Potent cross-neutralization of respiratory syncytial virus and human metapneumovirus through a structurally conserved antibody recognition mode. 2023

Xiaolin Wen, and Naveenchandra Suryadevara, and Nurgun Kose, and Jing Liu, and Xiaoyan Zhan, and Laura S Handal, and Lauren E Williamson, and Andrew Trivette, and Robert H Carnahan, and Theodore S Jardetzky, and James E Crowe
Department of Structural Biology, Stanford University School of Medical School, Stanford, CA 94305, USA.

Respiratory syncytial virus (RSV) and human metapneumovirus (hMPV) infections pose a significant health burden. Using pre-fusion conformation fusion (F) proteins, we isolated a panel of anti-F antibodies from a human donor. One antibody (RSV-199) potently cross-neutralized 8 RSV and hMPV strains by recognizing antigenic site III, which is partially conserved in RSV and hMPV F. Next, we determined the cryoelectron microscopy (cryo-EM) structures of RSV-199 bound to RSV F trimers, hMPV F monomers, and an unexpected dimeric form of hMPV F. These structures revealed how RSV-199 engages both RSV and hMPV F proteins through conserved interactions of the antibody heavy-chain variable region and how variability within heavy-chain complementarity-determining region 3 (HCDR3) can be accommodated at the F protein interface in site-III-directed antibodies. Furthermore, RSV-199 offered enhanced protection against RSV A and B strains and hMPV in cotton rats. These findings highlight the mechanisms of broad neutralization and therapeutic potential of RSV-199.

UI MeSH Term Description Entries
D007135 Immunoglobulin Variable Region That region of the immunoglobulin molecule that varies in its amino acid sequence and composition, and comprises the binding site for a specific antigen. It is located at the N-terminus of the Fab fragment of the immunoglobulin. It includes hypervariable regions (COMPLEMENTARITY DETERMINING REGIONS) and framework regions. Variable Region, Ig,Variable Region, Immunoglobulin,Framework Region, Immunoglobulin,Fv Antibody Fragments,Fv Fragments,Ig Framework Region,Ig Variable Region,Immunoglobulin Framework Region,Immunoglobulin Fv Fragments,Immunoglobulin V,Antibody Fragment, Fv,Antibody Fragments, Fv,Fragment, Fv,Fragment, Fv Antibody,Fragment, Immunoglobulin Fv,Fragments, Fv,Fragments, Fv Antibody,Fragments, Immunoglobulin Fv,Framework Region, Ig,Framework Regions, Ig,Framework Regions, Immunoglobulin,Fv Antibody Fragment,Fv Fragment,Fv Fragment, Immunoglobulin,Fv Fragments, Immunoglobulin,Ig Framework Regions,Ig Variable Regions,Immunoglobulin Framework Regions,Immunoglobulin Fv Fragment,Immunoglobulin Variable Regions,Regions, Immunoglobulin Variable,Variable Regions, Ig,Variable Regions, Immunoglobulin
D006801 Humans Members of the species Homo sapiens. Homo sapiens,Man (Taxonomy),Human,Man, Modern,Modern Man
D000914 Antibodies, Viral Immunoglobulins produced in response to VIRAL ANTIGENS. Viral Antibodies
D014760 Viral Fusion Proteins Proteins, usually glycoproteins, found in the viral envelopes of a variety of viruses. They promote cell membrane fusion and thereby may function in the uptake of the virus by cells. Fusion Proteins, Viral,Viral Fusion Glycoproteins,F Protein (Sendai Virus),F Protein Measles Virus,F Protein Newcastle Disease Virus,F Protein SV,F-Glycoprotein SV,F1 Polypeptide (Paramyxovirus),Fusion Glycoprotein, Viral,Fusion VP1 Protein,Glycoprotein, Viral Fusion,Measles Fusion Protein,Mumps Virus Fusion Protein,Paramyxovirus Fusion Protein,Sendai Virus Fusion Protein,Viral Fusion-GP,Virus Fusion Proteins,Fusion Glycoproteins, Viral,Fusion Protein, Measles,Fusion Protein, Paramyxovirus,Fusion Proteins, Virus,Fusion-GP, Viral,Glycoproteins, Viral Fusion,Proteins, Virus Fusion,VP1 Protein, Fusion,Viral Fusion GP,Viral Fusion Glycoprotein
D057134 Antibodies, Neutralizing Antibodies that reduce or abolish some biological activity of a soluble antigen or infectious agent, usually a virus. Neutralizing Antibodies,Antibody, Neutralizing,Neutralizing Antibody
D018113 Respiratory Syncytial Virus, Human The type species of PNEUMOVIRUS and an important cause of lower respiratory disease in infants and young children. It frequently presents with bronchitis and bronchopneumonia and is further characterized by fever, cough, dyspnea, wheezing, and pallor. HRSV Human respiratory syncytial virus,Human respiratory syncytial virus,human RSV,RSV, human,human RSVs
D020285 Cryoelectron Microscopy Electron microscopy involving rapid freezing of the samples. The imaging of frozen-hydrated molecules and organelles permits the best possible resolution closest to the living state, free of chemical fixatives or stains. Electron Cryomicroscopy,Cryo-electron Microscopy,Cryo electron Microscopy,Cryo-electron Microscopies,Cryoelectron Microscopies,Cryomicroscopies, Electron,Cryomicroscopy, Electron,Electron Cryomicroscopies,Microscopies, Cryo-electron,Microscopies, Cryoelectron,Microscopy, Cryo-electron,Microscopy, Cryoelectron
D029121 Metapneumovirus A genus of the subfamily PNEUMOVIRINAE, containing two members: Turkey rhinotracheitis virus and a human Metapneumovirus. Virions lack HEMAGGLUTININ and NEURAMINIDASE. Avian Metapneumovirus,Avian Pneumovirus,Human Metapneumovirus,Metapneumovirus, Avian,Metapneumovirus, Human,Pneumovirus, Avian,Rhinotracheitis Virus, Turkey,Turkey Rhinotracheitis Virus,Human Metapneumoviruses,Metapneumoviruses,Metapneumoviruses, Human

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