['Our previous studies demonstrated that hepatitis C virus (HCV) envelope glycoproteins 1 and 2 (E1 and E2) display distinct reactivity to different cell-surface molecules. In this study, we characterized the interaction of E1 and E2 with apolipoproteins in facilitating virus entry. The results suggested a higher neutralization of vesicular stomatitis virus (VSV)/HCV E1-G pseudotype infectivity by antibodies to apolipoprotein E (ApoE) than apolipoprotein B (ApoB), with VSV/HCV E2-G pseudotype infectivity remaining largely unaffected. Neutralization of cell-culture-grown HCV infectivity by antiserum to ApoE and, to a lesser extent, by ApoB further verified their involvement in virus entry. HCV E1, but not E2, displayed binding with ApoE and ApoB by enzyme-linked immunosorbent assay. Binding of E1 with apolipoproteins were further supported by coimmunoprecipitation from human hepatocytes expressing E1. Rabbit antiserum to a selected E1 ectodomain-derived peptide displayed ∼ 50% neutralization of E1-G pseudotype infectivity. Furthermore, E1 ectodomain-derived synthetic peptides significantly inhibited the interaction of E1 with both the apolipoproteins. Investigation on the role of low-density lipoprotein receptor (LDL-R) as a hepatocyte surface receptor for virus entry suggested a significant reduction in E1-G pseudotype plaque numbers (∼ 70%) by inhibiting LDL-R ligand-binding activity using human proprotein convertase subtilisin/kexin type 9 and platelet factor-4, whereas they had a minimal inhibitory effect on the E2-G pseudotype.'] Does hepatitis C virus E1 envelope glycoprotein interact with apolipoproteins in facilitating entry into hepatocytes?