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

Publikation: Bidrag til tidsskriftTidsskriftartikelForskningfagfællebedømt

  • Fei Xiao
  • Isabel Fofana
  • Laura Heydmann
  • Heidi Barth
  • Eric Soulier
  • François Habersetzer
  • Michel Doffoël
  • Bukh, Jens
  • Arvind H Patel
  • Mirjam B Zeisel
  • Thomas F Baumert

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.

OriginalsprogEngelsk
Artikelnummere1004128
TidsskriftP L o S Pathogens
Vol/bind10
Udgave nummer5
Sider (fra-til)1-15
Antal sider16
ISSN1553-7366
DOI
StatusUdgivet - maj 2014

ID: 131071228