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

Jan Hellert, Julian Buchrieser, Florence Larrous, Andrea Minola, Guilherme Dias Melo, Leah Soriaga, Patrick England, Ahmed Haouz, Amalio Telenti, Olivier Schwartz, Davide Corti, Hervé Bourhy () and Félix A. Rey ()
Additional contact information
Jan Hellert: Structural Virology Unit, Institut Pasteur
Julian Buchrieser: Institut Pasteur
Florence Larrous: Institut Pasteur
Andrea Minola: Humabs BioMed SA, a subsidiary of Vir Biotechnology Inc.
Guilherme Dias Melo: Institut Pasteur
Leah Soriaga: Vir Biotechnology Inc
Patrick England: Molecular Biophysics Platform C2RT, Institut Pasteur
Ahmed Haouz: Crystallography Platform C2RT, Institut Pasteur
Amalio Telenti: Vir Biotechnology Inc
Olivier Schwartz: Institut Pasteur
Davide Corti: Humabs BioMed SA, a subsidiary of Vir Biotechnology Inc.
Hervé Bourhy: Institut Pasteur
Félix A. Rey: Structural Virology Unit, Institut Pasteur

Nature Communications, 2020, vol. 11, issue 1, 1-8

Abstract: Abstract 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.

Date: 2020
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DOI: 10.1038/s41467-020-14398-7

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