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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

Authors

Annalisa Meola

Alexander V. Tarr

Patrick England

Luke W. Meredith

Patrick McClure

Steven K.H. Foung

Jane A. McKeating

Jonathan K. Ball

Felix A. Rey

Thomas Krey



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.

Journal Article Type Article
Publication Date Feb 28, 2015
Print ISSN 0022-538X
Electronic ISSN 1098-5514
Publisher American Society for Microbiology
Peer Reviewed Peer Reviewed
Volume 89
Issue 4
Pages 2170-2181
APA6 Citation Meola, A., Tarr, A. V., England, P., Meredith, L. W., McClure, P., Foung, S. K., …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. doi:10.1128/JVI.02190-14
DOI https://doi.org/10.1128/JVI.02190-14
Publisher URL https://jvi.asm.org/content/89/4/2170
PMID 00034856
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