Molecular rationale for antibody-mediated targeting of the hantavirus fusion glycoprotein

• Published in: eLife Vol. 9
• Main Authors: Rissanen, Ilona, Stass, Robert, Krumm, Stefanie A, Seow, Jeffrey, Hulswit, Ruben Jg, Paesen, Guido C, Hepojoki, Jussi, Vapalahti, Olli, Lundkvist, Åke, Reynard, Olivier, Volchkov, Viktor, Doores, Katie J, Huiskonen, Juha T, Bowden, Thomas A
• Format: Journal Article
• Language: English
• Published: England eLife Science Publications, Ltd 22-12-2020; eLife Sciences Publications, Ltd; eLife Sciences Publications Ltd
• Subjects: Analysis; Animals; Antibodies, Monoclonal - immunology; Antibodies, Neutralizing - immunology; Antibodies, Viral - immunology; Arvicolinae; glycoprotein; hantavirus; HEK293 Cells; Humans; Immune response; Microbiology and Infectious Disease; Monoclonal antibodies; neutralizing antibody; Puumala virus - immunology; Structural Biology and Molecular Biophysics; structure; viral fusion; Viral Fusion Proteins - immunology; hantavirus; infectious disease; viral fusion; microbiology; neutralizing antibody; glycoprotein; structural biology; molecular biophysics; virus; structure
• ISSN: 2050-084X; 2050-084X
• DOI: 10.7554/eLife.58242

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)
lattice. This work provides a structure-based blueprint for rationalizing antibody-mediated targeting of hantaviruses.