Xiao, F. et al. (2014) Hepatitis C virus cell-cell transmission and resistance to direct-acting antiviral agents. PLoS Pathogens, 10(5), e1004128. (doi: 10.1371/journal.ppat.1004128) (PMID:24830295) (PMCID:PMC4022730)
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Abstract
Hepatitis C virus (HCV) is transmitted between hepatocytes via classical cell entry but also uses direct cell-cell transfer to infect neighboring hepatocytes. Viral cell-cell transmission has been shown to play an important role in viral persistence allowing evasion from neutralizing antibodies. In contrast, the role of HCV cell-cell transmission for antiviral resistance is unknown. Aiming to address this question we investigated the phenotype of HCV strains exhibiting resistance to direct-acting antivirals (DAAs) in state-of-the-art model systems for cell-cell transmission and spread. Using HCV genotype 2 as a model virus, we show that cell-cell transmission is the main route of viral spread of DAA-resistant HCV. Cell-cell transmission of DAA-resistant viruses results in viral persistence and thus hampers viral eradication. We also show that blocking cell-cell transmission using host-targeting entry inhibitors (HTEIs) was highly effective in inhibiting viral dissemination of resistant genotype 2 viruses. Combining HTEIs with DAAs prevented antiviral resistance and led to rapid elimination of the virus in cell culture model. In conclusion, our work provides evidence that cell-cell transmission plays an important role in dissemination and maintenance of resistant variants in cell culture models. Blocking virus cell-cell transmission prevents emergence of drug resistance in persistent viral infection including resistance to HCV DAAs.
Item Type: | Articles |
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Status: | Published |
Refereed: | Yes |
Glasgow Author(s) Enlighten ID: | Patel, Professor Arvind |
Authors: | Xiao, F., Fofana, I., Heydmann, L., Barth, H., Soulier, E., Habersetzer, F., Doffoël, M., Bukh, J., Patel, A. H., Zeisel, M. B., and Baumert, T. F. |
College/School: | College of Medical Veterinary and Life Sciences > School of Infection & Immunity College of Medical Veterinary and Life Sciences > School of Infection & Immunity > Centre for Virus Research |
Journal Name: | PLoS Pathogens |
Publisher: | Public Library of Science |
ISSN: | 1553-7366 |
ISSN (Online): | 1553-7374 |
Copyright Holders: | Copyright © 2014 The Authors |
First Published: | First published in PLoS Pathogens 10(5):e1004128 |
Publisher Policy: | Reproduced under a Creative Commons License |
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