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

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 fr...

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Autores principales: Meister, Toni Luise, Brüggemann, Yannick, Nocke, Maximilian K., Ulrich, Rainer G., Schuhenn, Jonas, Sutter, Kathrin, Gömer, André, Bader, Verian, Winklhofer, Konstanze F., Broering, Ruth, Verhoye, Lieven, Meuleman, Philip, Vondran, Florian W. R., Camuzet, Charline, Cocquerel, Laurence, Todt, Daniel, Steinmann, Eike
Formato: Online Artículo Texto
Lenguaje:English
Publicado: National Academy of Sciences 2022
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9407633/
https://www.ncbi.nlm.nih.gov/pubmed/35969792
http://dx.doi.org/10.1073/pnas.2202653119
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author Meister, Toni Luise
Brüggemann, Yannick
Nocke, Maximilian K.
Ulrich, Rainer G.
Schuhenn, Jonas
Sutter, Kathrin
Gömer, André
Bader, Verian
Winklhofer, Konstanze F.
Broering, Ruth
Verhoye, Lieven
Meuleman, Philip
Vondran, Florian W. R.
Camuzet, Charline
Cocquerel, Laurence
Todt, Daniel
Steinmann, Eike
author_facet Meister, Toni Luise
Brüggemann, Yannick
Nocke, Maximilian K.
Ulrich, Rainer G.
Schuhenn, Jonas
Sutter, Kathrin
Gömer, André
Bader, Verian
Winklhofer, Konstanze F.
Broering, Ruth
Verhoye, Lieven
Meuleman, Philip
Vondran, Florian W. R.
Camuzet, Charline
Cocquerel, Laurence
Todt, Daniel
Steinmann, Eike
author_sort Meister, Toni Luise
collection PubMed
description 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.
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spelling pubmed-94076332022-08-26 A ribavirin-induced ORF2 single-nucleotide variant produces defective hepatitis E virus particles with immune decoy function Meister, Toni Luise Brüggemann, Yannick Nocke, Maximilian K. Ulrich, Rainer G. Schuhenn, Jonas Sutter, Kathrin Gömer, André Bader, Verian Winklhofer, Konstanze F. Broering, Ruth Verhoye, Lieven Meuleman, Philip Vondran, Florian W. R. Camuzet, Charline Cocquerel, Laurence Todt, Daniel Steinmann, Eike Proc Natl Acad Sci U S A Biological Sciences 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. National Academy of Sciences 2022-08-15 2022-08-23 /pmc/articles/PMC9407633/ /pubmed/35969792 http://dx.doi.org/10.1073/pnas.2202653119 Text en Copyright © 2022 the Author(s). Published by PNAS. https://creativecommons.org/licenses/by-nc-nd/4.0/This open access article is distributed under Creative Commons Attribution-NonCommercial-NoDerivatives License 4.0 (CC BY-NC-ND) (https://creativecommons.org/licenses/by-nc-nd/4.0/) .
spellingShingle Biological Sciences
Meister, Toni Luise
Brüggemann, Yannick
Nocke, Maximilian K.
Ulrich, Rainer G.
Schuhenn, Jonas
Sutter, Kathrin
Gömer, André
Bader, Verian
Winklhofer, Konstanze F.
Broering, Ruth
Verhoye, Lieven
Meuleman, Philip
Vondran, Florian W. R.
Camuzet, Charline
Cocquerel, Laurence
Todt, Daniel
Steinmann, Eike
A ribavirin-induced ORF2 single-nucleotide variant produces defective hepatitis E virus particles with immune decoy function
title A ribavirin-induced ORF2 single-nucleotide variant produces defective hepatitis E virus particles with immune decoy function
title_full A ribavirin-induced ORF2 single-nucleotide variant produces defective hepatitis E virus particles with immune decoy function
title_fullStr A ribavirin-induced ORF2 single-nucleotide variant produces defective hepatitis E virus particles with immune decoy function
title_full_unstemmed A ribavirin-induced ORF2 single-nucleotide variant produces defective hepatitis E virus particles with immune decoy function
title_short A ribavirin-induced ORF2 single-nucleotide variant produces defective hepatitis E virus particles with immune decoy function
title_sort ribavirin-induced orf2 single-nucleotide variant produces defective hepatitis e virus particles with immune decoy function
topic Biological Sciences
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9407633/
https://www.ncbi.nlm.nih.gov/pubmed/35969792
http://dx.doi.org/10.1073/pnas.2202653119
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