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Functional and immunogenic characterization of diverse HCV glycoprotein E2 variants

Khera, Tanvi; Behrendt, Patrick; Bankwitz, Dorothea; Brown, Richard J.P.; Todt, Daniel; Doepke, Mandy; Khan, Abdul Ghafoor; Schulze, Kai; Law, John; Logan, Michael; Hockman, Darren; Wong, Jason Alexander Ji-Xhin; Dold, Leona; Gonzalez-Motos, Victor; Spengler, Ulrich; Viejo-Borbolla, Abel; Ströh, Luisa J; Krey, Thomas; Tarr, Alexander W.; Steinmann, Eike; Manns, Michael P.; Klein, Florian; Guzman, Carlos A.; Marcotrigiano, Joseph; Houghton, Michael; Pietschmann, Thomas

Functional and immunogenic characterization of diverse HCV glycoprotein E2 variants Thumbnail


Authors

Tanvi Khera

Patrick Behrendt

Dorothea Bankwitz

Richard J.P. Brown

Daniel Todt

Mandy Doepke

Abdul Ghafoor Khan

Kai Schulze

John Law

Michael Logan

Darren Hockman

Jason Alexander Ji-Xhin Wong

Leona Dold

Victor Gonzalez-Motos

Ulrich Spengler

Abel Viejo-Borbolla

Luisa J Ströh

Thomas Krey

Eike Steinmann

Michael P. Manns

Florian Klein

Carlos A. Guzman

Joseph Marcotrigiano

Michael Houghton

Thomas Pietschmann



Abstract

© 2018 European Association for the Study of the Liver Background & Aims: Induction of cross-reactive antibodies targeting conserved epitopes of the envelope proteins E1E2 is a key requirement for an hepatitis C virus vaccine. Conserved epitopes like the viral CD81-binding site are targeted by rare broadly neutralizing antibodies. However, these viral segments are occluded by variable regions and glycans. We aimed to identify antigens exposing conserved epitopes and to characterize their immunogenicity. Methods: We created hepatitis C virus variants with mutated glycosylation sites and/or hypervariable region 1 (HVR1). Exposure of the CD81 binding site and conserved epitopes was quantified by soluble CD81 and antibody interaction and neutralization assays. E2 or E1-E2 heterodimers with mutations causing epitope exposure were used to immunize mice. Vaccine-induced antibodies were examined and compared with patient-derived antibodies. Results: Mutant viruses bound soluble CD81 and antibodies targeting the CD81 binding site with enhanced efficacy. Mice immunized with E2 or E1E2 heterodimers incorporating these modifications mounted strong, cross-binding, and non-interfering antibodies. E2-induced antibodies neutralized the autologous virus but they were not cross-neutralizing. Conclusions: Viruses lacking the HVR1 and selected glycosylation sites expose the CD81 binding site and cross-neutralization antibody epitopes. Recombinant E2 proteins carrying these modifications induce strong cross-binding but not cross-neutralizing antibodies. Lay summary: Conserved viral epitopes can be made considerably more accessible for binding of potently neutralizing antibodies by deletion of hypervariable region 1 and selected glycosylation sites. Recombinant E2 proteins carrying these mutations are unable to elicit cross-neutralizing antibodies suggesting that exposure of conserved epitopes is not sufficient to focus antibody responses on production of cross-neutralizing antibodies.

Citation

Khera, T., Behrendt, P., Bankwitz, D., Brown, R. J., Todt, D., Doepke, M., …Pietschmann, T. (2019). Functional and immunogenic characterization of diverse HCV glycoprotein E2 variants. Journal of Hepatology, 70(4), 593-602. https://doi.org/10.1016/j.jhep.2018.11.003

Journal Article Type Article
Acceptance Date Nov 2, 2018
Online Publication Date Nov 13, 2018
Publication Date Apr 1, 2019
Deposit Date Apr 30, 2019
Publicly Available Date Mar 29, 2024
Journal Journal of Hepatology
Print ISSN 0168-8278
Electronic ISSN 1600-0641
Publisher Elsevier
Peer Reviewed Peer Reviewed
Volume 70
Issue 4
Pages 593-602
DOI https://doi.org/10.1016/j.jhep.2018.11.003
Keywords HCV; Glycoproteins; Immunogen; Antibodies; Recombinant proteins
Public URL https://nottingham-repository.worktribe.com/output/1860731
Publisher URL https://www.sciencedirect.com/science/article/pii/S0168827818325273?via%3Dihub
Additional Information This article is maintained by: Elsevier; Article Title: Functional and immunogenic characterization of diverse HCV glycoprotein E2 variants; Journal Title: Journal of Hepatology; CrossRef DOI link to publisher maintained version: https://doi.org/10.1016/j.jhep.2018.11.003; Content Type: article; Copyright: © 2018 European Association for the Study of the Liver. Published by Elsevier B.V. All rights reserved.