Hepatitis C Virus Cell-Cell Transmission and Resistance to Direct-Acting Antiviral Agents

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. © 2014 xiao et al.