The epitope arrangement on flavivirus particles contributes to Mab C10's extraordinary neutralization breadth across Zika and dengue viruses.

Autor:	Sharma A; Institut Pasteur, Université de Paris, CNRS UMR3569, Unité de Virologie Structurale, 75015 Paris, France., Zhang X; Institut Pasteur, Université de Paris, CNRS UMR3569, Unité de Virologie Structurale, 75015 Paris, France; Interdisciplinary Center for Brain Information, the Brain Cognition and Brain Disease Institute, Faculty of Life and Health Sciences, Shenzhen Institute of Advanced Technology, Chinese Academy of Sciences, Shenzhen-Hong Kong Institute of Brain Science-Shenzhen Fundamental Research Institutions, Shenzhen, Guangdong 518055, China., Dejnirattisai W; Wellcome Centre for Human Genetics, Nuffield Department of Medicine, University of Oxford, Oxford, UK., Dai X; Department of Microbiology, Immunology and Molecular Genetics, University of California, Los Angeles, Los Angeles, CA 90095, USA; Department of Molecular and Medical Pharmacology, University of California, Los Angeles, Los Angeles, CA 90095, USA., Gong D; Department of Molecular and Medical Pharmacology, University of California, Los Angeles, Los Angeles, CA 90095, USA., Wongwiwat W; Wellcome Centre for Human Genetics, Nuffield Department of Medicine, University of Oxford, Oxford, UK., Duquerroy S; Institut Pasteur, Université de Paris, CNRS UMR3569, Unité de Virologie Structurale, 75015 Paris, France; Université Paris-Saclay, Faculté des Sciences, F-91405 Orsay, France., Rouvinski A; Institut Pasteur, Université de Paris, CNRS UMR3569, Unité de Virologie Structurale, 75015 Paris, France., Vaney MC; Institut Pasteur, Université de Paris, CNRS UMR3569, Unité de Virologie Structurale, 75015 Paris, France., Guardado-Calvo P; Institut Pasteur, Université de Paris, CNRS UMR3569, Unité de Virologie Structurale, 75015 Paris, France., Haouz A; Institut Pasteur, Université de Paris, CNRS UMR 3528, Center for Technological Resources and Research, 75015 Paris, France., England P; Institut Pasteur, Université de Paris, CNRS UMR 3528, Center for Technological Resources and Research, 75015 Paris, France., Sun R; Department of Molecular and Medical Pharmacology, University of California, Los Angeles, Los Angeles, CA 90095, USA; California NanoSystems Institute, University of California, Los Angeles, Los Angeles, CA 90095, USA., Zhou ZH; Department of Microbiology, Immunology and Molecular Genetics, University of California, Los Angeles, Los Angeles, CA 90095, USA; California NanoSystems Institute, University of California, Los Angeles, Los Angeles, CA 90095, USA., Mongkolsapaya J; Wellcome Centre for Human Genetics, Nuffield Department of Medicine, University of Oxford, Oxford, UK; Dengue Hemorrhagic Fever Research Unit, Office for Research and Development, Faculty of Medicine, Siriraj Hospital, Mahidol University, Bangkok, Thailand., Screaton GR; Division of Medical Sciences, University of Oxford, Oxford, UK. Electronic address: gavin.screaton@medsci.ox.ac.uk., Rey FA; Institut Pasteur, Université de Paris, CNRS UMR3569, Unité de Virologie Structurale, 75015 Paris, France. Electronic address: felix.rey@pasteur.fr.
Jazyk:	angličtina
Zdroj:	Cell [Cell] 2021 Dec 09; Vol. 184 (25), pp. 6052-6066.e18. Date of Electronic Publication: 2021 Nov 30.
DOI:	10.1016/j.cell.2021.11.010
Abstrakt:	The human monoclonal antibody C10 exhibits extraordinary cross-reactivity, potently neutralizing Zika virus (ZIKV) and the four serotypes of dengue virus (DENV1-DENV4). Here we describe a comparative structure-function analysis of C10 bound to the envelope (E) protein dimers of the five viruses it neutralizes. We demonstrate that the C10 Fab has high affinity for ZIKV and DENV1 but not for DENV2, DENV3, and DENV4. We further show that the C10 interaction with the latter viruses requires an E protein conformational landscape that limits binding to only one of the three independent epitopes per virion. This limited affinity is nevertheless counterbalanced by the particle's icosahedral organization, which allows two different dimers to be reached by both Fab arms of a C10 immunoglobulin. The epitopes' geometric distribution thus confers C10 its exceptional neutralization breadth. Our results highlight the importance not only of paratope/epitope complementarity but also the topological distribution for epitope-focused vaccine design. Competing Interests: Declaration of interests F.A.R. is a board member and shareholder of EureKARE and MELETIUS Therapeutics. G.R.S. is member of the GSK Vaccines Scientific Advisory Board and a founding shareholder of RQ Biotechnology. G.R.S., F.A.R., P.G.-C., M.-C.V, A.R., S.D., and J.M. are authors in a patent concerning EDE mAbs, including C8 and C10:US20180037611A1 (2018): Anti-dengue vaccines and antibodies. G.R.S., F.A.R., M.-C.V., A.R., and J.M. are authors of patent CA3066488A1 (2017): Neutralising antibody against dengue for use in a method of prevention and/or treatment. (Copyright © 2021 The Authors. Published by Elsevier Inc. All rights reserved.)
Databáze:	MEDLINE
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