title: Scavenger receptor class B member 1 (SCARB1) variants modulate hepatitis C virus replication cycle and viral load.
abstract: 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.
  
  
  
  We analyzed key coding non-synonymous as well as non-coding SCARB1 variants using virological in vitro and human genetics approaches.
  
  
  
  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.
  
  
  
  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.
  
  
  
  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.
authors.affiliation: 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.
authors.forename: Sandra
authors.initials: S
authors.lastname: Westhaus
authors.affiliation: 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.
authors.forename: Maximilian
authors.initials: M
authors.lastname: Deest
authors.affiliation: 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.
authors.forename: Anna T X
authors.initials: ATX
authors.lastname: Nguyen
authors.affiliation: Clinic for Pediatric Pneumology and Neonatology, Hannover Medical School, Hannover, Germany; German Center for Lung Research (DLZ), partner site BREATH.
authors.forename: Frauke
authors.initials: F
authors.lastname: Stanke
authors.affiliation: Department for Pediatric Hematology and Oncology, Hannover Medical School, Hannover, Germany.
authors.forename: Dirk
authors.initials: D
authors.lastname: Heckl
authors.affiliation: 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.
authors.forename: Rui
authors.initials: R
authors.lastname: Costa
authors.affiliation: Department Experimental Hematology, Hannover Medical School, Hannover, Germany.
authors.forename: Axel
authors.initials: A
authors.lastname: Schambach
authors.affiliation: Department of Gastroenterology, Hepatology und Endocrinology, Hannover Medical School, Hannover, Germany; German Center for Infection Research (DZIF), Hannover-Braunschweig Site, Germany.
authors.forename: Michael P
authors.initials: MP
authors.lastname: Manns
authors.affiliation: Department of Gastroenterology and Rheumatology - Section Hepatology, University Hospital Leipzig, Leipzig, Germany.
authors.forename: Thomas
authors.initials: T
authors.lastname: Berg
authors.affiliation: German Center for Infection Research (DZIF), Hannover-Braunschweig Site, Germany; Department of General, Visceral and Transplant Surgery, Hannover Medical School, Hannover, Germany.
authors.forename: Florian W R
authors.initials: FWR
authors.lastname: Vondran
authors.affiliation: 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.
authors.forename: Christoph
authors.initials: C
authors.lastname: Sarrazin
authors.affiliation: 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.
authors.forename: Sandra
authors.initials: S
authors.lastname: Ciesek
authors.affiliation: 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. Electronic address: vonHahn.Thomas@mh-hannover.de.
authors.forename: Thomas
authors.initials: T
authors.lastname: von Hahn
mesh_terms: D002460:Cell Line; D014644:Genetic Variation; D016174:Hepacivirus / Q000502:physiology*; D006526:Hepatitis C / Q000235:genetics* / Q000821:virology*; D054884:Host-Pathogen Interactions / Q000235:genetics* / Q000502:physiology*; D006801:Humans; D020641:Polymorphism, Single Nucleotide; D051122:Scavenger Receptors, Class B / Q000235:genetics* / Q000502:physiology*; D014759:Viral Envelope Proteins / Q000502:physiology; D019562:Viral Load; D053586:Virus Internalization; D014779:Virus Replication
chemical_list: C495124:SCARB1 protein, human; D051122:Scavenger Receptors, Class B; D014759:Viral Envelope Proteins; C091015:glycoprotein E2, Hepatitis C virus
keywords: Haplotype; Hepatitis C virus (HCV); SCARB1 gene; Scavenger receptor class B type I (SR-BI); Single nucleotide polymorphism (SNP)