title: Mouse Systems to Model Hepatitis C Virus Treatment and Associated Resistance.
abstract: While addition of the first-approved protease inhibitors (PIs), telaprevir and boceprevir, to pegylated interferon (PEG-IFN) and ribavirin (RBV) combination therapy significantly increased sustained virologic response (SVR) rates, PI-based triple therapy for the treatment of chronic hepatitis C virus (HCV) infection was prone to the emergence of resistant viral variants. Meanwhile, multiple direct acting antiviral agents (DAAs) targeting either the HCV NS3/4A protease, NS5A or NS5B polymerase have been approved and these have varying potencies and distinct propensities to provoke resistance. The pre-clinical in vivo assessment of drug efficacy and resistant variant emergence underwent a great evolution over the last decade. This field had long been hampered by the lack of suitable small animal models that robustly support the entire HCV life cycle. In particular, chimeric mice with humanized livers (humanized mice) and chimpanzees have been instrumental for studying HCV inhibitors and the evolution of drug resistance. In this review, we present the different in vivo HCV infection models and discuss their applicability to assess HCV therapy response and emergence of resistant variants.
authors.affiliation: Center for Vaccinology, Department of Clinical Chemistry, Microbiology and Immunology, Ghent University, Ghent 9000, Belgium. ahmed.mesalam@ugent.be.|Therapeutic Chemistry Department, National Research Centre (NRC), Dokki, Cairo 12622, Egypt. ahmed.mesalam@ugent.be.
authors.forename: Ahmed Atef
authors.initials: AA
authors.lastname: Mesalam
authors.affiliation: Center for Vaccinology, Department of Clinical Chemistry, Microbiology and Immunology, Ghent University, Ghent 9000, Belgium. koen.vercauteren@ugent.be.|Laboratory of Virology and Infectious Disease, The Rockefeller University, New York, NY 10065, USA. koen.vercauteren@ugent.be.
authors.forename: Koen
authors.initials: K
authors.lastname: Vercauteren
authors.affiliation: Center for Vaccinology, Department of Clinical Chemistry, Microbiology and Immunology, Ghent University, Ghent 9000, Belgium. philip.meuleman@ugent.be.
authors.forename: Philip
authors.initials: P
authors.lastname: Meuleman
mesh_terms: D000818:Animals; D000998:Antiviral Agents / Q000008:administration & dosage*; D004195:Disease Models, Animal; D004353:Drug Evaluation, Preclinical / Q000379:methods; D024882:Drug Resistance, Viral; D016174:Hepacivirus / Q000187:drug effects*; D006526:Hepatitis C / Q000188:drug therapy* / Q000821:virology*; D006801:Humans; D051379:Mice; D002679:Pan troglodytes
chemical_list: D000998:Antiviral Agents
keywords: HCV; animal models; deep sequencing; direct acting antiviral agents; humanized mice; resistance; therapy