Lipoprotein Lipase Inhibits Hepatitis C Virus ({HCV}) Infection by Blocking Virus Cell Entry

  • Maillard P
  • Walic M
  • Meuleman P
 et al. 
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A distinctive feature of {HCV} is that its life cycle depends on lipoprotein metabolism. Viral morphogenesis and secretion follow the very low-density lipoprotein ({VLDL}) biogenesis pathway and, consequently, infectious {HCV} in the serum is associated with triglyceride-rich lipoproteins ({TRL}). Lipoprotein lipase ({LPL}) hydrolyzes {TRL} within chylomicrons and {VLDL} but, independently of its catalytic activity, it has a bridging activity, mediating the hepatic uptake of chylomicrons and {VLDL} remnants. We previously showed that exogenously added {LPL} increases {HCV} binding to hepatoma cells by acting as a bridge between virus-associated lipoproteins and cell surface heparan sulfate, while simultaneously decreasing infection levels. We show here that {LPL} efficiently inhibits cell infection with two {HCV} strains produced in hepatoma cells or in primary human hepatocytes transplanted into {uPA}-{SCID} mice with fully functional human {ApoB}-lipoprotein profiles. Viruses produced in vitro or in vivo were separated on iodixanol gradients into low and higher density populations, and the infection of Huh 7.5 cells by both virus populations was inhibited by {LPL}. The effect of {LPL} depended on its enzymatic activity. However, the lipase inhibitor tetrahydrolipstatin restored only a minor part of {HCV} infectivity, suggesting an important role of the {LPL} bridging function in the inhibition of infection. We followed {HCV} cell entry by immunoelectron microscopy with anti-envelope and anti-core antibodies. These analyses demonstrated the internalization of virus particles into hepatoma cells and their presence in intracellular vesicles and associated with lipid droplets. In the presence of {LPL}, {HCV} was retained at the cell surface. We conclude that {LPL} efficiently inhibits {HCV} infection by acting on {TRL} associated with {HCV} particles through mechanisms involving its lipolytic function, but mostly its bridging function. These mechanisms lead to immobilization of the virus at the cell surface. {HCV}-associated lipoproteins may therefore be a promising target for the development of new therapeutic approaches.

Author-supplied keywords

  • apolipoprotein-b
  • buoyant density
  • human hepatocytes
  • human liver
  • in-vivo
  • low-density-lipoprotein
  • membrane-fusion
  • rich lipoproteins
  • upa-scid mouse
  • virion-associated cholesterol

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  • Patrick Maillard

  • Marine Walic

  • Philip Meuleman

  • Farzin Roohvand

  • Thierry Huby

  • Wilfried Le Goff

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