Mannan-binding lectin(MBL)is a soluble innate immune protein that binds to glycosylated targets.MBL acts as an opsonin and activates complement,contributing to the destruction and clearance of infecting microorganisms Hepatitis C virus(HCV)encodes two envelope glycopro.teins E1 and E2,expressed as non-covalent E1/E2heterodimers in the viral envelope.E1 and E2 are potential ligands for MBL.Here we describe an analysis of the interaction between HCV and MBL using recombinant soluble E2 ectodomain fragment,the full-length E1/E2 heterodimer,expressed in vitro,and assess the effect of this interaction on virus entry.A binding assay using antibody capture of full length E1/E2 heterodimers was used to demonstrate calcium dependent,saturating binding of MBL to HCV glycoproteins.Competition with various saccharides further confirmed that the interaction was via the lectin domain of MBL.MBL binds to E1/E2 representing a broad range of virus genotypes.MBL was shown to neutralize the entry into Huh-7 cells of HCV pseudoparticles(HCVpp)bearing E1/E2 from a wide range of genotypes.HCVpp were neutralized to varying degrees.MBL was also shown to neutralize an authentic cell culture infectious virus,strain JFH-1(HCVcc).Furthermore,binding of MBL to E1/E2 was able to activate the complement system via MBL-associated serine protease 2.In conclusion,MBL interacts directly with HCV glycoproteins,which are present on the surface of the virion,resulting in neutralization of HCV particles.