Hepatitis C virus cell-cell transmission and resistance to direct-acting antiviral agents

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
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 > Institute of Infection Immunity and Inflammation
Journal Name:PLoS Pathogens
Publisher:Public Library of Science
ISSN:1553-7374
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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Project CodeAward NoProject NamePrincipal InvestigatorFunder's NameFunder RefLead Dept
656491Basis of the host range and tissue tropism for hepatitis C virusArvind PatelMedical Research Council (MRC)MC_UU_12014/2MVLS III - CENTRE FOR VIRUS RESEARCH