title: Increased replicative fitness can lead to decreased drug sensitivity of hepatitis C virus.
abstract: Passage of hepatitis C virus (HCV) in human hepatoma cells resulted in populations that displayed partial resistance to alpha interferon (IFN-α), telaprevir, daclatasvir, cyclosporine, and ribavirin, despite no prior exposure to these drugs. Mutant spectrum analyses and kinetics of virus production in the absence and presence of drugs indicate that resistance is not due to the presence of drug resistance mutations in the mutant spectrum of the initial or passaged populations but to increased replicative fitness acquired during passage. Fitness increases did not alter host factors that lead to shutoff of general host cell protein synthesis and preferential translation of HCV RNA. The results imply that viral replicative fitness is a mechanism of multidrug resistance in HCV. Importance: Viral drug resistance is usually attributed to the presence of amino acid substitutions in the protein targeted by the drug. In the present study with HCV, we show that high viral replicative fitness can confer a general drug resistance phenotype to the virus. The results exclude the possibility that genomes with drug resistance mutations are responsible for the observed phenotype. The fact that replicative fitness can be a determinant of multidrug resistance may explain why the virus is less sensitive to drug treatments in prolonged chronic HCV infections that favor increases in replicative fitness.
authors.affiliation: Centro de Biología Molecular Severo Ochoa (CSIC-UAM), Consejo Superior de Investigaciones Científicas (CSIC), Madrid, Spain.
authors.forename: Julie
authors.initials: J
authors.lastname: Sheldon
authors.affiliation: Centro de Biología Molecular Severo Ochoa (CSIC-UAM), Consejo Superior de Investigaciones Científicas (CSIC), Madrid, Spain.
authors.forename: Nathan M
authors.initials: NM
authors.lastname: Beach
authors.affiliation: Centro de Biología Molecular Severo Ochoa (CSIC-UAM), Consejo Superior de Investigaciones Científicas (CSIC), Madrid, Spain.
authors.forename: Elena
authors.initials: E
authors.lastname: Moreno
authors.affiliation: Centro de Biología Molecular Severo Ochoa (CSIC-UAM), Consejo Superior de Investigaciones Científicas (CSIC), Madrid, Spain Centro de Investigación Biomédica en Red de Enfermedades Hepáticas y Digestivas (CIBERehd), Barcelona, Spain.
authors.forename: Isabel
authors.initials: I
authors.lastname: Gallego
authors.affiliation: Centro de Biología Molecular Severo Ochoa (CSIC-UAM), Consejo Superior de Investigaciones Científicas (CSIC), Madrid, Spain.
authors.forename: David
authors.initials: D
authors.lastname: Piñeiro
authors.affiliation: Centro de Biología Molecular Severo Ochoa (CSIC-UAM), Consejo Superior de Investigaciones Científicas (CSIC), Madrid, Spain.
authors.forename: Encarnación
authors.initials: E
authors.lastname: Martínez-Salas
authors.affiliation: Liver Unit, Internal Medicine Hospital Universitari Vall d'Hebron, Vall d'Hebron Institut de Recerca (VHIR), Barcelona, Spain Roche Diagnostics, S.L., Sant Cugat del Valles, Spain.
authors.forename: Josep
authors.initials: J
authors.lastname: Gregori
authors.affiliation: Centro de Investigación Biomédica en Red de Enfermedades Hepáticas y Digestivas (CIBERehd), Barcelona, Spain Liver Unit, Internal Medicine Hospital Universitari Vall d'Hebron, Vall d'Hebron Institut de Recerca (VHIR), Barcelona, Spain Universitat Autonoma de Barcelona, Barcelona, Spain.
authors.forename: Josep
authors.initials: J
authors.lastname: Quer
authors.affiliation: Centro de Investigación Biomédica en Red de Enfermedades Hepáticas y Digestivas (CIBERehd), Barcelona, Spain Liver Unit, Internal Medicine Hospital Universitari Vall d'Hebron, Vall d'Hebron Institut de Recerca (VHIR), Barcelona, Spain Universitat Autonoma de Barcelona, Barcelona, Spain.
authors.forename: Juan Ignacio
authors.initials: JI
authors.lastname: Esteban
authors.affiliation: Center for the Study of Hepatitis C, Laboratory of Virology and Infectious Disease, Rockefeller University, New York, New York, USA.
authors.forename: Charles M
authors.initials: CM
authors.lastname: Rice
authors.affiliation: Centro de Biología Molecular Severo Ochoa (CSIC-UAM), Consejo Superior de Investigaciones Científicas (CSIC), Madrid, Spain Centro de Investigación Biomédica en Red de Enfermedades Hepáticas y Digestivas (CIBERehd), Barcelona, Spain edomingo@cbm.uam.es cperales@cbm.uam.es.
authors.forename: Esteban
authors.initials: E
authors.lastname: Domingo
authors.affiliation: Centro de Biología Molecular Severo Ochoa (CSIC-UAM), Consejo Superior de Investigaciones Científicas (CSIC), Madrid, Spain Centro de Investigación Biomédica en Red de Enfermedades Hepáticas y Digestivas (CIBERehd), Barcelona, Spain edomingo@cbm.uam.es cperales@cbm.uam.es.
authors.forename: Celia
authors.initials: C
authors.lastname: Perales
mesh_terms: D000998:Antiviral Agents / Q000494:pharmacology; D015153:Blotting, Western; D045744:Cell Line, Tumor; D024882:Drug Resistance, Viral / Q000235:genetics*; D016174:Hepacivirus / Q000187:drug effects* / Q000235:genetics / Q000502:physiology; D006801:Humans; D009154:Mutation; D060888:Real-Time Polymerase Chain Reaction; D012692:Serial Passage; D014779:Virus Replication
chemical_list: D000998:Antiviral Agents