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
Richard J.P. Brown
Abdul Ghafoor Khan
Jason Alexander Ji-Xhin Wong
Luisa J Ströh
ALEXANDER TARR firstname.lastname@example.org
Michael P. Manns
Carlos A. Guzman
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.
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.
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.
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.
|Journal Article Type||Article|
|Journal||Journal of Hepatology|
|Peer Reviewed||Peer Reviewed|
|APA6 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. doi:10.1016/j.jhep.2018.11.003|
|Keywords||HCV; Glycoproteins; Immunogen; Antibodies; Recombinant proteins|
|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.|
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