Cargando…
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...
Autores principales: | , , , , , , , , , , , , , , , , |
---|---|
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 |
_version_ | 1784774411591614464 |
---|---|
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. |
format | Online Article Text |
id | pubmed-9407633 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2022 |
publisher | National Academy of Sciences |
record_format | MEDLINE/PubMed |
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 |
work_keys_str_mv | AT meistertoniluise aribavirininducedorf2singlenucleotidevariantproducesdefectivehepatitisevirusparticleswithimmunedecoyfunction AT bruggemannyannick aribavirininducedorf2singlenucleotidevariantproducesdefectivehepatitisevirusparticleswithimmunedecoyfunction AT nockemaximiliank aribavirininducedorf2singlenucleotidevariantproducesdefectivehepatitisevirusparticleswithimmunedecoyfunction AT ulrichrainerg aribavirininducedorf2singlenucleotidevariantproducesdefectivehepatitisevirusparticleswithimmunedecoyfunction AT schuhennjonas aribavirininducedorf2singlenucleotidevariantproducesdefectivehepatitisevirusparticleswithimmunedecoyfunction AT sutterkathrin aribavirininducedorf2singlenucleotidevariantproducesdefectivehepatitisevirusparticleswithimmunedecoyfunction AT gomerandre aribavirininducedorf2singlenucleotidevariantproducesdefectivehepatitisevirusparticleswithimmunedecoyfunction AT baderverian aribavirininducedorf2singlenucleotidevariantproducesdefectivehepatitisevirusparticleswithimmunedecoyfunction AT winklhoferkonstanzef aribavirininducedorf2singlenucleotidevariantproducesdefectivehepatitisevirusparticleswithimmunedecoyfunction AT broeringruth aribavirininducedorf2singlenucleotidevariantproducesdefectivehepatitisevirusparticleswithimmunedecoyfunction AT verhoyelieven aribavirininducedorf2singlenucleotidevariantproducesdefectivehepatitisevirusparticleswithimmunedecoyfunction AT meulemanphilip aribavirininducedorf2singlenucleotidevariantproducesdefectivehepatitisevirusparticleswithimmunedecoyfunction AT vondranflorianwr aribavirininducedorf2singlenucleotidevariantproducesdefectivehepatitisevirusparticleswithimmunedecoyfunction AT camuzetcharline aribavirininducedorf2singlenucleotidevariantproducesdefectivehepatitisevirusparticleswithimmunedecoyfunction AT cocquerellaurence aribavirininducedorf2singlenucleotidevariantproducesdefectivehepatitisevirusparticleswithimmunedecoyfunction AT todtdaniel aribavirininducedorf2singlenucleotidevariantproducesdefectivehepatitisevirusparticleswithimmunedecoyfunction AT steinmanneike aribavirininducedorf2singlenucleotidevariantproducesdefectivehepatitisevirusparticleswithimmunedecoyfunction AT meistertoniluise ribavirininducedorf2singlenucleotidevariantproducesdefectivehepatitisevirusparticleswithimmunedecoyfunction AT bruggemannyannick ribavirininducedorf2singlenucleotidevariantproducesdefectivehepatitisevirusparticleswithimmunedecoyfunction AT nockemaximiliank ribavirininducedorf2singlenucleotidevariantproducesdefectivehepatitisevirusparticleswithimmunedecoyfunction AT ulrichrainerg ribavirininducedorf2singlenucleotidevariantproducesdefectivehepatitisevirusparticleswithimmunedecoyfunction AT schuhennjonas ribavirininducedorf2singlenucleotidevariantproducesdefectivehepatitisevirusparticleswithimmunedecoyfunction AT sutterkathrin ribavirininducedorf2singlenucleotidevariantproducesdefectivehepatitisevirusparticleswithimmunedecoyfunction AT gomerandre ribavirininducedorf2singlenucleotidevariantproducesdefectivehepatitisevirusparticleswithimmunedecoyfunction AT baderverian ribavirininducedorf2singlenucleotidevariantproducesdefectivehepatitisevirusparticleswithimmunedecoyfunction AT winklhoferkonstanzef ribavirininducedorf2singlenucleotidevariantproducesdefectivehepatitisevirusparticleswithimmunedecoyfunction AT broeringruth ribavirininducedorf2singlenucleotidevariantproducesdefectivehepatitisevirusparticleswithimmunedecoyfunction AT verhoyelieven ribavirininducedorf2singlenucleotidevariantproducesdefectivehepatitisevirusparticleswithimmunedecoyfunction AT meulemanphilip ribavirininducedorf2singlenucleotidevariantproducesdefectivehepatitisevirusparticleswithimmunedecoyfunction AT vondranflorianwr ribavirininducedorf2singlenucleotidevariantproducesdefectivehepatitisevirusparticleswithimmunedecoyfunction AT camuzetcharline ribavirininducedorf2singlenucleotidevariantproducesdefectivehepatitisevirusparticleswithimmunedecoyfunction AT cocquerellaurence ribavirininducedorf2singlenucleotidevariantproducesdefectivehepatitisevirusparticleswithimmunedecoyfunction AT todtdaniel ribavirininducedorf2singlenucleotidevariantproducesdefectivehepatitisevirusparticleswithimmunedecoyfunction AT steinmanneike ribavirininducedorf2singlenucleotidevariantproducesdefectivehepatitisevirusparticleswithimmunedecoyfunction |