Chlorcyclizine Inhibits Viral Fusion of Hepatitis C Virus Entry by Directly Targeting HCV Envelope Glycoprotein 1.
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ABSTRACT:
SUBMITTER: Hu Z
PROVIDER: S-EPMC7368827 | biostudies-literature |
REPOSITORIES: biostudies-literature
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Project description:Hepatitis C virus (HCV) glycoproteins E1 and E2 form a heterodimer to constitute viral envelope proteins, which play an essential role in virus entry. E1 does not directly interact with host receptors, and its functions in viral entry are exerted mostly through its interaction with E2 that directly binds the receptors. HCV enters the host cell via receptor-mediated endocytosis during which the fusion of viral and host endosomal membranes occurs to release viral genome to cytoplasm. A putative fusion peptide in E1 has been proposed to participate in membrane fusion, but its exact role and underlying molecular mechanisms remain to be deciphered. Recently solved crystal structures of the E2 ectodomains and N-terminal of E1 fail to reveal a classical fusion-like structure in HCV envelope glycoproteins. In addition, accumulating evidence suggests that E1 also plays an important role in virus assembly. In this mini-review, we summarize current knowledge on HCV E1 including its structure and biological functions in virus entry, fusion, and assembly, which may provide clues for developing HCV vaccines and more effective antivirals.
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Project description: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.Together, the results suggested an association between HCV E1 and apolipoproteins, which may facilitate virus entry through LDL-R into mammalian cells.
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