Journal
VIROLOGY
Volume 394, Issue 1, Pages 99-108Publisher
ACADEMIC PRESS INC ELSEVIER SCIENCE
DOI: 10.1016/j.virol.2009.08.037
Keywords
Hepatitis; HCV; LDL-R; Lipoprotein; ApoE; ApoB; Entry; Receptor
Categories
Funding
- National Institutes of Health [DA024536, AI060389]
- Burroughs-Wellcome Fund
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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 OF 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. (C) 2009 Elsevier Inc. All rights reserved.
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