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.
Inserm, U1110, Strasbourg, France; Université de Strasbourg, Strasbourg, France.
Fei
F
Xiao
Inserm, U1110, Strasbourg, France; Université de Strasbourg, Strasbourg, France.
Isabel
I
Fofana
Inserm, U1110, Strasbourg, France; Université de Strasbourg, Strasbourg, France.
Laura
L
Heydmann
Inserm, U1110, Strasbourg, France; Université de Strasbourg, Strasbourg, France; Laboratoire de Virologie, Hôpitaux Universitaires de Strasbourg, Strasbourg, France.
Heidi
H
Barth
Inserm, U1110, Strasbourg, France; Université de Strasbourg, Strasbourg, France.
Eric
E
Soulier
Inserm, U1110, Strasbourg, France; Université de Strasbourg, Strasbourg, France; Pôle Hépato-digestif, Hôpitaux Universitaires de Strasbourg, Strasbourg, France.
François
F
Habersetzer
Inserm, U1110, Strasbourg, France; Université de Strasbourg, Strasbourg, France; Pôle Hépato-digestif, Hôpitaux Universitaires de Strasbourg, Strasbourg, France.
Michel
M
Doffoël
Copenhagen Hepatitis C Program (CO-HEP), Department of Infectious Diseases and Clinical Research Centre, Hvidovre Hospital and Department of International Health, Immunology and Microbiology, Faculty of Health and Medical Sciences, University of Copenhagen, Copenhagen, Denmark.
Jens
J
Bukh
MRC-University of Glasgow Centre for Virus Research, Glasgow, United Kingdom.
Arvind H
AH
Patel
Inserm, U1110, Strasbourg, France; Université de Strasbourg, Strasbourg, France.
Mirjam B
MB
Zeisel
Inserm, U1110, Strasbourg, France; Université de Strasbourg, Strasbourg, France; Pôle Hépato-digestif, Hôpitaux Universitaires de Strasbourg, Strasbourg, France; Gastrointestinal Unit, Massachusetts General Hospital, Harvard Medical School, Boston, Massachusetts, United States of America.
Thomas F
TF
Baumert
D057134:Antibodies, Neutralizing / Q000378:metabolism; D000998:Antiviral Agents / Q000494:pharmacology*; D002219:Carbamates; D002450:Cell Communication / Q000276:immunology; D002478:Cells, Cultured; D024882:Drug Resistance, Viral / Q000276:immunology; D016174:Hepacivirus / Q000187:drug effects* / Q000254:growth & development / Q000502:physiology*; D006526:Hepatitis C / Q000276:immunology* / Q000473:pathology / Q000821:virology*; D006801:Humans; D007093:Imidazoles / Q000494:pharmacology; D009842:Oligopeptides / Q000494:pharmacology; D011392:Proline / Q000031:analogs & derivatives / Q000494:pharmacology; D011759:Pyrrolidines; D014633:Valine / Q000031:analogs & derivatives; D019562:Viral Load / Q000276:immunology; D053586:Virus Internalization / Q000187:drug effects
D057134:Antibodies, Neutralizing; D000998:Antiviral Agents; D002219:Carbamates; D007093:Imidazoles; D009842:Oligopeptides; D011759:Pyrrolidines; C486464:telaprevir; C512204:N-(3-amino-1-(cyclobutylmethyl)-2,3-dioxopropyl)-3-(2-((((1,1-dimethylethyl)amino)carbonyl)amino)-3,3-dimethyl-1-oxobutyl)-6,6-dimethyl-3-azabicyclo(3.1.0)hexan-2-carboxamide; D011392:Proline; D014633:Valine; C549273:daclatasvir