title: 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.
authors: INSERM, U758, 69007 Lyon, France.
authors: Marlène
authors: M
authors: Dreux
authors: Thomas
authors: T
authors: Pietschmann
authors: Christelle
authors: C
authors: Granier
authors: Cécile
authors: C
authors: Voisset
authors: Sylvie
authors: S
authors: Ricard-Blum
authors: Philippe-Emmanuel
authors: PE
authors: Mangeot
authors: Zhenyong
authors: Z
authors: Keck
authors: Steven
authors: S
authors: Foung
authors: Ngoc
authors: N
authors: Vu-Dac
authors: Jean
authors: J
authors: Dubuisson
authors: Ralf
authors: R
authors: Bartenschlager
authors: Dimitri
authors: D
authors: Lavillette
authors: Francois-Loïc
authors: FL
authors: Cosset