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J Hepatol. 2018 Nov 13. pii: S0168-8278(18)32527-3. doi: 10.1016/j.jhep.2018.11.003. [Epub ahead of print]

Functional and immunogenic characterization of diverse HCV glycoprotein E2 variants.

Author information

1
Institute of Experimental Virology, TWINCORE, Centre for Experimental and Clinical Infection Research; a Joint Venture between the Medical School Hannover (MHH) and the Helmholtz Centre for Infection Research (HZI), Hannover, Germany.
2
Institute of Experimental Virology, TWINCORE, Centre for Experimental and Clinical Infection Research; a Joint Venture between the Medical School Hannover (MHH) and the Helmholtz Centre for Infection Research (HZI), Hannover, Germany; Department of Gastroenterology, Hepatology and Endocrinology, Hannover Medical School, Hannover, Germany; German Centre for Infection Research (DZIF), partner site Hannover-Braunschweig, Germany.
3
Institute of Experimental Virology, TWINCORE, Centre for Experimental and Clinical Infection Research; a Joint Venture between the Medical School Hannover (MHH) and the Helmholtz Centre for Infection Research (HZI), Hannover, Germany; Department of Molecular and Medical Virology, Ruhr-University Bochum, Bochum, Germany.
4
National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, MD 20892-9806, USA.
5
Department of Vaccinology and Applied Microbiology, Helmholtz Centre for Infection Research, Braunschweig, Germany.
6
Li Ka Shing Institute of Virology, Department of Medical Microbiology & Immunology, University of Alberta, Edmonton, Canada.
7
Institute of Virology, Center for Molecular Medicine Cologne (CMMC), University of Cologne, Cologne, Germany; German Centre for Infection Research (DZIF), partner site Cologne, Germany.
8
Institute of Virology, Hannover Medical School, 30625 Hannover, Germany.
9
Department of Internal Medicine 1, Rheinische Friedrich-Wilhelms-University Bonn, Bonn, Germany.
10
Institute of Virology, Hannover Medical School, 30625 Hannover, Germany; German Centre for Infection Research (DZIF), partner site Hannover-Braunschweig, Germany.
11
NIHR Nottingham Digestive Diseases Biomedical Research Centre and School of Life Sciences, The University of Nottingham, Nottingham, UK.
12
Institute of Experimental Virology, TWINCORE, Centre for Experimental and Clinical Infection Research; a Joint Venture between the Medical School Hannover (MHH) and the Helmholtz Centre for Infection Research (HZI), Hannover, Germany; German Centre for Infection Research (DZIF), partner site Hannover-Braunschweig, Germany; Department of Molecular and Medical Virology, Ruhr-University Bochum, Bochum, Germany.
13
Department of Gastroenterology, Hepatology and Endocrinology, Hannover Medical School, Hannover, Germany; German Centre for Infection Research (DZIF), partner site Hannover-Braunschweig, Germany.
14
Institute of Experimental Virology, TWINCORE, Centre for Experimental and Clinical Infection Research; a Joint Venture between the Medical School Hannover (MHH) and the Helmholtz Centre for Infection Research (HZI), Hannover, Germany; German Centre for Infection Research (DZIF), partner site Hannover-Braunschweig, Germany. Electronic address: thomas.pietschmann@twincore.de.

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.

KEYWORDS:

Antibodies; Glycoproteins; HCV; Immunogen; Recombinant proteins

PMID:
30439392
DOI:
10.1016/j.jhep.2018.11.003

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