Structures of complexes formed by H5 influenza hemagglutinin with a potent broadly neutralizing human monoclonal antibody

Monoclonal antibody FLD194 isolated from a Vietnamese H5N1 survivor neutralizes all three clades of H5N1 viruses that have so far caused human infections. It is, therefore, a candidate for use in antiviral immunotherapy. Structural analysis of the HA-Fab complex shows the antibody-binding site is ad...

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Bibliographic Details
Published in:Proceedings of the National Academy of Sciences - PNAS 2015-07, Vol.112 (30), p.9430-9435
Main Authors: Xiong, Xiaoli, Davide Corti, Junfeng Liu, Debora Pinna, Mathilde Foglierini, Lesley J. Calder, Stephen R. Martin, Yi Pu Lin, Philip A. Walker, Patrick J. Collins, Isabella Monne, Amorsolo L. Suguitan, Celia Santos, Nigel J. Temperton, Kanta Subbarao, Antonio Lanzavecchia, Steven J. Gamblin, John J. Skehel
Format: Article
Language:English
Subjects:
Animals
Antibodies, Monoclonal - chemistry
Antibodies, Neutralizing - chemistry
Antibodies, Viral - chemistry
Binding Sites
Biological Sciences
Crystallography, X-Ray
Epitopes - chemistry
H5N1
Hemagglutinin Glycoproteins, Influenza Virus - chemistry
hemagglutinins
Hemagglutinins - chemistry
human diseases
Humans
Hydrogen-Ion Concentration
Immunoglobulin Fragments - chemistry
Immunoglobulin G - chemistry
immunotherapy
Influenza
Influenza A Virus, H5N1 Subtype - immunology
Influenza Vaccines - immunology
influenza virus
membrane fusion
Mice
Mice, Inbred BALB C
Monoclonal antibodies
Mutation
neutralization
Neutralization Tests
neutralizing antibody
pathogenicity
Protein Binding
Protein Conformation
Public health
receptors
Solvents - chemistry
Viruses
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Summary:Monoclonal antibody FLD194 isolated from a Vietnamese H5N1 survivor neutralizes all three clades of H5N1 viruses that have so far caused human infections. It is, therefore, a candidate for use in antiviral immunotherapy. Structural analysis of the HA-Fab complex shows the antibody-binding site is adjacent to, but does not involve, the sialic acid-binding site. The antibody neutralizes infectivity by restricting the access of receptors to HA using its Fc region in a way that may also be used by numerous other antibodies that bind at a distance from the receptor-binding site. The HA-Fab complex contains an HA subunit which has some of the features of HA in the conformation that is required for membrane fusion activity. H5N1 avian influenza viruses remain a threat to public health mainly because they can cause severe infections in humans. These viruses are widespread in birds, and they vary in antigenicity forming three major clades and numerous antigenic variants. The most important features of the human monoclonal antibody FLD194 studied here are its broad specificity for all major clades of H5 influenza HAs, its high affinity, and its ability to block virus infection, in vitro and in vivo. As a consequence, this antibody may be suitable for anti-H5 therapy and as a component of stockpiles, together with other antiviral agents, for health authorities to use if an appropriate vaccine was not available. Our mutation and structural analyses indicate that the antibody recognizes a relatively conserved site near the membrane distal tip of HA, near to, but distinct from, the receptor-binding site. Our analyses also suggest that the mechanism of infectivity neutralization involves prevention of receptor recognition as a result of steric hindrance by the Fc part of the antibody. Structural analyses by EM indicate that three Fab fragments are bound to each HA trimer. The structure revealed by X-ray crystallography is of an HA monomer bound by one Fab. The monomer has some similarities to HA in the fusion pH conformation, and the monomer’s formation, which results from the presence of isopropanol in the crystallization solvent, contributes to considerations of the process of change in conformation required for membrane fusion.
ISSN:0027-8424
1091-6490
DOI:10.1073/pnas.1510816112