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题目:: Hepatitis C virus cell-cell transmission and resistance to direct-acting antiviral agents.
作者:: Xiao(Fei),Fofana(Isabel),Heydmann(Laura),Barth(Heidi),Soulier(Eric),Habersetzer(François),Doffoël(Michel),Bukh(Jens),Patel(Arvind H),Zeisel(Mirjam B),Baumert(Thomas F)
状态:: 发布时间2014-05-16 , 更新时间 2016-12-06
期刊:: PLoS Pathog
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.
语言:: eng
DOI:

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