title: Targeting a host-cell entry factor barricades antiviral-resistant HCV variants from on-therapy breakthrough in human-liver mice.
abstract: Direct-acting antivirals (DAAs) inhibit hepatitis C virus (HCV) infection by targeting viral proteins that play essential roles in the replication process. However, selection of resistance-associated variants (RAVs) during DAA therapy has been a cause of therapeutic failure. In this study, we wished to address whether such RAVs could be controlled by the co-administration of host-targeting entry inhibitors that prevent intrahepatic viral spread.
  
  
  
  We investigated the effect of adding an entry inhibitor (the anti-scavenger receptor class B type I mAb1671) to a DAA monotherapy (the protease inhibitor ciluprevir) in human-liver mice chronically infected with HCV of genotype 1b. Clinically relevant non-laboratory strains were used to achieve viraemia consisting of a cloud of related viral variants (quasispecies) and the emergence of RAVs was monitored at high resolution using next-generation sequencing.
  
  
  
  HCV-infected human-liver mice receiving DAA monotherapy rapidly experienced on-therapy viral breakthrough. Deep sequencing of the HCV protease domain confirmed the manifestation of drug-resistant mutants upon viral rebound. In contrast, none of the mice treated with a combination of the DAA and the entry inhibitor experienced on-therapy viral breakthrough, despite detection of RAV emergence in some animals.
  
  
  
  This study provides preclinical in vivo evidence that addition of an entry inhibitor to an anti-HCV DAA regimen restricts the breakthrough of DAA-resistant viruses. Our approach is an excellent strategy to prevent therapeutic failure caused by on-therapy rebound of DAA-RAVs. Inclusion of an entry inhibitor to the newest DAA combination therapies may further increase response rates, especially in difficult-to-treat patient populations.
authors: Department Clinical Chemistry, Microbiology and Immunology, Center for Vaccinology, Ghent University, Ghent, Belgium.
authors: Koen
authors: K
authors: Vercauteren
authors: Institute of Experimental Virology, TWINCORE, Centre for Experimental and Clinical Infection Research; a joint venture between the Medical School Hannover (MHH) and the Helmholtz Centre for Infection Research (HZI), Hannover, Germany.
authors: Richard J P
authors: RJ
authors: Brown
authors: Department Clinical Chemistry, Microbiology and Immunology, Center for Vaccinology, Ghent University, Ghent, Belgium.
authors: Ahmed Atef
authors: AA
authors: Mesalam
authors: Institute of Experimental Virology, TWINCORE, Centre for Experimental and Clinical Infection Research; a joint venture between the Medical School Hannover (MHH) and the Helmholtz Centre for Infection Research (HZI), Hannover, Germany.
authors: Juliane
authors: J
authors: Doerrbecker
authors: Genome Analytics, Helmholtz Centre for Infection Research, Braunschweig, Germany.
authors: Sabin
authors: S
authors: Bhuju
authors: Genome Analytics, Helmholtz Centre for Infection Research, Braunschweig, Germany.
authors: Robert
authors: R
authors: Geffers
authors: Department Clinical Chemistry, Microbiology and Immunology, Center for Vaccinology, Ghent University, Ghent, Belgium.
authors: Naomi
authors: N
authors: Van Den Eede
authors: School of Life Sciences and the NIHR Nottingham Digestive Diseases Biomedical Research Unit, University of Nottingham, Queen's Medical Centre, Nottingham, UK.
authors: C Patrick
authors: CP
authors: McClure
authors: CEINGE, Naples, Italy.
authors: Fulvia
authors: F
authors: Troise
authors: Department Clinical Chemistry, Microbiology and Immunology, Center for Vaccinology, Ghent University, Ghent, Belgium.
authors: Lieven
authors: L
authors: Verhoye
authors: Institut National de la Santé et de la Recherche Médicale, U1110, Strasbourg, France.|Université de Strasbourg, Strasbourg et Pole Hépato-digestif, Hopitaux Universitaires de Strasbourg, Strasbourg, France.
authors: Thomas
authors: T
authors: Baumert
authors: Department Clinical Chemistry, Microbiology and Immunology, Center for Vaccinology, Ghent University, Ghent, Belgium.
authors: Ali
authors: A
authors: Farhoudi
authors: CEINGE, Naples, Italy.
authors: Riccardo
authors: R
authors: Cortese
authors: School of Life Sciences and the NIHR Nottingham Digestive Diseases Biomedical Research Unit, University of Nottingham, Queen's Medical Centre, Nottingham, UK.
authors: Jonathan K
authors: JK
authors: Ball
authors: Department Clinical Chemistry, Microbiology and Immunology, Center for Vaccinology, Ghent University, Ghent, Belgium.
authors: Geert
authors: G
authors: Leroux-Roels
authors: Institute of Experimental Virology, TWINCORE, Centre for Experimental and Clinical Infection Research; a joint venture between the Medical School Hannover (MHH) and the Helmholtz Centre for Infection Research (HZI), Hannover, Germany.|German Centre for Infection Research (DZIF), Partner site Hannover-Braunschweig, Hannover, Germany.
authors: Thomas
authors: T
authors: Pietschmann
authors: CEINGE, Naples, Italy.|Department of Molecular Medicine and Medical Biotechnology, University of Naples Federico II, Naples, Italy.
authors: Alfredo
authors: A
authors: Nicosia
authors: Department Clinical Chemistry, Microbiology and Immunology, Center for Vaccinology, Ghent University, Ghent, Belgium.
authors: Philip
authors: P
authors: Meuleman
mesh_terms: D019943:Amino Acid Substitution; D000818:Animals; D000998:Antiviral Agents / Q000494:pharmacology*; D004195:Disease Models, Animal; D024882:Drug Resistance, Viral / Q000235:genetics*; D005838:Genotype; D016174:Hepacivirus / Q000187:drug effects / Q000235:genetics*; D019698:Hepatitis C, Chronic / Q000188:drug therapy; D008099:Liver / Q000187:drug effects; D051379:Mice; D020125:Mutation, Missense; D011480:Protease Inhibitors / Q000494:pharmacology*; D017361:Viral Nonstructural Proteins / Q000235:genetics; D012324:RNA-Dependent RNA Polymerase
chemical_list: D000998:Antiviral Agents; D011480:Protease Inhibitors; D017361:Viral Nonstructural Proteins; C087036:NS-5 protein, hepatitis C virus; D012324:RNA-Dependent RNA Polymerase
keywords: ANTIVIRAL THERAPY; CHRONIC VIRAL HEPATITIS; HCV; HEPATITIS C; LIVER