Contributors: Virologie Structurale - Structural Virology; Institut Pasteur Paris (IP)-Centre National de la Recherche Scientifique (CNRS); Virus et Immunité - Virus and immunity (CNRS-UMR3569); Lyssavirus, épidémiologie et neuropathologie - Lyssavirus Epidemiology and Neuropathology; Institut Pasteur Paris (IP); Humabs BioMed SA; Vir Biotechnology Inc San Francisco; Biophysique Moléculaire (plateforme) - Molecular Biophysics (platform); Cristallographie (Plateforme) - Crystallography (Platform); This work was funded by Institut Pasteur. F.A.R. received additional funding from the CNRS, the Labex IBEID (ANR-10-IHUB-0002), the GIS IBiSA (Infrastructures en biologie santé et agronomie), grant ANR-13-ISV8-0002-01 and the Région Ile de France in order to support the work of J.H. (Domaine d’intérêt majeur innovative technologies for life sciences, DIM 1HEALTH). O.S. received funding from ANRS, Sidaction, the Vaccine Research Institute (ANR-10-LABX-77), the Labex IBEID (ANR-10-IHUB-0002), the “TIMTAMDEN” ANR-14-CE14-0029, the “CHIKV-Viro-Immuno” ANR-14-CE14-0015-01, L’Oréal Sponsorship, the CNRS and the Gilead HIV cure program. H.B., F.L. and G.D.M. received funding from the INFECT-ERA 2016 project ANR 16-IFEC-0006-01 ToRRENT.Part of this work was performed at the UtechS Photonic BioImaging (PBI) platform, member of France Life Imaging network (grant ANR-11-INBS-0006).; ANR-13-ISV8-0002,flavistem,La protéine E des flavivirus : interactions et fusion membranaire(2013); ANR-10-LABX-0077,VRI,Initiative for the creation of a Vaccine Research Institute(2010); ANR-14-CE14-0029,TIMTAMDEN,Rôle des récepteurs TIM et TAM dans l'infection des cellules cibles par le virus de la dengue(2014); ANR-14-CE14-0015,CHIKV-Viro-Immuno,Multiplication et Relation avec l'hôte du virus Chikungunya(2014); ANR-16-IFEC-0006,ToRRENT,Towards a combined post-exposure prophylaxis and successful treatment of rabies in humans(2016); ANR-11-INBS-0006,FLI,France Life Imaging(2011)
نبذة مختصرة : International audience ; 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.
Processing Request
No Comments.