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Lipoprotein Lipase Inhibits Hepatitis C Virus (HCV) Infection by Blocking Virus Cell Entry
- Source :
- PLoS ONE, PLoS ONE, 2011, 6 (10), pp.e26637. ⟨10.1371/journal.pone.0026637⟩, PLoS ONE, Vol 6, Iss 10, p e26637 (2011), PLOS ONE
- Publication Year :
- 2011
- Publisher :
- HAL CCSD, 2011.
-
Abstract
- International audience; 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.
- Subjects :
- RNA viruses
Viral Diseases
Very low-density lipoprotein
UPA-SCID MOUSE
Hepacivirus
Mice, SCID
MESH: Base Sequence
Biochemistry
Membrane Fusion
Polymerase Chain Reaction
Mice
chemistry.chemical_compound
Viral classification
MESH: Microscopy, Immunoelectron
[SDV.MHEP.MI]Life Sciences [q-bio]/Human health and pathology/Infectious diseases
Lipid droplet
MESH: Animals
MESH: Hepacivirus
MESH: Mice, SCID
Microscopy, Immunoelectron
IN-VIVO
[SDV.MP.VIR] Life Sciences [q-bio]/Microbiology and Parasitology/Virology
Lipoprotein lipase
Multidisciplinary
MESH: Lipoproteins
Infectious Diseases
Low-density lipoprotein
[SDV.MP.VIR]Life Sciences [q-bio]/Microbiology and Parasitology/Virology
[SDV.MHEP.MI] Life Sciences [q-bio]/Human health and pathology/Infectious diseases
MESH: Microscopy, Electron, Transmission
Medicine
lipids (amino acids, peptides, and proteins)
Research Article
MESH: Lipoprotein Lipase
MESH: DNA Primers
MESH: Cell Line, Tumor
APOLIPOPROTEIN-B
Lipoproteins
Immunoelectron microscopy
Science
LOW-DENSITY-LIPOPROTEIN
MEMBRANE-FUSION
Biology
Microbiology
BUOYANT DENSITY
Microscopy, Electron, Transmission
HUMAN LIVER
Virology
Cell Line, Tumor
Animals
Humans
Secretion
MESH: Mice
DNA Primers
MESH: Humans
Base Sequence
Biology and Life Sciences
Proteins
MESH: Polymerase Chain Reaction
[SDV.MHEP.HEG]Life Sciences [q-bio]/Human health and pathology/Hépatology and Gastroenterology
Molecular biology
[SDV.MHEP.HEG] Life Sciences [q-bio]/Human health and pathology/Hépatology and Gastroenterology
digestive system diseases
Lipoprotein Lipase
HUMAN HEPATOCYTES
chemistry
RICH LIPOPROTEINS
VIRION-ASSOCIATED CHOLESTEROL
Lipoprotein
Chylomicron
Subjects
Details
- Language :
- English
- ISSN :
- 19326203
- Database :
- OpenAIRE
- Journal :
- PLoS ONE, PLoS ONE, 2011, 6 (10), pp.e26637. ⟨10.1371/journal.pone.0026637⟩, PLoS ONE, Vol 6, Iss 10, p e26637 (2011), PLOS ONE
- Accession number :
- edsair.doi.dedup.....bc11f2673818f088502ab50f155e84ff
- Full Text :
- https://doi.org/10.1371/journal.pone.0026637⟩