Role of Hepatitis C Virus Envelope Glycoprotein E1 in Virus Entry and Assembly

Abstract

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.

Keywords: E1; envelope protein; fusion; hepatitis C virus; virus assembly; virus entry.

Figure 1

Schematic diagram of hepatitis C virus (HCV) E1 envelope protein. E1 contains N-terminal domain (NTD, 192–239), putative fusion peptide (pFP, 272–285), conserved region (CR, 302–329), and C-terminal transmembrane domain (TMD, 350–381). CxxC motif in NTD and GxxxG motif in TMD are marked in orange and yellow, respectively. Four N-glycosylation sites (N196, N209, N234, and N305) conserved in all genotypes and one genotype 1b/6-specific site (N250) are labeled in green diamond, and conserved cysteine residues are labeled in red ball (intra- and intermolecular disulfide bounds in solid and dash line, respectively). Antibody epitopes, recognized by antibodies H-111 (9), A4 (10), A6 (11), IGH505, and IGH526 (12, 13), are marked with line segments. Of them H-111, IGH505, and IGH526 have been shown to neutralizing viral infection. The numbers correspond to the position of amino acid residues in the HCV polyprotein, with the first residue of E1 starting at 192. Sequence logos were generated based on 184 E1 sequences of genotype 1–6 from the Los Alamos hepatitis C sequence database (14) using WebLogo (15).