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

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

*Corresponding author for this work
78 Citations (Scopus)

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 β-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 β-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.

Original languageEnglish
JournalJournal of Virology
Volume89
Issue number4
Pages (from-to)2170-2181
Number of pages12
ISSN0022-538X
DOIs
Publication statusPublished - 2015

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