Genetic determinants of host- and virus-derived insertions for hepatitis E virus replication
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Published:2024-06-06
Issue:1
Volume:15
Page:
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ISSN:2041-1723
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Container-title:Nature Communications
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language:en
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Short-container-title:Nat Commun
Author:
Wißing Michael Hermann, Meister Toni LuiseORCID, Nocke Maximilian Klaus, Gömer André, Masovic Mejrema, Knegendorf LeonardORCID, Brüggemann Yannick, Bader VerianORCID, Siddharta Anindya, Bock Claus-ThomasORCID, Ploss AlexanderORCID, Kenney Scott P., Winklhofer Konstanze F., Behrendt Patrick, Wedemeyer Heiner, Steinmann EikeORCID, Todt DanielORCID
Abstract
AbstractHepatitis 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.
Funder
Deutsche Forschungsgemeinschaft Bundesministerium für Bildung und Forschung Bundesministerium für Gesundheit Deutsches Zentrum für Infektionsforschung
Publisher
Springer Science and Business Media LLC
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