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.
Highlights
Chronic Hepatitis C virus (HCV) infection is one of the major causes of liver fibrosis, liver cirrhosis and hepatocellular carcinoma (HCC)
Several studies have demonstrated that a rapid induction of neutralizing antibodies along with a broadly reactive T-cell response leads to spontaneous clearance of acute HCV infections [8,9]
The extreme genetic diversity of circulating HCV genotypes [20] is a major challenge for vaccine development and antibody responses often target glycoprotein regions that have a high mutation rate [21] and/or immunodominant epitopes that serve as decoy epitopes
Summary
Chronic Hepatitis C virus (HCV) infection is one of the major causes of liver fibrosis, liver cirrhosis and hepatocellular carcinoma (HCC). Several studies have demonstrated that a rapid induction of neutralizing antibodies (nAbs) along with a broadly reactive T-cell response leads to spontaneous clearance of acute HCV infections [8,9]. Passive transfer of potent broadly nAbs (bnAbs) prior to the challenge protects from infection with heterologous viruses [17,18] and viral clearance during an acute infection leads, in about 80% of the cases, to clearance of subsequent reinfections due to a rapid induction of cross-reactive nAbs [19]. The extreme genetic diversity of circulating HCV genotypes [20] is a major challenge for vaccine development and antibody responses often target glycoprotein regions that have a high mutation rate [21] and/or immunodominant epitopes that serve as decoy epitopes. In this review we aim to focus in particular on the structural characterization of E1, E2 and the E1E2 heterodimer as a basis for rational B cell vaccine design strategies
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