Khera, Tanvi, Behrendt, Patrick, Bankwitz, Dorothea, Brown, Richard J. P., Todt, Daniel ORCID: 0000-0002-3564-1014, 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 ORCID: 0000-0001-6395-4010, Stroeh, Luisa J., Krey, Thomas, Tarr, Alexander W., Steinmann, Eike ORCID: 0000-0002-3654-9965, Manns, Michael P., Klein, Florian, Guzman, Carlos A., Marcotrigiano, Joseph, Houghton, Michael and Pietschmann, Thomas (2019). Functional and immunogenic characterization of diverse HCV glycoprotein E2 variants. J. Hepatol., 70 (4). S. 593 - 603. AMSTERDAM: ELSEVIER SCIENCE BV. ISSN 1600-0641

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Abstract

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. (C) 2018 European Association for the Study of the Liver. Published by Elsevier B.V. All rights reserved.

Item Type: Journal Article
Creators:
CreatorsEmailORCIDORCID Put Code
Khera, TanviUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Behrendt, PatrickUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Bankwitz, DorotheaUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Brown, Richard J. P.UNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Todt, DanielUNSPECIFIEDorcid.org/0000-0002-3564-1014UNSPECIFIED
Doepke, MandyUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Khan, Abdul GhafoorUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Schulze, KaiUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Law, JohnUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Logan, MichaelUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Hockman, DarrenUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Wong, Jason Alexander Ji-XhinUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Dold, LeonaUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Gonzalez-Motos, VictorUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Spengler, UlrichUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Viejo-Borbolla, AbelUNSPECIFIEDorcid.org/0000-0001-6395-4010UNSPECIFIED
Stroeh, Luisa J.UNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Krey, ThomasUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Tarr, Alexander W.UNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Steinmann, EikeUNSPECIFIEDorcid.org/0000-0002-3654-9965UNSPECIFIED
Manns, Michael P.UNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Klein, FlorianUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Guzman, Carlos A.UNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Marcotrigiano, JosephUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Houghton, MichaelUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Pietschmann, ThomasUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
URN: urn:nbn:de:hbz:38-153097
DOI: 10.1016/j.jhep.2018.11.003
Journal or Publication Title: J. Hepatol.
Volume: 70
Number: 4
Page Range: S. 593 - 603
Date: 2019
Publisher: ELSEVIER SCIENCE BV
Place of Publication: AMSTERDAM
ISSN: 1600-0641
Language: English
Faculty: Unspecified
Divisions: Unspecified
Subjects: no entry
Uncontrolled Keywords:
KeywordsLanguage
HEPATITIS-C-VIRUS; N-LINKED GLYCANS; ENVELOPE GLYCOPROTEIN; NEUTRALIZING ANTIBODIES; VACCINE; INFECTION; DOMAINMultiple languages
Gastroenterology & HepatologyMultiple languages
Refereed: Yes
URI: http://kups.ub.uni-koeln.de/id/eprint/15309

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