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Integrative functional genomics decodes herpes simplex virus 1

Adam W. Whisnant, Christopher S. Jürges, Thomas Hennig, Emanuel Wyler, Bhupesh Prusty, Andrzej J Rutkowski, Anne L’hernault, Margarete Göbel, Kristina Döring, Jennifer Menegatti, Robin Antrobus, Nicholas J. Matheson, Florian W.H. Künzig, Guido Mastrobuoni, Chris Bielow, Stefan Kempa, Liang Chunguang, Thomas Dandekar, Ralf Zimmer, Markus Landthaler, Friedrich Grässer, Paul J. Lehner, Caroline C. Friedel, View ORCID ProfileFlorian Erhard, View ORCID ProfileLars Dölken
doi: https://doi.org/10.1101/603654
Adam W. Whisnant
1Institute for Virology and Immunobiology, Julius-Maximilians-University Würzburg, Versbacher Straße 7, 97078 Würzburg, Germany
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Christopher S. Jürges
1Institute for Virology and Immunobiology, Julius-Maximilians-University Würzburg, Versbacher Straße 7, 97078 Würzburg, Germany
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Thomas Hennig
1Institute for Virology and Immunobiology, Julius-Maximilians-University Würzburg, Versbacher Straße 7, 97078 Würzburg, Germany
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Emanuel Wyler
2Berlin Institute for Medical Systems Biology, Max-Delbrück-Center for Molecular Medicine, 13125 Berlin, Germany
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Bhupesh Prusty
1Institute for Virology and Immunobiology, Julius-Maximilians-University Würzburg, Versbacher Straße 7, 97078 Würzburg, Germany
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Andrzej J Rutkowski
3Department of Medicine, University of Cambridge, Box 157, Addenbrookes Hospital, Hills Road, CB2 0QQ Cambridge, UK
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Anne L’hernault
3Department of Medicine, University of Cambridge, Box 157, Addenbrookes Hospital, Hills Road, CB2 0QQ Cambridge, UK
4AstraZeneca UK Ltd, Oncology R&D, Cambridge Science Park, Milton Road, Cambridge, CB4 0WG, UK
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Margarete Göbel
5Core Unit Systems Medicine, Julius-Maximilians-University Würzburg, Josef-Schneider-Str. 2 / D15, 97080 Würzburg, Germany
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Kristina Döring
5Core Unit Systems Medicine, Julius-Maximilians-University Würzburg, Josef-Schneider-Str. 2 / D15, 97080 Würzburg, Germany
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Jennifer Menegatti
6Institute of Virology, Saarland University Medical School Homburg/Saar, Germany
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Robin Antrobus
7Department of Medicine, Cambridge Institute for Medical Research, Cambridge Biomedical Campus, Hills Road, Cambridge CB2 0XY, UK
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Nicholas J. Matheson
3Department of Medicine, University of Cambridge, Box 157, Addenbrookes Hospital, Hills Road, CB2 0QQ Cambridge, UK
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Florian W.H. Künzig
1Institute for Virology and Immunobiology, Julius-Maximilians-University Würzburg, Versbacher Straße 7, 97078 Würzburg, Germany
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Guido Mastrobuoni
2Berlin Institute for Medical Systems Biology, Max-Delbrück-Center for Molecular Medicine, 13125 Berlin, Germany
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Chris Bielow
2Berlin Institute for Medical Systems Biology, Max-Delbrück-Center for Molecular Medicine, 13125 Berlin, Germany
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Stefan Kempa
2Berlin Institute for Medical Systems Biology, Max-Delbrück-Center for Molecular Medicine, 13125 Berlin, Germany
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Liang Chunguang
8Department of Bioinformatics, Biocenter, Am Hubland, Julius-Maximilians-University Würzburg, 97074 Würzburg, Germany
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Thomas Dandekar
8Department of Bioinformatics, Biocenter, Am Hubland, Julius-Maximilians-University Würzburg, 97074 Würzburg, Germany
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Ralf Zimmer
9Institute of Informatics, Ludwig-Maximilians-Universität München, Amalienstr. 17, 80333 Munich, Germany
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Markus Landthaler
2Berlin Institute for Medical Systems Biology, Max-Delbrück-Center for Molecular Medicine, 13125 Berlin, Germany
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Friedrich Grässer
6Institute of Virology, Saarland University Medical School Homburg/Saar, Germany
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Paul J. Lehner
7Department of Medicine, Cambridge Institute for Medical Research, Cambridge Biomedical Campus, Hills Road, Cambridge CB2 0XY, UK
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Caroline C. Friedel
9Institute of Informatics, Ludwig-Maximilians-Universität München, Amalienstr. 17, 80333 Munich, Germany
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Florian Erhard
1Institute for Virology and Immunobiology, Julius-Maximilians-University Würzburg, Versbacher Straße 7, 97078 Würzburg, Germany
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  • ORCID record for Florian Erhard
  • For correspondence: florian.erhard@uni-wuerzburg.de lars.doelken@uni-wuerzburg.de
Lars Dölken
1Institute for Virology and Immunobiology, Julius-Maximilians-University Würzburg, Versbacher Straße 7, 97078 Würzburg, Germany
3Department of Medicine, University of Cambridge, Box 157, Addenbrookes Hospital, Hills Road, CB2 0QQ Cambridge, UK
10Helmholtz Institute for RNA-based Infection Research (HIRI), Helmholtz-Center for Infection Research (HZI), 97080 Würzburg, Germany
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  • ORCID record for Lars Dölken
  • For correspondence: florian.erhard@uni-wuerzburg.de lars.doelken@uni-wuerzburg.de
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Summary

Since the genome of herpes simplex virus 1 (HSV-1) was first sequenced more than 30 years ago, its predicted 80 genes have been intensively studied. Here, we unravel the complete viral transcriptome and translatome during lytic infection with base-pair resolution by computational integration of multi-omics data. We identified a total of 201 viral transcripts and 284 open reading frames (ORFs) including all known and 46 novel large ORFs. Multiple transcript isoforms expressed from individual gene loci explain translation of the vast majority of novel viral ORFs as well as N-terminal extensions (NTEs) and truncations thereof. We show that key viral regulators and structural proteins possess NTEs, which initiate from non-canonical start codons and govern subcellular protein localization and packaging. We validated a novel non-canonical large spliced ORF in the ICP0 locus and identified a 93 aa ORF overlapping ICP34.5 that is thus also deleted in the FDA-approved oncolytic virus Imlygic. Finally, we extend the current nomenclature to include all novel viral gene products. Taken together, this work provides a valuable resource for future functional studies, vaccine design and oncolytic therapies.

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Posted April 09, 2019.
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Integrative functional genomics decodes herpes simplex virus 1
Adam W. Whisnant, Christopher S. Jürges, Thomas Hennig, Emanuel Wyler, Bhupesh Prusty, Andrzej J Rutkowski, Anne L’hernault, Margarete Göbel, Kristina Döring, Jennifer Menegatti, Robin Antrobus, Nicholas J. Matheson, Florian W.H. Künzig, Guido Mastrobuoni, Chris Bielow, Stefan Kempa, Liang Chunguang, Thomas Dandekar, Ralf Zimmer, Markus Landthaler, Friedrich Grässer, Paul J. Lehner, Caroline C. Friedel, Florian Erhard, Lars Dölken
bioRxiv 603654; doi: https://doi.org/10.1101/603654
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Integrative functional genomics decodes herpes simplex virus 1
Adam W. Whisnant, Christopher S. Jürges, Thomas Hennig, Emanuel Wyler, Bhupesh Prusty, Andrzej J Rutkowski, Anne L’hernault, Margarete Göbel, Kristina Döring, Jennifer Menegatti, Robin Antrobus, Nicholas J. Matheson, Florian W.H. Künzig, Guido Mastrobuoni, Chris Bielow, Stefan Kempa, Liang Chunguang, Thomas Dandekar, Ralf Zimmer, Markus Landthaler, Friedrich Grässer, Paul J. Lehner, Caroline C. Friedel, Florian Erhard, Lars Dölken
bioRxiv 603654; doi: https://doi.org/10.1101/603654

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