title: The kinase-inhibitor sorafenib inhibits multiple steps of the Hepatitis C Virus infectious cycle in vitro.
abstract: Hepatitis C Virus (HCV) chronic infection is a major cause of hepatocellular carcinoma. Sorafenib is the only medical treatment that has been approved for the treatment of this cancer. It is a multikinase inhibitor with anti-tumor activity against a wide variety of cancers. Sorafenib blocks angiogenesis and tumor cell proliferation through inhibition of kinases, such as VEGFR2, PDGFR, or the serine/threonine kinases RAF. Previous studies have reported an anti-HCV effect of sorafenib in vitro, but various mechanisms of action have been described. The aim of this study was to clarify the action of sorafenib on the complete HCV infectious cycle. In order to examine the action of sorafenib on all steps of the HCV infectious cycle, we used a combination of validated cell culture models, based on the HuH-7 reference cell line and primary human hepatocytes. We found that sorafenib blocks HCV infection by altering the viral entry step and the production of viral particles. Moreover, we observed that treatment with sorafenib lead to a modification of Claudin-1 expression and localization, which could partly be responsible for the anti-HCV effect. Collectively, our findings confirm the anti-HCV effect of sorafenib in vitro, while highlighting the complexity of the action of sorafenib on the HCV infectious cycle.
authors.affiliation: EA4294, Laboratoire de Virologie, Centre Hospitalier Universitaire et Université de Picardie Jules Verne, Amiens, France.
authors.forename: Véronique
authors.initials: V
authors.lastname: Descamps
authors.affiliation: EA4294, Laboratoire de Virologie, Centre Hospitalier Universitaire et Université de Picardie Jules Verne, Amiens, France.
authors.forename: François
authors.initials: F
authors.lastname: Helle
authors.affiliation: EA4666, Laboratoire de Biochimie, Centre Hospitalier Universitaire et Université de Picardie Jules Verne, Amiens, France.
authors.forename: Christophe
authors.initials: C
authors.lastname: Louandre
authors.affiliation: EA4294, Laboratoire de Virologie, Centre Hospitalier Universitaire et Université de Picardie Jules Verne, Amiens, France.
authors.forename: Elodie
authors.initials: E
authors.lastname: Martin
authors.affiliation: EA4294, Laboratoire de Virologie, Centre Hospitalier Universitaire et Université de Picardie Jules Verne, Amiens, France.
authors.forename: Etienne
authors.initials: E
authors.lastname: Brochot
authors.affiliation: EA4294, Laboratoire de Virologie, Centre Hospitalier Universitaire et Université de Picardie Jules Verne, Amiens, France.
authors.forename: Laure
authors.initials: L
authors.lastname: Izquierdo
authors.affiliation: EA4294, Laboratoire de Virologie, Centre Hospitalier Universitaire et Université de Picardie Jules Verne, Amiens, France.
authors.forename: Carole
authors.initials: C
authors.lastname: Fournier
authors.affiliation: EA4294, Laboratoire de Virologie, Centre Hospitalier Universitaire et Université de Picardie Jules Verne, Amiens, France.
authors.forename: Thomas W
authors.initials: TW
authors.lastname: Hoffmann
authors.affiliation: EA4294, Laboratoire de Virologie, Centre Hospitalier Universitaire et Université de Picardie Jules Verne, Amiens, France.
authors.forename: Sandrine
authors.initials: S
authors.lastname: Castelain
authors.affiliation: EA4294, Laboratoire de Virologie, Centre Hospitalier Universitaire et Université de Picardie Jules Verne, Amiens, France.
authors.forename: Gilles
authors.initials: G
authors.lastname: Duverlie
authors.affiliation: EA4666, Laboratoire de Biochimie, Centre Hospitalier Universitaire et Université de Picardie Jules Verne, Amiens, France.
authors.forename: Antoine
authors.initials: A
authors.lastname: Galmiche
authors.affiliation: EA4294, Laboratoire de Virologie, Centre Hospitalier Universitaire et Université de Picardie Jules Verne, Amiens, France. Electronic address: catherine.francois@u-picardie.fr.
authors.forename: Catherine
authors.initials: C
authors.lastname: François
mesh_terms: D000998:Antiviral Agents / Q000494:pharmacology*; D002478:Cells, Cultured; D016174:Hepacivirus / Q000187:drug effects* / Q000502:physiology; D022781:Hepatocytes / Q000187:drug effects / Q000821:virology*; D006801:Humans; D009536:Niacinamide / Q000031:analogs & derivatives* / Q000494:pharmacology; D010671:Phenylurea Compounds / Q000494:pharmacology*; D000077157:Sorafenib; D053586:Virus Internalization / Q000187:drug effects; D014779:Virus Replication / Q000187:drug effects
chemical_list: D000998:Antiviral Agents; D010671:Phenylurea Compounds; D009536:Niacinamide; D000077157:Sorafenib
keywords: Antiviral activity; Claudin-1; Hepatitis C Virus; Sorafenib