Molecular rationale for antibody-mediated targeting of the hantavirus fusion glycoprotein
Ilona Rissanen,
Robert Stass,
Stefanie A Krumm,
Jeffrey Seow,
Ruben JG Hulswit,
Guido C Paesen,
Jussi Hepojoki,
Olli Vapalahti,
Åke Lundkvist,
Olivier Reynard,
Viktor Volchkov,
Katie J Doores,
Juha T Huiskonen,
Thomas A Bowden
Affiliations
Ilona Rissanen
Division of Structural Biology, Wellcome Centre for Human Genetics, University of Oxford, Oxford, United Kingdom; Helsinki Institute of Life Science HiLIFE, University of Helsinki, Helsinki, Finland; Molecular and Integrative Biosciences Research Programme, The Faculty of Biological and Environmental Sciences, University of Helsinki, Helsinki, Finland
Robert Stass
Division of Structural Biology, Wellcome Centre for Human Genetics, University of Oxford, Oxford, United Kingdom
Stefanie A Krumm
Department of Infectious Diseases, King's College London, Guy's Hospital, London, United Kingdom
Jeffrey Seow
Department of Infectious Diseases, King's College London, Guy's Hospital, London, United Kingdom
Ruben JG Hulswit
Division of Structural Biology, Wellcome Centre for Human Genetics, University of Oxford, Oxford, United Kingdom
Guido C Paesen
Division of Structural Biology, Wellcome Centre for Human Genetics, University of Oxford, Oxford, United Kingdom
Jussi Hepojoki
Institute of Veterinary Pathology, Vetsuisse Faculty, University of Zürich, Zürich, Switzerland; Department of Virology, Medicum, Faculty of Medicine, University of Helsinki, Helsinki, Finland
Olli Vapalahti
Departments of Virology and Veterinary Biosciences, University of Helsinki and HUSLAB, Helsinki University Hospital, Helsinki, Finland
Åke Lundkvist
Zoonosis Science Center, Department of Medical Biochemistry and Microbiology, Uppsala University, Uppsala, Sweden
Olivier Reynard
CIRI, Centre International de Recherche en Infectiologie, INSERM U1111, CNRS UMR5308, Université Lyon, Lyon, France
Viktor Volchkov
CIRI, Centre International de Recherche en Infectiologie, INSERM U1111, CNRS UMR5308, Université Lyon, Lyon, France
Katie J Doores
Department of Infectious Diseases, King's College London, Guy's Hospital, London, United Kingdom
Division of Structural Biology, Wellcome Centre for Human Genetics, University of Oxford, Oxford, United Kingdom; Helsinki Institute of Life Science HiLIFE, University of Helsinki, Helsinki, Finland; Molecular and Integrative Biosciences Research Programme, The Faculty of Biological and Environmental Sciences, University of Helsinki, Helsinki, Finland
The intricate lattice of Gn and Gc glycoprotein spike complexes on the hantavirus envelope facilitates host-cell entry and is the primary target of the neutralizing antibody-mediated immune response. Through study of a neutralizing monoclonal antibody termed mAb P-4G2, which neutralizes the zoonotic pathogen Puumala virus (PUUV), we provide a molecular-level basis for antibody-mediated targeting of the hantaviral glycoprotein lattice. Crystallographic analysis demonstrates that P-4G2 binds to a multi-domain site on PUUV Gc and may preclude fusogenic rearrangements of the glycoprotein that are required for host-cell entry. Furthermore, cryo-electron microscopy of PUUV-like particles in the presence of P-4G2 reveals a lattice-independent configuration of the Gc, demonstrating that P-4G2 perturbs the (Gn-Gc)4 lattice. This work provides a structure-based blueprint for rationalizing antibody-mediated targeting of hantaviruses.
