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

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., Khan, A. G., Schulze, K., Law, J., Logan, M., Hockman, D., Wong, J. A. J.-X., Dold, L., Gonzalez-Motos, V., Spengler, U., Viejo-Borbolla, A., Ströh, L. J., Krey, T., Tarr, A. W., Steinmann, E., …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: Nov 14, 2019
• 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.
• Contract Date: May 9, 2019