PLoS Pathogens | |
Hepatitis C Virus Cell-Cell Transmission and Resistance to Direct-Acting Antiviral Agents | |
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
【 预 览 】
Files | Size | Format | View |
---|---|---|---|
RO201902013847415ZK.pdf | 1736KB | download |