Xiao, FeiFofana, IsabelHeydmann, LauraBarth, HeidiSoulier, EricHabersetzer, FrançoisDoffoël, MichelBukh, JensPatel, Arvind H.Zeisel, Mirjam B.Baumert, Thomas F.2014-07-072014Xiao, F., I. Fofana, L. Heydmann, H. Barth, E. Soulier, F. Habersetzer, M. Doffoël, 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. http://dx.doi.org/10.1371/journal.ppat.1004128.1553-7366http://nrs.harvard.edu/urn-3:HUL.InstRepos:12406955Hepatitis 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.en-USBiology and life sciencesMicrobiologyVirologyViral ClassificationOrganismsVirusesRNA virusesMedicine and health sciencesGastroenterology and hepatologyLiver diseasesInfectious hepatitisHepatitis CInfectious DiseasesViral DiseasesHepatitisJournal Article2014-07-0710.1371/journal.ppat.1004128