4 This association with VLDL allows the virus to bind to target cells through lipoprotein receptors.5 The low-density lipoprotein (LDL) receptor (LDLR) has, therefore, been proposed as another entry factor for HCV.6 Furthermore, by utilizing HCV particles isolated from patients, a correlation has been shown between the accumulation of HCV RNA into primary hepatocytes, expression of LDLR messenger RNA, and LDL entry.7 Finally, the potential involvement of the LDLR in HCV entry has also been recently reported in the hepatitis C virus produced in cell culture check details (HCVcc) system.8, 9 Nascent VLDL particles released into plasma are not ligands for the LDLR. However,

upon processing by lipoprotein lipase (LPL), which hydrolyzes the triglycerides in the core of lipoprotein particles, a large proportion (70%) of the resulting intermediate density lipoproteins (IDLs) is efficiently removed from plasma by hepatocytes.

This process is believed to depend on the interaction between LDLR and apolipoprotein E (ApoE), located on Inhibitor Library cell assay IDL. The remaining IDL in the circulation is converted to LDL by a reaction catalyzed by hepatic lipase, which further reduces the amount of triglycerides in lipoprotein particles and enables interaction between LDLR and apolipoprotein B (ApoB) exposed on LDL particles.10 Although data from several studies support the involvement of the LDLR in HCV entry, some discrepancies remain. Here, we reinvestigated the role of the LDLR in the HCV life cycle by comparing MCE virus entry to the mechanism of lipoprotein uptake. We show that HCV particles can interact with the LDLR. However, this interaction does not necessarily lead to a productive infection. Furthermore, our data indicate a role for the LDLR as a lipid-providing receptor, which modulates viral RNA replication. ApoB, apolipoprotein B; ApoE, apolipoprotein

E; CD, cluster of differentiation; CEs, cholesterol esters; CHO, Chinese hamster ovary; DiI, 1,1′-dioctadecyl 3,3,3′-tetramethylindocarbocyanine; DMEM, Dulbecco’s modified Eagle’s medium; ER, endoplasmic reticulum; FBS, fetal bovine serum; HCV, hepatitis C virus; HCVcc, hepatitis C virus produced in cell culture; HCVpp, hepatitis C virus pseudoparticle; hLDLR, human low-density lipoprotein receptor; HSPG, heparan sulfate proteoglycan; IDL, intermediate-density lipoprotein; LDL, low-density lipoprotein; LDLR, low-density lipoprotein receptor; LPL, lipoprotein lipase; mAb, monoclonal antibody; PBS, phosphate-buffered saline; PC, phosphatidylcholine; PE, phosphatidylethanolamine; RT-qPCR, quantitative real-time reverse-transcriptase polymerase chain reaction; SINV, Sindbis virus; sLDLR, soluble form of human low-density lipoprotein receptor; SRBI, scavenger receptor BI; siRNA, small interfering RNA; THL, tetrahydrolipstatin; VLDL, very-low-density lipoprotein; ????VSV, vesicular stomatitis virus.