Structural flexibility of a conserved antigenic region in Hepatitis C virus glycoprotein E2 recognized by broadly neutralizing antibodies

Meola, Annalisa; Tarr, Alexander V.; England, Patrick; Meredith, Luke W.; McClure, Patrick; Foung, Steven K.H.; McKeating, Jane A.; Ball, Jonathan K.; Rey, Felix A.; Krey, Thomas

Abstract

Neutralizing antibodies (NAbs) targeting glycoprotein E2 are important for the control of hepatitis C virus (HCV) infection. One conserved antigenic site (amino acids 412 to 423) is disordered in the reported E2 structure, but a synthetic peptide mimicking this site forms a ?-hairpin in complex with three independent NAbs. Our structure of the same peptide in complex with NAb 3/11 demonstrates a strikingly different extended conformation. We also show that residues 412 to 423 are essential for virus entry but not for E2 folding. Together with the neutralizing capacity of the 3/11 Fab fragment, this indicates an unexpected structural flexibility within this epitope. NAbs 3/11 and AP33 (recognizing the extended and ?-hairpin conformations, respectively) display similar neutralizing activities despite converse binding kinetics. Our results suggest that HCV utilizes conformational flexibility as an immune evasion strategy, contributing to the limited immunogenicity of this epitope in patients, similar to the conformational flexibility described for other enveloped and nonenveloped viruses.

Citation

Meola, A., Tarr, A. V., England, P., Meredith, L. W., McClure, P., Foung, S. K., McKeating, J. A., Ball, J. K., Rey, F. A., & Krey, T. (2015). Structural flexibility of a conserved antigenic region in Hepatitis C virus glycoprotein E2 recognized by broadly neutralizing antibodies. Journal of Virology, 89(4), 2170-2181. https://doi.org/10.1128/JVI.02190-14

• Journal Article Type: Article
• Acceptance Date: Nov 26, 2014
• Online Publication Date: Jan 26, 2015
• Publication Date: Feb 28, 2015
• Deposit Date: Oct 24, 2017
• Print ISSN: 0022-538X
• Electronic ISSN: 1098-5514
• Publisher: American Society for Microbiology
• Peer Reviewed: Peer Reviewed
• Volume: 89
• Issue: 4
• Pages: 2170-2181
• DOI: https://doi.org/10.1128/JVI.02190-14
• Public URL: https://nottingham-repository.worktribe.com/output/1106077
• Publisher URL: https://jvi.asm.org/content/89/4/2170
• PMID: 00034856