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Structure of the prefusion-locking broadly neutralizing antibody RVC20 bound to the rabies virus glycoprotein

Rabies virus (RABV) causes fatal encephalitis in more than 59,000 people yearly. Upon the bite of an infected animal, the development of clinical disease can be prevented with post-exposure prophylaxis (PEP), which includes the administration of Rabies immunoglobulin (RIG). However, the high cost an...

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Autores principales: Hellert, Jan, Buchrieser, Julian, Larrous, Florence, Minola, Andrea, de Melo, Guilherme Dias, Soriaga, Leah, England, Patrick, Haouz, Ahmed, Telenti, Amalio, Schwartz, Olivier, Corti, Davide, Bourhy, Hervé, Rey, Félix A.
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Nature Publishing Group UK 2020
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6992781/
https://www.ncbi.nlm.nih.gov/pubmed/32001700
http://dx.doi.org/10.1038/s41467-020-14398-7
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author Hellert, Jan
Buchrieser, Julian
Larrous, Florence
Minola, Andrea
de Melo, Guilherme Dias
Soriaga, Leah
England, Patrick
Haouz, Ahmed
Telenti, Amalio
Schwartz, Olivier
Corti, Davide
Bourhy, Hervé
Rey, Félix A.
author_facet Hellert, Jan
Buchrieser, Julian
Larrous, Florence
Minola, Andrea
de Melo, Guilherme Dias
Soriaga, Leah
England, Patrick
Haouz, Ahmed
Telenti, Amalio
Schwartz, Olivier
Corti, Davide
Bourhy, Hervé
Rey, Félix A.
author_sort Hellert, Jan
collection PubMed
description Rabies virus (RABV) causes fatal encephalitis in more than 59,000 people yearly. Upon the bite of an infected animal, the development of clinical disease can be prevented with post-exposure prophylaxis (PEP), which includes the administration of Rabies immunoglobulin (RIG). However, the high cost and limited availability of serum-derived RIG severely hamper its wide use in resource-limited countries. A safe low-cost alternative is provided by using broadly neutralizing monoclonal antibodies (bnAbs). Here we report the X-ray structure of one of the most potent and most broadly reactive human bnAbs, RVC20, in complex with its target domain III of the RABV glycoprotein (G). The structure reveals that the RVC20 binding determinants reside in a highly conserved surface of G, rationalizing its broad reactivity. We further show that RVC20 blocks the acid-induced conformational change required for membrane fusion. Our results may guide the future development of direct antiviral small molecules for Rabies treatment.
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spelling pubmed-69927812020-02-03 Structure of the prefusion-locking broadly neutralizing antibody RVC20 bound to the rabies virus glycoprotein Hellert, Jan Buchrieser, Julian Larrous, Florence Minola, Andrea de Melo, Guilherme Dias Soriaga, Leah England, Patrick Haouz, Ahmed Telenti, Amalio Schwartz, Olivier Corti, Davide Bourhy, Hervé Rey, Félix A. Nat Commun Article Rabies virus (RABV) causes fatal encephalitis in more than 59,000 people yearly. Upon the bite of an infected animal, the development of clinical disease can be prevented with post-exposure prophylaxis (PEP), which includes the administration of Rabies immunoglobulin (RIG). However, the high cost and limited availability of serum-derived RIG severely hamper its wide use in resource-limited countries. A safe low-cost alternative is provided by using broadly neutralizing monoclonal antibodies (bnAbs). Here we report the X-ray structure of one of the most potent and most broadly reactive human bnAbs, RVC20, in complex with its target domain III of the RABV glycoprotein (G). The structure reveals that the RVC20 binding determinants reside in a highly conserved surface of G, rationalizing its broad reactivity. We further show that RVC20 blocks the acid-induced conformational change required for membrane fusion. Our results may guide the future development of direct antiviral small molecules for Rabies treatment. Nature Publishing Group UK 2020-01-30 /pmc/articles/PMC6992781/ /pubmed/32001700 http://dx.doi.org/10.1038/s41467-020-14398-7 Text en © The Author(s) 2020 Open Access This article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made. The images or other third party material in this article are included in the article’s Creative Commons license, unless indicated otherwise in a credit line to the material. If material is not included in the article’s Creative Commons license and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this license, visit http://creativecommons.org/licenses/by/4.0/.
spellingShingle Article
Hellert, Jan
Buchrieser, Julian
Larrous, Florence
Minola, Andrea
de Melo, Guilherme Dias
Soriaga, Leah
England, Patrick
Haouz, Ahmed
Telenti, Amalio
Schwartz, Olivier
Corti, Davide
Bourhy, Hervé
Rey, Félix A.
Structure of the prefusion-locking broadly neutralizing antibody RVC20 bound to the rabies virus glycoprotein
title Structure of the prefusion-locking broadly neutralizing antibody RVC20 bound to the rabies virus glycoprotein
title_full Structure of the prefusion-locking broadly neutralizing antibody RVC20 bound to the rabies virus glycoprotein
title_fullStr Structure of the prefusion-locking broadly neutralizing antibody RVC20 bound to the rabies virus glycoprotein
title_full_unstemmed Structure of the prefusion-locking broadly neutralizing antibody RVC20 bound to the rabies virus glycoprotein
title_short Structure of the prefusion-locking broadly neutralizing antibody RVC20 bound to the rabies virus glycoprotein
title_sort structure of the prefusion-locking broadly neutralizing antibody rvc20 bound to the rabies virus glycoprotein
topic Article
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6992781/
https://www.ncbi.nlm.nih.gov/pubmed/32001700
http://dx.doi.org/10.1038/s41467-020-14398-7
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