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, Daniel Todt

Research output: Contribution to journalArticlepeer-review


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.

Original languageEnglish (US)
Article number4855
JournalNature communications
Issue number1
StatePublished - Dec 2024

All Science Journal Classification (ASJC) codes

  • General Chemistry
  • General Biochemistry, Genetics and Molecular Biology
  • General Physics and Astronomy


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