title: Silibinin inhibits hepatitis C virus entry into hepatocytes by hindering clathrin-dependent trafficking.
abstract: Hepatitis C virus (HCV) is a global health concern infecting 170 million people worldwide. Previous studies indicate that the extract from milk thistle known as silymarin and its main component silibinin inhibit HCV infection. Here we investigated the mechanism of anti-HCV action of silymarin-derived compounds at the molecular level. By using live-cell confocal imaging, single particle tracking, transmission electron microscopy and biochemical approaches on HCV-infected human hepatoma cells and primary hepatocytes, we show that silibinin potently inhibits HCV infection and hinders HCV entry by slowing down trafficking through clathrin-coated pits and vesicles. Detailed analyses revealed that silibinin altered the formation of both clathrin-coated pits and vesicles in cells and caused abnormal uptake and trafficking of transferrin, a well-known cargo of the clathrin endocytic pathway. Silibinin also inhibited infection by other viruses that enter cells by clathrin-mediated endocytosis including reovirus, vesicular stomatitis and influenza viruses. Our study demonstrates that silibinin inhibits HCV early steps of infection by affecting endosomal trafficking of virions. It provides new insights into the molecular mechanisms of action of silibinin against HCV entry and also suggests that silibinin is a potential broad-spectrum antiviral therapy.
authors.affiliation: UMR CNRS 5086, IBCP, Lyon, France; UMR Inserm U1052/CNRS 5286, Cancer Research Center of Lyon, University of Lyon, Lyon, France.
authors.forename: Julie
authors.initials: J
authors.lastname: Blaising
authors.forename: Pierre L
authors.initials: PL
authors.lastname: Lévy
authors.forename: Claire
authors.initials: C
authors.lastname: Gondeau
authors.forename: Capucine
authors.initials: C
authors.lastname: Phelip
authors.forename: Mihayl
authors.initials: M
authors.lastname: Varbanov
authors.forename: Elodie
authors.initials: E
authors.lastname: Teissier
authors.forename: Florence
authors.initials: F
authors.lastname: Ruggiero
authors.forename: Stephen J
authors.initials: SJ
authors.lastname: Polyak
authors.forename: Nicholas H
authors.initials: NH
authors.lastname: Oberlies
authors.forename: Tijana
authors.initials: T
authors.lastname: Ivanovic
authors.forename: Steeve
authors.initials: S
authors.lastname: Boulant
authors.forename: Eve-Isabelle
authors.initials: EI
authors.lastname: Pécheur
mesh_terms: D000998:Antiviral Agents / Q000378:metabolism*; D002478:Cells, Cultured; D002966:Clathrin / Q000378:metabolism*; D003584:Cytological Techniques; D004705:Endocytosis / Q000187:drug effects*; D016174:Hepacivirus / Q000187:drug effects* / Q000502:physiology; D022781:Hepatocytes / Q000187:drug effects* / Q000502:physiology / Q000821:virology; D006801:Humans; D018613:Microscopy, Confocal; D046529:Microscopy, Electron, Transmission; D020944:Silybum marianum / Q000737:chemistry; D000077385:Silybin; D012838:Silymarin / Q000302:isolation & purification / Q000378:metabolism*; D053586:Virus Internalization / Q000187:drug effects*
chemical_list: D000998:Antiviral Agents; D002966:Clathrin; D012838:Silymarin; D000077385:Silybin