Abstract
ABSTRACTThe hepatitis C virus (HCV) glycoprotein E2 is the major target of neutralizing antibodies and is therefore highly relevant for vaccine design. Its structure features a central immunoglobulin (Ig)-like β-sandwich that contributes to the binding site for the cellular receptor CD81. We show that a synthetic peptide corresponding to a β-strand of this Ig-like domain forms an α-helix in complex with the anti-E2 antibody DAO5, demonstrating an inside-out flip of hydrophobic residues and a secondary structure change in the composite CD81 binding site. A detailed interaction analysis of DAO5 and cross-competing neutralizing antibodies with soluble E2 revealed that the Ig-like domain is trapped by different antibodies in at least two distinct conformations. DAO5 specifically captures retrovirus particles bearing HCV glycoproteins (HCVpp) and infectious cell culture-derived HCV particles (HCVcc). Infection of cells by DAO5-captured HCVpp can be blocked by a cross-competing neutralizing antibody, indicating that a single virus particle simultaneously displays E2 molecules in more than one conformation on its surface. Such conformational plasticity of the HCV E2 receptor binding site has important implications for immunogen design.
Highlights
The hepatitis C virus (HCV) glycoprotein E2 is the major target of neutralizing antibodies and is highly relevant for vaccine design
In this study, we found that an important part of the CD81 binding site within the HCV glycoprotein E2, the CD81 binding loop, adopts more than one distinct conformbio.asm.org 9 mation at the surface of both HCV pseudoparticles (HCVpp) and HCVcc
One of these conformations has been observed in complex with the human broadly neutralizing nAbs (bnAbs) AR3C [10]; insights into another one are provided by our crystal structure of monoclonal antibodies (MAbs) DAO5 in complex with an epitope peptide
Summary
The hepatitis C virus (HCV) glycoprotein E2 is the major target of neutralizing antibodies and is highly relevant for vaccine design. Infection of cells by DAO5-captured HCVpp can be blocked by a cross-competing neutralizing antibody, indicating that a single virus particle simultaneously displays E2 molecules in more than one conformation on its surface Such conformational plasticity of the HCV E2 receptor binding site has important implications for immunogen design. IMPORTANCE Recent advances in the treatment of hepatitis C virus (HCV) infection with direct-acting antiviral drugs have enabled the control of this major human pathogen Due to their high costs and limited accessibility in combination with the lack of awareness of the mostly asymptomatic infection, there is an unchanged urgent need for an effective vaccine. Further evidence for the flexibility of the HCV glycoproteins comes from the observations that the oligomeric status as well as the disulfide connectivity of the HCV glycoproteins fluctuate during the HCV replication cycle [11, 12]
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