Characterization of the inhibition of hepatitis C virus entry by In vitro–generated and patient-derived oxidized low-density lipoprotein

Authors

  • Sandra Westhaus,

    1. Institute for Molecular Biology, Medizinische Hochschule Hannover, Hannover, Germany
    2. Department of Gastroenterology, Hepatology and Endocrinology, Medizinische Hochschule Hannover, Hannover, Germany
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  • Dorothea Bankwitz,

    1. Division of Experimental Virology, Twincore Center for Experimental and Clinical Infection Research, Hannover, Germany
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  • Stefanie Ernst,

    1. Institute for Biometry, Medizinische Hochschule Hannover, Hannover, Germany
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  • Katrin Rohrmann,

    1. Institute for Molecular Biology, Medizinische Hochschule Hannover, Hannover, Germany
    2. Department of Gastroenterology, Hepatology and Endocrinology, Medizinische Hochschule Hannover, Hannover, Germany
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  • Ilka Wappler,

    1. Division of Experimental Virology, Twincore Center for Experimental and Clinical Infection Research, Hannover, Germany
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  • Clemens Agné,

    1. Department of Gastroenterology, Hepatology and Endocrinology, Medizinische Hochschule Hannover, Hannover, Germany
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  • Maren Luchtefeld,

    1. Department of Cardiology and Angiology, Medizinische Hochschule Hannover, Hannover, Germany
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  • Bernhard Schieffer,

    1. Department of Cardiology and Angiology, Medizinische Hochschule Hannover, Hannover, Germany
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  • Christoph Sarrazin,

    1. Medizinische Klinik I, Zentrum der Inneren Medizin, Klinikum der Johann-Wolfgang-Goethe-Universität, Frankfurt am Main, Germany
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  • Michael P. Manns,

    1. Department of Gastroenterology, Hepatology and Endocrinology, Medizinische Hochschule Hannover, Hannover, Germany
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  • Thomas Pietschmann,

    1. Division of Experimental Virology, Twincore Center for Experimental and Clinical Infection Research, Hannover, Germany
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  • Sandra Ciesek,

    1. Division of Experimental Virology, Twincore Center for Experimental and Clinical Infection Research, Hannover, Germany
    2. Department of Gastroenterology, Hepatology and Endocrinology, Medizinische Hochschule Hannover, Hannover, Germany
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  • Thomas von Hahn

    Corresponding author
    1. Institute for Molecular Biology, Medizinische Hochschule Hannover, Hannover, Germany
    2. Department of Gastroenterology, Hepatology and Endocrinology, Medizinische Hochschule Hannover, Hannover, Germany
    • Medizinische Hochschule Hannover, Institut für Molekularbiologie, Carl-Neuberg-Straße 1, 30625 Hannover, Germany
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    • fax: +49 511 532-4896


  • Potential conflict of interest: Dr. Manns is on the speakers' bureau of, consults for, and received grants from Roche, Gilead, Bristol-Myers Squibb, Merck, and Janssen. He is also on the speakers' bureau of GlaxoSmithKline. He consults for, and received grants from, Novartis and Boehringer-Ingelheim. He consults for Tibotec and Vertex. Dr. Pietschmann consults for Biotest and Janssen. Dr. Ciesek is on the speakers' bureau of MSD and received grants from Novartis.

  • This study was funded by the DFG Emmy Noether Program (grant no.: HA 4393/2-1; to T.v.H.) as well as SFB900 (project A6) and a grant from the Initiative and Networking Fund of the Helmholtz Association (grant no.: SO-024; to T.P.) and a DFG grant (no. Ci 171/2-1; to S.C.). The authors thank Jens Bukh (University of Copenhagen, Denmark), Alfredo Nicosia (Okairos, Basel, Switzerland), and Charlie Rice (The Rockefeller University, New York, NY) for providing reagents and Heiner Wedemeyer and the HepNet serum Bank for providing sera.

Abstract

Oxidized low-density lipoprotein (oxLDL) has been reported as an inhibitor of hepatitis C virus (HCV) cell entry, making it the only known component of human lipid metabolism with an antiviral effect on HCV. However, several questions remain open, including its effect on full-length cell-culture–grown HCV (HCVcc) of different genotypes or on other steps of the viral replication cycle, its mechanism of action, and whether endogenous oxLDL shares the anti-HCV properties of in vitro–generated oxLDL. We combined molecular virology tools with oxLDL serum measurements in different patient cohorts to address these questions. We found that oxLDL inhibits HCVcc at least as potently as HCV pseudoparticles. There was moderate variation between genotypes, with genotype 4 appearing the most oxLDL sensitive. Intracellular RNA replication and assembly and release of new particles were unaffected. HCV particles entering target cells lost oxLDL sensitivity with time kinetics parallel to anti-SR-BI (scavenger receptor class B type I), but significantly earlier than anti-CD81, suggesting that oxLDL acts by perturbing interaction between HCV and SR-BI. Finally, in chronically HCV-infected individuals, endogenous serum oxLDL levels did not correlate with viral load, but in HCV-negative sera, high endogenous oxLDL had a negative effect on HCV infectivity in vitro. Conclusion: oxLDL is a potent pangenotype HCV entry inhibitor that maintains its activity in the context of human serum and targets an early step of HCV entry. (HEPATOLOGY 2013)

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