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Role of low-density lipoprotein receptor in the hepatitis C virus life cycle

Authors

  • Anna Albecka,

    1. Institut Pasteur de Lille, Center for Infection and Immunity of Lille, Lille, France; Inserm U1019, Lille, France; CNRS UMR8204, Lille, France; The University of Lille Nord de France, Lille, France
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  • Sandrine Belouzard,

    1. Institut Pasteur de Lille, Center for Infection and Immunity of Lille, Lille, France; Inserm U1019, Lille, France; CNRS UMR8204, Lille, France; The University of Lille Nord de France, Lille, France
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  • Anne Op de Beeck,

    1. Laboratoire de Virologie Moléculaire, Université Libre de Bruxelles, Brussels, Belgium
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  • Véronique Descamps,

    1. Laboratoire de Virologie EA4294, Centre Hospitalier Universitaire d'Amiens, Université de Picardie Jules Verne, Amiens, France
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  • Lucie Goueslain,

    1. Institut Pasteur de Lille, Center for Infection and Immunity of Lille, Lille, France; Inserm U1019, Lille, France; CNRS UMR8204, Lille, France; The University of Lille Nord de France, Lille, France
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  • Justine Bertrand-Michel,

    1. Lipidomic-MetaToul Platform, INSERM, UMR1048, Toulouse, France
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  • François Tercé,

    1. Lipidomic-MetaToul Platform, INSERM, UMR1048, Toulouse, France
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  • Gilles Duverlie,

    1. Laboratoire de Virologie EA4294, Centre Hospitalier Universitaire d'Amiens, Université de Picardie Jules Verne, Amiens, France
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  • Yves Rouillé,

    1. Institut Pasteur de Lille, Center for Infection and Immunity of Lille, Lille, France; Inserm U1019, Lille, France; CNRS UMR8204, Lille, France; The University of Lille Nord de France, Lille, France
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  • Jean Dubuisson

    Corresponding author
    1. Institut Pasteur de Lille, Center for Infection and Immunity of Lille, Lille, France; Inserm U1019, Lille, France; CNRS UMR8204, Lille, France; The University of Lille Nord de France, Lille, France
    • Molecular and Cellular Virology of Hepatitis C, CIIL, Inserm (U1019) and CNRS (UMR8204), Institut Pasteur de Lille, Bâtiment IBL, 1 rue Calmette, BP447, 59021 Lille, France===

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    • fax: (+33) 3 20 87 12 01


  • Potential conflict of interest: Nothing to report.

  • This work was supported by the French “Agence Nationale de Recherche sur le Sida et les hépatites virales” (ANRS) and by a Marie Curie Research Training Network (MRTN-CT-2006-035599). A.A. was successively supported by a Marie Curie Research Training Network (MRTN-CT-2006-035599) and by a fellowship from the ANRS. J.D. was an international scholar of the Howard Hughes Medical Institute.

Abstract

Hepatitis C virus (HCV) particles are known to be in complex with lipoproteins. As a result of this interaction, the low-density lipoprotein (LDL) receptor (LDLR) has been proposed as a potential entry factor for HCV; however, its implication in virus entry remains unclear. Here, we reinvestigated the role of the LDLR in the HCV life cycle by comparing virus entry to the mechanism of lipoprotein uptake. A small interfering RNA targeting the LDLR in Huh-7 cells reduced HCV infectivity, confirming that this receptor plays a role in the life cycle of HCV generated in cell culture. However, kinetics of internalization were much faster for lipoproteins than for infectious HCV particles. Furthermore, a decrease in HCV RNA replication was observed by blocking the LDLR with a specific antibody, and this was associated with an increase in the ratio of phosphatidylethanolamine to phosphatidylcholine in host cells. Nevertheless, a soluble form of the LDLR inhibited both HCV entry into the hepatocytes and its binding to the LDLR expressed on Chinese hamster ovary cells, suggesting a direct interaction between the HCV particle and the LDLR. Finally, we showed that modification of HCV particles by lipoprotein lipase (LPL) reduces HCV infectivity and increases HCV binding to LDLR. Importantly, LPL treatment also induced an increase in RNA internalization, suggesting that LDLR, at least in some conditions, leads to nonproductive internalization of HCV. Conclusion: The LDLR is not essential for infectious HCV particle entry, whereas the physiological function of this receptor is important for optimal replication of the HCV genome. (HEPATOLOGY 2012)

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