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Nat Commun. 2017 May 23;8:15411. doi: 10.1038/ncomms15411.

Covalently linked dengue virus envelope glycoprotein dimers reduce exposure of the immunodominant fusion loop epitope.

Author information

1
Institut Pasteur, Département de Virologie, Unité de Virologie Structurale, 75724 Paris Cedex 15, France.
2
CNRS UMR 3569 Virologie, 75724 Paris Cedex 15, France.
3
Division of Immunology and Inflammation, Department of Medicine, Hammersmith Hospital Campus, Imperial College London, w12 0NN London, UK.
4
Université Paris-Sud, Faculté des Sciences, 91405 Orsay, France.
5
Institut Pasteur, Protéopôle, CNRS UMR 3528, 75724 Paris Cedex 15, France.
6
Dengue Haemorrhagic Fever Research Unit, Office for Research and Development, Faculty of Medicine, Siriraj Hospital, Mahidol University, Bangkok 10700, Thailand.

Abstract

A problem in the search for an efficient vaccine against dengue virus is the immunodominance of the fusion loop epitope (FLE), a segment of the envelope protein E that is buried at the interface of the E dimers coating mature viral particles. Anti-FLE antibodies are broadly cross-reactive but poorly neutralizing, displaying a strong infection enhancing potential. FLE exposure takes place via dynamic 'breathing' of E dimers at the virion surface. In contrast, antibodies targeting the E dimer epitope (EDE), readily exposed at the E dimer interface over the region of the conserved fusion loop, are very potent and broadly neutralizing. We here engineer E dimers locked by inter-subunit disulfide bonds, and show by X-ray crystallography and by binding to a panel of human antibodies that these engineered dimers do not expose the FLE, while retaining the EDE exposure. These locked dimers are strong immunogen candidates for a next-generation vaccine.

PMID:
28534525
PMCID:
PMC5457521
DOI:
10.1038/ncomms15411
[Indexed for MEDLINE]
Free PMC Article

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