title: Characterization of the inhibition of hepatitis C virus entry by in vitro-generated and patient-derived oxidized low-density lipoprotein.
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.
  
  
  CONCLUSIONS
  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.
authors.affiliation: Institute for Molecular Biology, Medizinische Hochschule Hannover, Hannover, Germany.
authors.forename: Sandra
authors.initials: S
authors.lastname: Westhaus
authors.forename: Dorothea
authors.initials: D
authors.lastname: Bankwitz
authors.forename: Stefanie
authors.initials: S
authors.lastname: Ernst
authors.forename: Katrin
authors.initials: K
authors.lastname: Rohrmann
authors.forename: Ilka
authors.initials: I
authors.lastname: Wappler
authors.forename: Clemens
authors.initials: C
authors.lastname: Agné
authors.forename: Maren
authors.initials: M
authors.lastname: Luchtefeld
authors.forename: Bernhard
authors.initials: B
authors.lastname: Schieffer
authors.forename: Christoph
authors.initials: C
authors.lastname: Sarrazin
authors.forename: Michael P
authors.initials: MP
authors.lastname: Manns
authors.forename: Thomas
authors.initials: T
authors.lastname: Pietschmann
authors.forename: Sandra
authors.initials: S
authors.lastname: Ciesek
authors.forename: Thomas
authors.initials: T
authors.lastname: von Hahn
mesh_terms: D018955:CD36 Antigens / Q000502:physiology; D006528:Carcinoma, Hepatocellular / Q000473:pathology / Q000821:virology; D045744:Cell Line, Tumor; D002478:Cells, Cultured; D004279:DNA, Viral / Q000235:genetics; D005838:Genotype; D016174:Hepacivirus / Q000187:drug effects / Q000235:genetics* / Q000502:physiology*; D019698:Hepatitis C, Chronic / Q000097:blood*; D006801:Humans; D066298:In Vitro Techniques; D008077:Lipoproteins, LDL / Q000097:blood / Q000494:pharmacology*; D008113:Liver Neoplasms / Q000473:pathology / Q000821:virology; D019562:Viral Load; D014771:Virion / Q000502:physiology; D014779:Virus Replication / Q000187:drug effects* / Q000502:physiology
chemical_list: D018955:CD36 Antigens; D004279:DNA, Viral; D008077:Lipoproteins, LDL; C099252:oxidized low density lipoprotein