Human apolipoprotein E peptides inhibit hepatitis C virus entry by blocking virus binding

Abstract

Hepatitis C virus (HCV) entry is a multiple-step process involving a number of host factors and hence represents a promising target for new antiviral drug development. In search of novel inhibitors of HCV infection, we found that a human apolipoprotein E (apoE) peptide, hEP, containing both a receptor binding fragment and a lipid binding fragment of apoE, specifically blocked the entry of cell culture grown HCV (HCVcc) at sub-micromolar concentrations. hEP caused little cytotoxicity in vitro and remained active even if left 24 hours in cell culture. Interestingly, hEP inhibited neither HIV-HCV pseudotypes (HCVpp) nor HIV and Dengue virus (DENV) infection. Further characterization mapped the anti-HCV activity to a 32-residue region that harbors the receptor binding domain of apoE, but this fragment must contain a cysteine residue at the N-terminus to mediate dimer formation. The anti-HCV activity of the peptide appears to be dependent on both its length and sequence and correlates with its ability to bind lipids. Finally, we demonstrated that the apoE-derived peptides directly blocked the binding of both HCVcc and patient serum-derived virus to hepatoma cells as well as primary human hepatocytes. Conclusion apoE peptides potently inhibit HCV infection and suggest a direct role of apoE in mediating HCV entry. Our findings also highlight the potential of developing apoE mimetic peptides as novel HCV entry inhibitors by targeting HCV-host interactions.

Neglected but Important Role of Apolipoprotein E Exchange in Hepatitis C Virus Infection

“…apoB remains associated with triglyceride-rich lipoprotein (TRL) from the beginning of lipoprotein assembly and secretion to the end of remnant particle clearance, whereas exchangeable apolipoproteins are able to dissociate from one lipoprotein and reassociate with another lipoprotein in circulation through an intermediate lipid-free stage (16-18). Among exchangeable apolipoproteins, apoE is dispensable for HCV genome replication but essential for infectious HCV assembly and entry (19)(20)(21)(22)(23)(24)(25). Because apoE is a low-density lipoprotein receptor (LDLr) ligand, apoE exchange between lipoproteins is important for cholesterol transport and lipoprotein metabolism (18,26,27).…”

Sequence and Functional Analysis of the Envelope Glycoproteins of Hepatitis C Virus Variants Selectively Transmitted to a New Host

“…Moreover, there is growing evidence for the presence of lipid components within the viral particle, such as apolipoproteins B and E, which might facilitate viral entry. It is thus conceivable that the phenotypic properties conferred by a given E1E2 variant may differ in the context of the authentic viral particle and in HCVpp (41)(42)(43)(44). Studies using chimeric JFH-1-based HCV in cell culture (HCVcc) will clearly be required to address this specific question (45,46).…”

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] …”