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Virology. 2009 Nov 10;394(1):99-108. doi: 10.1016/j.virol.2009.08.037. Epub 2009 Sep 13.

Apolipoprotein E on hepatitis C virion facilitates infection through interaction with low-density lipoprotein receptor.

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1
Department of Immunology, University of Washington School of Medicine, Seattle, WA, USA.

Abstract

Hepatitis C virus (HCV) infection is a major cause of liver disease. HCV associates with host apolipoproteins and enters hepatocytes through complex processes involving some combination of CD81, claudin-1, occludin, and scavenger receptor BI. Here we show that infectious HCV resembles very low density lipoprotein (VLDL) and that entry involves co-receptor function of the low-density lipoprotein receptor (LDL-R). Blocking experiments demonstrate that beta-VLDL itself or anti-apolipoprotein E (apoE) antibody can block HCV entry. Knockdown of the LDL-R by treatment with 25-hydroxycholesterol or siRNA ablated ligand uptake and reduced HCV infection of cells, whereas infection was rescued upon cell ectopic LDL-R expression. Analyses of gradient-fractionated HCV demonstrate that apoE is associated with HCV virions exhibiting peak infectivity and dependence upon the LDL-R for cell entry. Our results define the LDL-R as a cooperative HCV co-receptor that supports viral entry and infectivity through interaction with apoE ligand present in an infectious HCV/lipoprotein complex comprising the virion. Disruption of HCV/LDL-R interactions by altering lipoprotein metabolism may therefore represent a focus for future therapy.

PMID:
19751943
PMCID:
PMC2767442
DOI:
10.1016/j.virol.2009.08.037
[Indexed for MEDLINE]
Free PMC Article
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