HCV Glycoprotein Structure and Implications for B-Cell Vaccine Development

Abstract

Despite the approval of highly efficient direct-acting antivirals in the last decade Hepatitis C virus (HCV) remains a global health burden and the development of a vaccine would constitute an important step towards the control of HCV. The high genetic variability of the viral glycoproteins E1 and E2, which carry the main neutralizing determinants, together with their intrinsic structural flexibility, the high level of glycosylation that shields conserved neutralization epitopes and immune evasion using decoy epitopes renders the design of an efficient vaccine challenging. Recent structural and functional analyses have highlighted the role of the CD81 receptor binding site on E2, which overlaps with those neutralization epitopes within E2 that have been structurally characterized to date. This CD81 binding site consists of three distinct segments including "epitope I", "epitope II" and the "CD81 binding loop". In this review we summarize the structural features of the HCV glycoproteins that have been derived from X-ray structures of neutralizing and non-neutralizing antibody fragments complexed with either recombinant E2 or epitope-derived linear peptides. We focus on the current understanding how neutralizing antibodies interact with their cognate antigen, the structural features of the respective neutralization epitopes targeted by nAbs and discuss the implications for informed vaccine design.

Keywords: Hepatitis C virus; glycoprotein; nAbs; neutralization epitope; neutralizing antibodies; vaccine.

Figure 1

Structurally characterized neutralization epitopes within Hepatitis C virus (HCV) E2. Cartoon representation of the E2 ectodomain crystallized in a complex with HEPC3 and HEPC46 Fab (PDB 6MEJ). The Fab fragments were removed for clarity. The ordered part of the hypervariable region 1 (dark green) and the composite CD81 binding site consisting of epitope I (aa412–423; palegreen), epitope II (aa434–446; orange) and the CD81-binding loop (aa518–535; blue) are highlighted in color. A conserved frontlayer epitope (residues 427–434, 438–443 and 529–531) that is targeted by several bnAbs derived from the VH1-69 germline gene (see text) is indicated by wider and transparent cartoon segments and labeled by colored arrows.