High Density Lipoprotein Inhibits Hepatitis C Virus-neutralizing Antibodies by Stimulating Cell Entry via Activation of the Scavenger Receptor BI

Abstract

Hepatitis C virus (HCV) exploits serum-dependent mechanisms that inhibit neutralizing antibodies. Here we demonstrate that high density lipoprotein (HDL) is a key serum factor that attenuates neutralization by monoclonal and HCV patient-derived polyclonal antibodies of infectious pseudo-particles (HCVpp) harboring authentic E1E2 glycoproteins and cell culture-grown genuine HCV (HCVcc). Over 10-fold higher antibody concentrations are required to neutralize either HCV-enveloped particles in the presence of HDL or human serum, and less than 3-5-fold reduction of infectious titers are obtained at saturating antibody concentrations, in contrast to complete inhibition in serum-free conditions. We show that HDL interaction with the scavenger receptor BI (SR-BI), a proposed cell entry co-factor of HCV and a receptor mediating lipid transfer with HDL, strongly reduces neutralization of HCVpp and HCVcc. We found that HDL activation of target cells strongly stimulates cell entry of viral particles by accelerating their endocytosis, thereby suppressing a 1-h time lag during which cell-bound virions are not internalized and can be targeted by antibodies. Compounds that inhibit lipid transfer functions of SR-BI fully restore neutralization by antibodies in human serum. We demonstrate that this functional HDL/SR-BI interaction only interferes with antibodies blocking HCV-E2 binding to CD81, a major HCV receptor, reflecting its prominent role during the cell entry process. Moreover, we identify monoclonal antibodies targeted to epitopes in the E1E2 complex that are not inhibited by HDL. Consistently, we show that antibodies targeted to HCV-E1 efficiently neutralize HCVpp and HCVcc in the presence of human serum. Hepatitis C virus (HCV),7 a member of the Flaviviridae family, is transmitted during parenteral exposures to infected material, such as contaminated blood or needles. Its genome encodes a precursor polyprotein of ϳ3,000 amino acids (1). Cleavage of this polyprotein generates 10 polypeptides, including a core protein, two surface glycoproteins, E1 and E2, and the nonstructural proteins.HCV is an enveloped virus, implying that specific cell surface molecules mediate the capture of viral particles and their penetration inside the infected cells. Several molecules have been proposed as cell entry receptors of HCV, and most of them have been isolated based on binding studies with soluble recombinant E2 protein or HCV-like particles. Potential receptors include the CD81 tetraspanin (2), the low density lipoproteins (LDL) receptor (3), the scavenger receptor BI (SR-BI) (4) that binds HDL, native, or modified LDL and very low density LDL (vLDL) (5), and several "capture" molecules that induce concentration of viral particles at the cell surface, hence allowing virions to find the cell entry receptors (6). Experimental data using infectious HCV pseudoparticles (HCVpp) harboring authentic E1E2 glycoproteins (7, 8) have substantiated the functional roles of CD81 and SR-BI in HCV entry (6). The requirement for CD81 in cell entry ha...

Serum cholesterol and statin use predict virological response to peginterferon and ribavirin therapy

“…Further study is necessary to delineate the role of a low HDL level in improving SVR rates. 25 Another important finding of this study is the link between statin use and improved SVR. An earlier pilot study by Sezaki et al 30 suggested that improved SVR rates might be obtained with the use of statins.…”

“…HDL, a scavenger receptor class B type 1 receptor ligand, may modulate the cell entry of the virus via scavenger receptor class B type 1. 25 Subsequently, a low HDL level would be expected, at least in theory, to decrease cellular infectivity.…”

Entry and replication of recombinant hepatitis C viruses in cell culture

“…Anti-E1/E2 Abs [9,11,62,148], patient sera [9], soluble E2 [46], lectins [150,151], anti-ApoE antibodies [29], apoE peptides [149] Abs, Erlotinib, Lapatinib, Gefitinib [141] EGF, TGF-α [141] HDL [138] ApoCI [139] BLTs [138,140] Abs, Dasatinib [141] Arbidol [144] Abs [109,137], ITX 5061 [134], natural ligands [135,136] Abs, soluble CD81 [9,11] Abs [142] Cldn1 peptide [143] Heparin, GAG nzymatic digestion [69,132] Abs, natural ligands, soluble LDL receptor [30,133] GAGs LDLR CD81 SR-BI Cldn1 Ocln…”

“…Anti-E1/E2 Abs [9,11,62,148], patient sera [9], soluble E2 [46], lectins [150,151], anti-ApoE antibodies [29], apoE peptides [149] Abs, Erlotinib, Lapatinib, Gefitinib [141] EGF, TGF-α [141] HDL [138] ApoCI [139] BLTs [138,140] Abs, Dasatinib [141] Arbidol [144] …”

Characterization of the inhibition of hepatitis C virus entry byIn vitro-generated and patient-derived oxidized low-density lipoprotein

“…20 Recent work has suggested that SR-BI fulfils at least two distinct functions during viral entry: one related to initial attachment and another during post-binding. 5,21,22 Among SR-BI ligands, HDL has a modest enhancing effect on HCV entry, 23 whereas oxLDL has been found to be a strong inhibitor. 24 oxLDL is a modified form of LDL that is generated early on in the pathogenesis of atherosclerosis, when native LDL deposited in early atherosclerotic lesions (''fatty streaks'') undergoes oxidative modifications.…”