Journal
PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA
Volume 112, Issue 30, Pages 9430-9435Publisher
NATL ACAD SCIENCES
DOI: 10.1073/pnas.1510816112
Keywords
influenza virus; neutralizing antibody; H5N1
Categories
Funding
- Medical Research Council [U117584222, U117512723, U117570592]
- NoFlu project, Fondazione Cariplo Vaccine Program [2009-3594]
- Division of Intramural Research, National Institute of Allergy and Infectious Diseases, National Institutes of Health
- MRC [G0600522] Funding Source: UKRI
- Cancer Research UK
- The Francis Crick Institute [10015] Funding Source: researchfish
- Medical Research Council [G0600522] Funding Source: researchfish
- The Francis Crick Institute [10080, 10078] Funding Source: researchfish
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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 formembrane fusion.
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