A ribavirin-induced ORF2 single-nucleotide variant produces defective hepatitis E virus particles with immune decoy function

Autor: Toni Luise Meister, Yannick Brüggemann, Maximilian K. Nocke, Rainer G. Ulrich, Jonas Schuhenn, Kathrin Sutter, André Gömer, Verian Bader, Konstanze F. Winklhofer, Ruth Broering, Lieven Verhoye, Philip Meuleman, Florian W. R. Vondran, Charline Camuzet, Laurence Cocquerel, Daniel Todt, Eike Steinmann
Přispěvatelé: Ruhr University Bochum (RUB), Friedrich-Loeffler-Institut (FLI), German Centre for Infection Research - partner site Hamburg-Lübeck-Borstel-Riems (DZIF), University of Duisburg-Essen, Universiteit Gent = Ghent University (UGENT), Hannover Medical School [Hannover] (MHH), Centre d’Infection et d’Immunité de Lille - INSERM U 1019 - UMR 9017 - UMR 8204 (CIIL), Institut Pasteur de Lille, Réseau International des Instituts Pasteur (RIIP)-Réseau International des Instituts Pasteur (RIIP)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Lille-Centre Hospitalier Régional Universitaire [Lille] (CHRU Lille)-Centre National de la Recherche Scientifique (CNRS), CHU Lille, European Virus Bioinformatics Center [Jena], German Centre for Infection Research (DZIF), Cocquerel, Laurence, Universität Duisburg-Essen = University of Duisburg-Essen [Essen]
Jazyk: angličtina
Rok vydání: 2022
Předmět:
Zdroj: PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA
Proceedings of the National Academy of Sciences of the United States of America
Proceedings of the National Academy of Sciences of the United States of America, 2022, ⟨10.1073/pnas.2202653119⟩
ISSN: 0027-8424
1091-6490
DOI: 10.1073/pnas.2202653119⟩
Popis: International audience; Hepatitis E virus (HEV) is the causative agent of hepatitis E in humans and is the leading cause of enterically transmitted viral hepatitis worldwide. Ribavirin (RBV) is currently the only treatment option for many patients; however, cases of treatment failures or posttreatment relapses have been frequently reported. RBV therapy was shown to be associated with an increase in HEV genome heterogeneity and the emergence of distinct HEV variants. In this study, we analyzed the impact of eight patient-derived open reading frame 2 (ORF2) single-nucleotide variants (SNVs), which occurred under RBV treatment, on the replication cycle and pathogenesis of HEV. The parental HEV strain and seven ORF2 variants showed comparable levels of RNA replication in human hepatoma cells and primary human hepatocytes. However, a P79S ORF2 variant demonstrated reduced RNA copy numbers released in the supernatant and an impairment in the production of infectious particles. Biophysical and biochemical characterization revealed that this SNV caused defective, smaller HEV particles with a loss of infectiousness. Furthermore, the P79S variant displayed an altered subcellular distribution of the ORF2 protein and was able to interfere with antibody-mediated neutralization of HEV in a competition assay. In conclusion, an SNV in the HEV ORF2 could be identified that resulted in altered virus particles that were noninfectious in vitro and in vivo, but could potentially serve as immune decoys. These findings provide insights in understanding the biology of circulating HEV variants and may guide development of personalized antiviral strategies in the future.
Databáze: OpenAIRE
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