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

• Main Authors: Fei Xiao, Isabel Fofana, Laura Heydmann, Heidi Barth, Eric Soulier, François Habersetzer, Michel Doffoël, Jens Bukh, Arvind H Patel, Mirjam B Zeisel, Thomas F Baumert
• Format: Article
• Language: English
• Published: Public Library of Science (PLoS) 2014-05-01
• Series: PLoS Pathogens
• Online Access: https://www.ncbi.nlm.nih.gov/pmc/articles/pmid/24830295/pdf/?tool=EBI

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.