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Scavenger receptor class B member 1 (SCARB1) variants modulate hepatitis C virus replication cycle and viral load

  • Author Footnotes
    † These authors contributed equally as joint first authors.
    Sandra Westhaus
    Footnotes
    † These authors contributed equally as joint first authors.
    Affiliations
    Department of Gastroenterology, Hepatology und Endocrinology, Hannover Medical School, Hannover, Germany

    Institute of Virology, University Hospital Essen, Essen, Germany

    German Center for Infection Research (DZIF), Hannover-Braunschweig Site, Germany
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  • Author Footnotes
    † These authors contributed equally as joint first authors.
    Maximilian Deest
    Footnotes
    † These authors contributed equally as joint first authors.
    Affiliations
    Department of Gastroenterology, Hepatology und Endocrinology, Hannover Medical School, Hannover, Germany

    German Center for Infection Research (DZIF), Hannover-Braunschweig Site, Germany

    Institute for Molecular Biology, Hannover Medical School, Hannover, Germany
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  • Anna T.X. Nguyen
    Affiliations
    Department of Gastroenterology, Hepatology und Endocrinology, Hannover Medical School, Hannover, Germany

    German Center for Infection Research (DZIF), Hannover-Braunschweig Site, Germany

    Institute for Molecular Biology, Hannover Medical School, Hannover, Germany
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  • Frauke Stanke
    Affiliations
    Clinic for Pediatric Pneumology and Neonatology, Hannover Medical School, Hannover, Germany

    German Center for Lung Research (DLZ), partner site BREATH
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  • Dirk Heckl
    Affiliations
    Department for Pediatric Hematology and Oncology, Hannover Medical School, Hannover, Germany
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  • Rui Costa
    Affiliations
    Department of Gastroenterology, Hepatology und Endocrinology, Hannover Medical School, Hannover, Germany

    German Center for Infection Research (DZIF), Hannover-Braunschweig Site, Germany

    Institute for Molecular Biology, Hannover Medical School, Hannover, Germany
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  • Axel Schambach
    Affiliations
    Department Experimental Hematology, Hannover Medical School, Hannover, Germany
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  • Michael P. Manns
    Affiliations
    Department of Gastroenterology, Hepatology und Endocrinology, Hannover Medical School, Hannover, Germany

    German Center for Infection Research (DZIF), Hannover-Braunschweig Site, Germany
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  • Thomas Berg
    Affiliations
    Department of Gastroenterology and Rheumatology – Section Hepatology, University Hospital Leipzig, Leipzig, Germany
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  • Florian W.R. Vondran
    Affiliations
    German Center for Infection Research (DZIF), Hannover-Braunschweig Site, Germany

    Department of General, Visceral and Transplant Surgery, Hannover Medical School, Hannover, Germany
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  • Christoph Sarrazin
    Affiliations
    Medical Clinic I, University Hospital Frankfurt, Frankfurt am Main, Germany

    Medizinische Klinik II, St. Josefs-Hospital, Wiesbaden, Germany

    German Center for Infection Research (DZIF); External Partner Site Frankfurt am Main, Germany
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  • Sandra Ciesek
    Affiliations
    Department of Gastroenterology, Hepatology und Endocrinology, Hannover Medical School, Hannover, Germany

    Institute of Virology, University Hospital Essen, Essen, Germany

    German Center for Infection Research (DZIF), Hannover-Braunschweig Site, Germany
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  • Thomas von Hahn
    Correspondence
    Corresponding author. Address: Medizinische Hochschule Hannover, Institut für Molekularbiologie, Carl-Neuberg-Str. 1, 30625 Hannover, Germany. Tel.: +49 511 532 4585; fax: +49 511 532 4896.
    Affiliations
    Department of Gastroenterology, Hepatology und Endocrinology, Hannover Medical School, Hannover, Germany

    German Center for Infection Research (DZIF), Hannover-Braunschweig Site, Germany

    Institute for Molecular Biology, Hannover Medical School, Hannover, Germany
    Search for articles by this author
  • Author Footnotes
    † These authors contributed equally as joint first authors.
Published:March 28, 2017DOI:https://doi.org/10.1016/j.jhep.2017.03.020

      Background & Aims

      There are numerous coding and non-coding variants in the SCARB1 gene that encodes scavenger receptor class B member 1 (SR-BI), a key receptor for both high density lipoproteins and hepatitis C virus (HCV). Many have been linked to clinical phenotypes, yet their impact on the HCV replication cycle is incompletely understood. The aim of this study was to analyze the impact of these variants on the molecular biology and clinical course of HCV.

      Methods

      We analyzed key coding non-synonymous as well as non-coding SCARB1 variants using virological in vitro and human genetics approaches.

      Results

      Non-synonymous variants: S112F and T175A have greatly reduced HCV receptor function. When present on the cell surface, these variants are impaired in their ability to interact with HCV E2.
      Non-coding variants: The G allele in rs3782287 is associated with decreased viral load. Haplotype analysis confirmed these findings and identified haplotype rs3782287 A/rs5888 C as a risk allele associated with increased viral load. We also detected a trend towards lower hepatic SR-BI expression in individuals with the rs3782287 GG genotype associated with low viral load suggesting a potential underlying mechanism.

      Conclusion

      Coding and non-coding genetic SCARB1 variants modulate the HCV replication cycle and possibly clinical features of hepatitis C. These findings underscore the relevance of SR-BI as an HCV receptor and contribute to our understanding of inter-individual variation in HCV infection.

      Lay summary

      The cell surface receptor SR-BI (scavenger receptor class B member 1), is essential for hepatitis C virus (HCV) entry into hepatocytes. Variations in the gene coding this receptor influence infectivity and viral load. We analyzed these variations to gain a better understanding of inter-individual differences over the course of HCV infection.

      Graphical abstract

      Keywords

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