2. Academic Validation
  3. Structural and mechanistic basis of neutralization by a pan-hantavirus protective antibody

Structural and mechanistic basis of neutralization by a pan-hantavirus protective antibody

  • Sci Transl Med. 2023 Jun 14;15(700):eadg1855. doi: 10.1126/scitranslmed.adg1855.
Eva Mittler 1,  Alexandra Serris 2,  Emma S Esterman 3,  Catalina Florez 4 5,  Laura C Polanco 1,  Cecilia M O'Brien 4 5,  Megan M Slough 1,  Janne Tynell 6 7,  Remigius Gröning 6,  Yan Sun 8,  Dafna M Abelson 9,  Anna Z Wec 3,  Denise Haslwanter 1,  Markus Keller 10,  Chunyan Ye 11,  Russel R Bakken 4,  Rohit K Jangra 1,  John M Dye 4,  Clas Ahlm 6,  C Garrett Rappazzo 3,  Rainer G Ulrich 10 12,  Larry Zeitlin 9,  James C Geoghegan 3,  Steven B Bradfute 11,  Simone Sidoli 8,  Mattias N E Forsell 6,  Tomas Strandin 7,  Felix A Rey 2,  Andrew S Herbert 4,  Laura M Walker 3,  Kartik Chandran 1,  Pablo Guardado-Calvo 2
Affiliations

Affiliations

  • 1 Department of Microbiology and Immunology, Albert Einstein College of Medicine, Bronx, NY 10461, USA.
  • 2 Institut Pasteur, Université Paris Cité, CNRS UMR3569, Structural Virology Unit, F-75015 Paris, France.
  • 3 Adimab LLC, Lebanon, NH 03766, USA.
  • 4 U.S. Army Medical Research Institute of Infectious Diseases, Fort Detrick, Frederick, MD 21702, USA.
  • 5 The Geneva Foundation, Tacoma, WA 98402, USA.
  • 6 Department of Clinical Microbiology, Umeå University, 90187 Umeå, Sweden.
  • 7 Zoonosis Unit, Department of Virology, Medical Faculty, University of Helsinki, 00290 Helsinki, Finland.
  • 8 Department of Biochemistry, Albert Einstein College of Medicine, Bronx, NY 10461, USA.
  • 9 Mapp Biopharmaceutical Inc., San Diego, CA 92121, USA.
  • 10 Institute of Novel and Emerging Infectious Diseases, Friedrich-Loeffler-Institut, Federal Research Institute for Animal Health, 17493 Greifswald-Insel Riems, Germany.
  • 11 Center for Global Health, Department of Internal Medicine, University of New Mexico Health Science Center, Albuquerque, NM 87131, USA.
  • 12 Partner site: Hamburg-Lübeck-Borstel-Riems, German Centre for Infection Research (DZIF), 17493 Greifswald-Insel Riems, Germany.
PMID: 37315110 DOI: 10.1126/scitranslmed.adg1855
Abstract

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.

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