Hepatitis C Virus Envelope Glycoproteins: A Balancing Act of Order and Disorder

Abstract

Chronic hepatitis C virus infection often leads to liver cirrhosis and primary liver cancer. In 2015, an estimated 71 million people were living with chronic HCV. Although infection rates have decreased in many parts of the world over the last several decades, incidence of HCV infection doubled between 2010 and 2014 in the United States mainly due to increases in intravenous drug use. The approval of direct acting antiviral treatments is a necessary component in the elimination of HCV, but inherent barriers to treatment (e.g., cost, lack of access to healthcare, adherence to treatment, resistance, etc.) prevent dramatic improvements in infection rates. An effective HCV vaccine would significantly slow the spread of the disease. Difficulties in the development of an HCV culture model system and expression of properly folded- and natively modified-HCV envelope glycoproteins E1 and E2 have hindered vaccine development efforts. The recent structural and biophysical studies of these proteins have demonstrated that the binding sites for the cellular receptor CD-81 and neutralizing antibodies are highly flexible in nature, which complicate vaccine design. Furthermore, the interactions between E1 and E2 throughout HCV infection is poorly understood, and structural flexibility may play a role in shielding antigenic epitopes during infection. Here we discuss the structural complexities of HCV E1 and E2.

Keywords: E1; E2; HCV; envelope glycoprotein; hepatitis C virus; vaccine design.

Figure 1

Crystal structures of the N-terminal domain of E1 and an E1 peptide in complex with antibody. (A) Linear diagram of E1 glycoprotein. The crystallized E1 constructs and PDB IDs are shown below the diagram. (B) N-terminal domain structure of E1 monomer (PDB ID: 4UOI). (C) The six molecules of the asymmetric unit of the E1 N-terminal domain. (D) Structure of E1 peptide (aa314–324) in complex with antibody IGH526 (PDB ID: 4N0Y). The surface of antibody IGH526 is colored yellow, with the E1 peptide colored according to atom type (light blue, red, orange, and dark blue for carbon, oxygen, sulfur and nitrogen, respectively). The E1 peptide is further shown as ribbon structure in the box.

Figure 2

Crystal structure of E2 in complex with antibody. (A) Linear diagram of E2 glycoprotein. The crystallized E2 core constructs and PDB IDs are shown below the diagram. (B) Ribbon representation of E2 (PDB ID: 4MWF and 4WEB).

Figure 3

Ribbon representation of E2 hydrophobic residue positions in CD81 binding loop. (A) E2 residue F537 and L539 (side chains are shown as red sticks) in the presence of a stabilizing Fab fragment (not depicted) (PDB ID: 4MWF). (B) Solvent exposed positions of residue F537 and L539 (side chains are shown as blue sticks) (PDB ID: 4WEB).

Figure 4

Different conformations of E2 412–423 peptide in complex with antibodies. The antibody surface is colored yellow, and the peptide is shown as sticks colored according to atom type (light blue, red, orange, and dark blue for carbon, oxygen, sulfur and nitrogen, respectively). E2 peptides are further highlighted in boxes and shown as light blue ribbon structures. (A) β-hairpin peptide in complex with HCV1 antibody (PDB ID: 4DGY). (B) “Open” conformation peptide in complex with neutralizing antibody 3/11 (PDB ID: 4WHY).