Silibinin inhibits hepatitis C virus entry into hepatocytes by hindering clathrin-dependent trafficking

Authors

  • Julie Blaising,

    1. UMR CNRS 5086, IBCP, Lyon, France
    2. UMR Inserm U1052/CNRS 5286, Cancer Research Center of Lyon, University of Lyon, Lyon, France
    Current affiliation:
    1. UMR Inserm U1052/CNRS 5286, Cancer Research Center of Lyon (CRCL), Université de Lyon, Lyon, France
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  • Pierre L. Lévy,

    1. UMR Inserm U1052/CNRS 5286, Cancer Research Center of Lyon, University of Lyon, Lyon, France
    Current affiliation:
    1. UMR Inserm U1052/CNRS 5286, Cancer Research Center of Lyon (CRCL), Université de Lyon, Lyon, France
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  • Claire Gondeau,

    1. Inserm U1040, Institut de Recherche en Biothérapie, Hôpital St Eloi, Montpellier, France
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  • Capucine Phelip,

    1. UMR Inserm U1052/CNRS 5286, Cancer Research Center of Lyon, University of Lyon, Lyon, France
    Current affiliation:
    1. UMR Inserm U1052/CNRS 5286, Cancer Research Center of Lyon (CRCL), Université de Lyon, Lyon, France
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  • Mihayl Varbanov,

    1. UMR CNRS 5086, IBCP, Lyon, France
    Current affiliation:
    1. UMR7565, Université de Lorraine, CNRS, Nancy, France
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  • Elodie Teissier,

    1. UMR CNRS 5086, IBCP, Lyon, France
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  • Florence Ruggiero,

    1. IGFL, ENS de Lyon, Lyon, France
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  • Stephen J. Polyak,

    1. Department of Laboratory Medicine, University of Washington, Seattle, WA, USA
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  • Nicholas H. Oberlies,

    1. Department of Chemistry and Biochemistry, University of North Carolina at Greensboro, Greensboro, NC, USA
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  • Tijana Ivanovic,

    1. Department of Biological Chemistry and Molecular Pharmacology, Harvard Medical School, Boston, MA, USA
    2. Department of Molecular, Cellular and Developmental Biology, University of Colorado, Boulder, CO, USA
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  • Steeve Boulant,

    Corresponding author
    1. Department of Cell Biology, Harvard Medical School, Boston, MA, USA
    Current affiliation:
    1. Department of Infectiology, CHS Nachwuchsgruppe am CellNetworks Cluster und DKFZ, University of Heidelberg, Germany
    • UMR CNRS 5086, IBCP, Lyon, France
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    • Equal contribution. The authors declare no conflict of interest.
  • Eve-Isabelle Pécheur

    Corresponding authorCurrent affiliation:
    1. UMR Inserm U1052/CNRS 5286, Cancer Research Center of Lyon (CRCL), Université de Lyon, Lyon, France
    • UMR CNRS 5086, IBCP, Lyon, France
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    • Equal contribution. The authors declare no conflict of interest.

For correspondence. E-mail eve-isabelle.pecheur@inserm.fr; Tel. (+33) 472681975; Fax (+33) 472681971. E-mail s.boulant@dkfz-heidelberg.de; Tel. (+49) 6221421560; Fax (+49) 6221 42 1559.

Summary

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 ofsilymarin-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.

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