BACKGROUND & AIMS: Hepatitis C virus (HCV) infection is a challenge to prevent and treat because of the rapid development of drug resistance and escape. Viral entry is required for initiation, spread, and maintenance of infection, making it an attractive target for antiviral strategies. The tight junction protein claudin-1 (CLDN1) has been shown to be required for entry of HCV into the cell. METHODS: Using genetic immunization, we produced 6 monoclonal antibodies against the host entry factor CLDN1. The effects of antibodies on HCV infection were analyzed in human cell lines and primary human hepatocytes. RESULTS: Competition and binding studies demonstrated that antibodies interacted with conformational epitopes of the first extracellular loop of CLDN1; binding of these antibodies required the motif W(30)-GLW(51)-C(54)-C(64) and residues in the N-terminal third of CLDN1. The monoclonal antibodies against CLDN1 efficiently inhibited infection by HCV of all major genotypes as well as highly variable HCV quasispecies isolated from individual patients. Furthermore, antibodies efficiently blocked cell entry of highly infectious escape variants of HCV that were resistant to neutralizing antibodies. CONCLUSIONS: Monoclonal antibodies against the HCV entry factor CLDN1 might be used to prevent HCV infection, such as after liver transplantation, and might also restrain virus spread in chronically infected patients.
BACKGROUND & AIMS:Hepatitis C virus (HCV) infection is a challenge to prevent and treat because of the rapid development of drug resistance and escape. Viral entry is required for initiation, spread, and maintenance of infection, making it an attractive target for antiviral strategies. The tight junction protein claudin-1 (CLDN1) has been shown to be required for entry of HCV into the cell. METHODS: Using genetic immunization, we produced 6 monoclonal antibodies against the host entry factor CLDN1. The effects of antibodies on HCV infection were analyzed in human cell lines and primary human hepatocytes. RESULTS: Competition and binding studies demonstrated that antibodies interacted with conformational epitopes of the first extracellular loop of CLDN1; binding of these antibodies required the motif W(30)-GLW(51)-C(54)-C(64) and residues in the N-terminal third of CLDN1. The monoclonal antibodies against CLDN1 efficiently inhibited infection by HCV of all major genotypes as well as highly variable HCV quasispecies isolated from individual patients. Furthermore, antibodies efficiently blocked cell entry of highly infectious escape variants of HCV that were resistant to neutralizing antibodies. CONCLUSIONS: Monoclonal antibodies against the HCV entry factor CLDN1 might be used to prevent HCV infection, such as after liver transplantation, and might also restrain virus spread in chronically infectedpatients.
Authors: Joachim Lupberger; Mirjam B Zeisel; Fei Xiao; Christine Thumann; Isabel Fofana; Laetitia Zona; Christopher Davis; Christopher J Mee; Marine Turek; Sebastian Gorke; Cathy Royer; Benoit Fischer; Muhammad N Zahid; Dimitri Lavillette; Judith Fresquet; François-Loïc Cosset; S Michael Rothenberg; Thomas Pietschmann; Arvind H Patel; Patrick Pessaux; Michel Doffoël; Wolfgang Raffelsberger; Olivier Poch; Jane A McKeating; Laurent Brino; Thomas F Baumert Journal: Nat Med Date: 2011-04-24 Impact factor: 53.440
Authors: Philip Meuleman; Maria Teresa Catanese; Lieven Verhoye; Isabelle Desombere; Ali Farhoudi; Christopher T Jones; Timothy Sheahan; Katarzyna Grzyb; Riccardo Cortese; Charles M Rice; Geert Leroux-Roels; Alfredo Nicosia Journal: Hepatology Date: 2011-12-16 Impact factor: 17.425
Authors: Muriel Lavie; Stéphane Sarrazin; Roland Montserret; Véronique Descamps; Thomas F Baumert; Gilles Duverlie; Karin Séron; François Penin; Jean Dubuisson Journal: J Virol Date: 2014-07-02 Impact factor: 5.103