1. Structural and mechanistic basis of neutralization by a pan-hantavirus protective antibody
- Author
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Mittler, Eva, Serris, Alexandra, Esterman, Emma, Florez, Catalina, Polanco, Laura, O’brien, Cecilia, Slough, Megan, Tynell, Janne, Gröning, Remigius, Sun, Yan, Abelson, Dafna, Wec, Anna, Haslwanter, Denise, Keller, Markus, Ye, Chunyan, Bakken, Russel, Jangra, Rohit, Dye, John, Ahlm, Clas, Rappazzo, C. Garrett, Ulrich, Rainer, Zeitlin, Larry, Geoghegan, James, Bradfute, Steven, Sidoli, Simone, Forsell, Mattias N.E., Strandin, Tomas, Rey, Felix, Herbert, Andrew, Walker, Laura, Chandran, Kartik, Guardado-Calvo, Pablo, Albert Einstein College of Medicine [New York], Virologie Structurale - Structural Virology, Institut Pasteur [Paris] (IP)-Centre National de la Recherche Scientifique (CNRS)-Université Paris Cité (UPCité), Adimab [Lebanon], U.S. Army Medical Research Institute of Infectious Diseases (USAMRIID), Umeå University, Mapp Biopharmaceutical Inc., Friedrich-Loeffler-Institut (FLI), The University of New Mexico [Albuquerque], Haaga-Helia University of Applied Sciences [Helsinki, Finland], This research was supported by NIAID of the NIH under award number U19AI142777 (Centers of Excellence in Translational Research) to K.C., L.M.W., J.M.D., A.S.H., S.B.B., M.N.E.F., and L.Z. M.N.E.F. was supported by a grant from the Swedish Research Council (no. 2020-06235). C.A. was supported by research grants from Region Västerbotten and Umeå University (RV-579011, RV-734361, and RV-965866). J.T. was supported by the Finnish Cultural Foundation (no. 00221066). R.K.J. was supported by grants from the NIH (R2AI156482, P20GM134974, and P20GM121307). R.G.U. was supported by the Bundesministerium für Bildung und Forschung (BMBF) within the Research Network Zoonotic Infectious Diseases (01KI1721A and 01KI2004A). T.S. was supported by the Academy of Finland (no. 321809). P.G.-C. was supported by a grant by the National French Research Agency (ANR-18-CE11-0011), and A.S. was supported with a fellowship by the French Fondation pour la Recherche Médicale (FDM20170638040). F.A.R. and P.G.-C. were supported by Labex IBEID (ANR-10-LABX-62-IBEID)., ANR-10-LABX-0062,IBEID,Integrative Biology of Emerging Infectious Diseases(2010), and ANR-18-CE11-0011,LISEFU,Base structurale de la détection des lipides dans la fusion virale(2018)
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[SDV]Life Sciences [q-bio] - Abstract
International audience; Emerging rodent-borne hantaviruses cause severe diseases in humans with no approved vaccines or therapeutics. We recently isolated a monoclonal broadly neutralizing antibody (nAb) from a Puumala virus-experienced human donor. Here, we report its structure bound to its target, the Gn/Gc glycoprotein heterodimer comprising the viral fusion complex. The structure explains the broad activity of the nAb: It recognizes conserved Gc fusion loop sequences and the main chain of variable Gn sequences, thereby straddling the Gn/Gc heterodimer and locking it in its prefusion conformation. We show that the nAb's accelerated dissociation from the divergent Andes virus Gn/Gc at endosomal acidic pH limits its potency against this highly lethal virus and correct this liability by engineering an optimized variant that sets a benchmark as a candidate pan-hantavirus therapeutic.
- Published
- 2023
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