title: Lipoprotein lipase mediates hepatitis C virus (HCV) cell entry and inhibits HCV infection.
abstract: The host-virus interactions leading to cell infection with hepatitis C virus (HCV) are not fully understood. The tetraspanin CD-81 and human scavenger receptor SR-BI/Cla1 are major receptors mediating virus cell entry. However, HCV in patients' sera is associated with lipoproteins and infectious potential of the virus depends on lipoproteins associated to virus particles. We show here that lipoprotein lipase (LPL), targeting triglyceride-rich lipoproteins (TRL) to the liver, mediates binding and internalization of HCV to different types of cells, acting as a bridge between virus-associated lipoproteins and cell surface heparan sulfate proteoglycans (HSPG). The dimeric structure and catalytic activity of LPL are required for LPL-mediated HCV uptake to cells. Unexpectedly, exogenous LPL significantly inhibits HCVcc infection in vitro. This effect is prevented by anti-LPL antibodies and by tetrahydrolipstatin (THL) a specific inhibitor of LPL enzymatic activity. In addition, we show that antibodies directed to apolipoprotein B (ApoB)-containing lipoproteins efficiently inhibits HCVcc infection. Our findings suggest that LPL mediates HCV cell entry by a mechanism similar to hepatic clearance of TRL from the circulation, promoting a non-productive virus uptake. These data provide new insight into mechanisms of HCV cell entry and suggest that LPL could modulate HCV infectivity in vivo.
authors.affiliation: Unité Hépacivirus Institut Pasteur, 25/28 Rue du Dr Roux, 75724 Paris Cedex 15, France.
authors.forename: Ursula
authors.initials: U
authors.lastname: Andréo
authors.forename: Patrick
authors.initials: P
authors.lastname: Maillard
authors.forename: Olga
authors.initials: O
authors.lastname: Kalinina
authors.forename: Marine
authors.initials: M
authors.lastname: Walic
authors.forename: Eliane
authors.initials: E
authors.lastname: Meurs
authors.forename: Michèle
authors.initials: M
authors.lastname: Martinot
authors.forename: Patrick
authors.initials: P
authors.lastname: Marcellin
authors.forename: Agata
authors.initials: A
authors.lastname: Budkowska
mesh_terms: D000818:Animals; D001055:Apolipoproteins B / Q000378:metabolism; D016466:CHO Cells; D002460:Cell Line; D045744:Cell Line, Tumor; D006224:Cricetinae; D003412:Cricetulus; D019281:Dimerization; D016174:Hepacivirus / Q000502:physiology*; D019812:Heparan Sulfate Proteoglycans / Q000378:metabolism; D006526:Hepatitis C / Q000821:virology*; D006801:Humans; D007783:Lactones / Q000494:pharmacology; D008071:Lipoprotein Lipase / Q000502:physiology*; D008264:Macrophages / Q000378:metabolism / Q000821:virology; D000077403:Orlistat; D018110:Receptors, Lipoprotein / Q000378:metabolism; D053586:Virus Internalization
chemical_list: D001055:Apolipoproteins B; D019812:Heparan Sulfate Proteoglycans; D007783:Lactones; D018110:Receptors, Lipoprotein; D000077403:Orlistat; D008071:Lipoprotein Lipase