%0 Journal Article
%T Hepatitis C Virus Cell-Cell Transmission and Resistance to Direct-Acting Antiviral Agents
%A Fei Xiao equal contributor
%A Isabel Fofana equal contributor
%A Laura Heydmann
%A Heidi Barth
%A Eric Soulier
%A Fran£żois Habersetzer
%A Michel Doffo£żl
%A Jens Bukh
%A Arvind H. Patel
%A Mirjam B. Zeisel
%A Thomas F. Baumert
%J PLOS Pathogens
%D 2014
%I Public Library of Science (PLoS)
%R doi/10.1371/journal.ppat.1004128
%X 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.
%U http://www.plospathogens.org/article/info%3Adoi%2F10.1371%2Fjournal.ppat.1004128