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

PLoS Pathogens

Michel Doffoël¹  Laura Heydmann¹  Fei Xiao¹  Mirjam B. Zeisel¹  Eric Soulier¹  Arvind H. Patel²  Isabel Fofana³  François Habersetzer³  Thomas F. Baumert³  Heidi Barth³  Jens Bukh³ 

[1] Inserm, U1110, Strasbourg, France;Laboratoire de Virologie, Hôpitaux Universitaires de Strasbourg, Strasbourg, France;Université de Strasbourg, Strasbourg, France

关键词: Hepatitis C virus;    Antimicrobial resistance;    Cell cultures;    Viral transmission;    infection;    Viral load;    Antibodies;    Flow cytometry;    RNA sequencing;   

DOI  :  10.1371/journal.ppat.1004128

学科分类：生物科学（综合）

来源: Public Library of Science

【 摘 要 】

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.

【 授权许可】

CC BY