3 years ago

Functional and immunogenic characterization of diverse HCV glycoprotein E2 variants

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 Ströh, Thomas Krey, Alexander W. Tarr, Eike Steinmann

Publication date: Available online 13 November 2018

Source: Journal of Hepatology

Author(s): 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 Ströh, Thomas Krey, Alexander W. Tarr, Eike Steinmann

Abstract
Background and Aims

Induction of cross-reactive antibodies targeting conserved epitopes of the envelope proteins E1E2 is a key requirement for an HCV 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 HCV 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 HVR1 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.

Graphical abstract

Graphical abstract for this article

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