title: Monoclonal anti-envelope antibody AP33 protects humanized mice against a patient-derived hepatitis C virus challenge.
abstract: End-stage liver disease (ESLD) caused by hepatitis C virus (HCV) infection is a major indication for liver transplantation. However, immediately after transplantation, the liver graft of viremic patients universally becomes infected by circulating virus, resulting in accelerated liver disease progression. Currently available direct-acting antiviral therapies have reduced efficacy in patients with ESLD and prophylactic strategies to prevent HCV recurrence are still highly needed. In this study, we compared the ability of two broadly reactive monoclonal antibodies (mAbs), designated 3/11 and AP33, recognizing a distinct, but overlapping, epitope in the viral E2 glycoprotein to protect humanized mice from a patient-derived HCV challenge. Their neutralizing activity was assessed using the HCV pseudoparticles and cell-culture-derived HCV systems expressing multiple patient-derived envelopes and a human-liver chimeric mouse model. HCV RNA was readily detected in all control mice challenged with a patient-derived HCV genotype 1b isolate, whereas 3 of 4 AP33-treated mice were completely protected. In contrast, only one of four 3/11-treated mice remained HCV-RNA negative throughout the observation period, whereas the other 3 had a viral load that was indistinguishable from that in the control group. The increased in vivo efficacy of AP33 was in line with its higher affinity and neutralizing capacity observed in vitro.
  
  
  CONCLUSIONS
  Although mAbs AP33 and 3/11 target the same region in E2, only mAb AP33 can efficiently protect from challenge with a heterologous HCV population in vivo. Given that mAb AP33 efficiently neutralizes viral variants that escaped the humoral immune response and reinfected the liver graft of transplant patients, it may be a valuable candidate to prevent HCV recurrence. In addition, our data are valuable for the design of a prophylactic vaccine.
authors.affiliation: Center for Vaccinology, Ghent University, Ghent, Belgium.
authors.forename: Isabelle
authors.initials: I
authors.lastname: Desombere
authors.affiliation: Inserm U1110, Institut de Recherche sur les Maladies Virales et Hépatiques, Strasbourg, France.|Université de Strasbourg, Strasbourg, France.|Laboratoire de Virologie, Hôpitaux Universitaires de Strasbourg, Strasbourg, France.
authors.forename: Samira
authors.initials: S
authors.lastname: Fafi-Kremer
authors.affiliation: Center for Vaccinology, Ghent University, Ghent, Belgium.
authors.forename: Freya
authors.initials: F
authors.lastname: Van Houtte
authors.affiliation: Inserm U1110, Institut de Recherche sur les Maladies Virales et Hépatiques, Strasbourg, France.|Université de Strasbourg, Strasbourg, France.|Institut Hopitalo-Universitaire, Pole Hépato-digestif, Hôpitaux Universitaires de Strasbourg, Strasbourg, France.
authors.forename: Patrick
authors.initials: P
authors.lastname: Pessaux
authors.affiliation: Center for Vaccinology, Ghent University, Ghent, Belgium.
authors.forename: Ali
authors.initials: A
authors.lastname: Farhoudi
authors.affiliation: Inserm U1110, Institut de Recherche sur les Maladies Virales et Hépatiques, Strasbourg, France.|Université de Strasbourg, Strasbourg, France.
authors.forename: Laura
authors.initials: L
authors.lastname: Heydmann
authors.affiliation: Center for Vaccinology, Ghent University, Ghent, Belgium.
authors.forename: Lieven
authors.initials: L
authors.lastname: Verhoye
authors.affiliation: MRC-University of Glasgow Center for Virus Research, University of Glasgow, Glasgow, United Kingdom.
authors.forename: Sarah
authors.initials: S
authors.lastname: Cole
authors.affiliation: Viral Hepatitis Research Group, Center for Human Virology, University of Birmingham, Birmingham, United Kingdom.
authors.forename: Jane A
authors.initials: JA
authors.lastname: McKeating
authors.affiliation: Center for Vaccinology, Ghent University, Ghent, Belgium.
authors.forename: Geert
authors.initials: G
authors.lastname: Leroux-Roels
authors.affiliation: Inserm U1110, Institut de Recherche sur les Maladies Virales et Hépatiques, Strasbourg, France.|Université de Strasbourg, Strasbourg, France.|Institut Hopitalo-Universitaire, Pole Hépato-digestif, Hôpitaux Universitaires de Strasbourg, Strasbourg, France.
authors.forename: Thomas F
authors.initials: TF
authors.lastname: Baumert
authors.affiliation: MRC-University of Glasgow Center for Virus Research, University of Glasgow, Glasgow, United Kingdom.
authors.forename: Arvind H
authors.initials: AH
authors.lastname: Patel
authors.affiliation: Center for Vaccinology, Ghent University, Ghent, Belgium.
authors.forename: Philip
authors.initials: P
authors.lastname: Meuleman
mesh_terms: D000818:Animals; D000911:Antibodies, Monoclonal / Q000494:pharmacology*; D002478:Cells, Cultured; D004195:Disease Models, Animal; D004797:Enzyme-Linked Immunosorbent Assay; D000939:Epitopes; D016174:Hepacivirus / Q000276:immunology*; D006526:Hepatitis C / Q000188:drug therapy* / Q000276:immunology*; D018937:Hepatitis C Antibodies / Q000276:immunology* / Q000378:metabolism; D006801:Humans; D051379:Mice; D008822:Mice, Transgenic; D018709:Statistics, Nonparametric; D014759:Viral Envelope Proteins / Q000276:immunology*
chemical_list: D000911:Antibodies, Monoclonal; D000939:Epitopes; D018937:Hepatitis C Antibodies; D014759:Viral Envelope Proteins