grant no. KK.01.1.1.01.0006, awarded to the Scientific Centre of Excellence for Virus Immunology and Vaccines and cofinanced by the European Regional Development Fund. The funders had no role in study design, data collection, and interpretation, or in the decision to submit the work for publication.
Publisher Copyright:
© 2020, The Author(s).
PY - 2020/12
Y1 - 2020/12
N2 - 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.
AB - 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.
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UR - http://www.scopus.com/inward/citedby.url?scp=85097437096&partnerID=8YFLogxK
U2 - 10.1038/s41467-020-20031-4
DO - 10.1038/s41467-020-20031-4
M3 - Article
C2 - 33303747
AN - SCOPUS:85097437096
SN - 2041-1723
VL - 11
JO - Nature communications
JF - Nature communications
IS - 1
M1 - 6324
ER -