Genetic determinants of host- and virus-derived insertions for hepatitis E virus replication

Michael Hermann Wißing, Toni Luise Meister, Maximilian Klaus Nocke, André Gömer, Mejrema Masovic, Leonard Knegendorf, Yannick Brüggemann, Verian Bader, Anindya Siddharta, Claus-Thomas Bock, Alexander Ploss, Scott P. Kenney, Konstanze F. Winklhofer, Patrick Behrendt, Heiner Wedemeyer, Eike Steinmann () and Daniel Todt ()
Additional contact information
Michael Hermann Wißing: Ruhr University Bochum
Toni Luise Meister: Ruhr University Bochum
Maximilian Klaus Nocke: Ruhr University Bochum
André Gömer: Ruhr University Bochum
Mejrema Masovic: Ruhr University Bochum
Leonard Knegendorf: a Joint Venture between the Medical School Hannover (MHH) and the Helmholtz Centre for Infection Research (HZI)
Yannick Brüggemann: Ruhr University Bochum
Verian Bader: Ruhr University Bochum
Anindya Siddharta: a Joint Venture between the Medical School Hannover (MHH) and the Helmholtz Centre for Infection Research (HZI)
Claus-Thomas Bock: Robert Koch Institute
Alexander Ploss: Princeton University
Scott P. Kenney: The Ohio State University
Konstanze F. Winklhofer: Ruhr University Bochum
Patrick Behrendt: a Joint Venture between the Medical School Hannover (MHH) and the Helmholtz Centre for Infection Research (HZI)
Heiner Wedemeyer: Hannover Medical School
Eike Steinmann: Ruhr University Bochum
Daniel Todt: Ruhr University Bochum

Nature Communications, 2024, vol. 15, issue 1, 1-16

Abstract: Abstract Hepatitis E virus (HEV) is a long-neglected RNA virus and the major causative agent of acute viral hepatitis in humans. Recent data suggest that HEV has a very heterogeneous hypervariable region (HVR), which can tolerate major genomic rearrangements. In this study, we identify insertions of previously undescribed sequence snippets in serum samples of a ribavirin treatment failure patient. These insertions increase viral replication while not affecting sensitivity towards ribavirin in a subgenomic replicon assay. All insertions contain a predicted nuclear localization sequence and alanine scanning mutagenesis of lysine residues in the HVR influences viral replication. Sequential replacement of lysine residues additionally alters intracellular localization in a fluorescence dye-coupled construct. Furthermore, distinct sequence patterns outside the HVR are identified as viral determinants that recapitulate the enhancing effect. In conclusion, patient-derived insertions can increase HEV replication and synergistically acting viral determinants in and outside the HVR are described. These results will help to understand the underlying principles of viral adaptation by viral- and host-sequence snatching during the clinical course of infection.

Date: 2024
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DOI: 10.1038/s41467-024-49219-8

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