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PLoS Pathogens. Influenza Human Monoclonal Antibody 1F1 Interacts with Three Major Antigenic Sites and Residues Mediating Human Receptor Specificity in H1N1 Viruses

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  • PLoS Pathogens. Influenza Human Monoclonal Antibody 1F1 Interacts with Three Major Antigenic Sites and Residues Mediating Human Receptor Specificity in H1N1 Viruses

    [Source: PLoS Pathogens, full text: (LINK). Abstract, edited.]
    Influenza Human Monoclonal Antibody 1F1 Interacts with Three Major Antigenic Sites and Residues Mediating Human Receptor Specificity in H1N1 Viruses


    Tshidi Tsibane<SUP>1</SUP><SUP>#</SUP>, Damian C. Ekiert<SUP>2</SUP><SUP>#</SUP>, Jens C. Krause<SUP>3</SUP><SUP>#</SUP>, Osvaldo Martinez<SUP>1</SUP>, James E. Crowe Jr.<SUP>3</SUP><SUP>,</SUP><SUP>4</SUP><SUP>*</SUP>, Ian A. Wilson<SUP>2</SUP><SUP>*</SUP>, Christopher F. Basler<SUP>1</SUP><SUP>*</SUP>
    <SUP></SUP>
    1 Department of Microbiology, Mount Sinai School of Medicine, New York City, New York, United States of America, 2 Department of Molecular Biology and the Skaggs Institute for Chemical Biology, The Scripps Research Institute, La Jolla, California, United States of America, 3 Department of Pediatrics, Vanderbilt University Medical Center, Nashville, Tennessee, United States of America, 4 Department of Microbiology and Immunology, Vanderbilt University Medical Center, Nashville, Tennessee, United States of America



    Abstract

    Most monoclonal antibodies (mAbs) to the influenza A virus hemagglutinin (HA) head domain exhibit very limited breadth of inhibitory activity due to antigenic drift in field strains. However, mAb 1F1, isolated from a 1918 influenza pandemic survivor, inhibits select human H1 viruses (1918, 1943, 1947, and 1977 isolates). The crystal structure of 1F1 in complex with the 1918 HA shows that 1F1 contacts residues that are classically defined as belonging to three distinct antigenic sites, Sa, Sb and Ca<SUB>2</SUB>. The 1F1 heavy chain also reaches into the receptor binding site (RBS) and interacts with residues that contact sialoglycan receptors and determine HA receptor specificity. The 1F1 epitope is remarkably similar to the previously described murine HC63 H3 epitope, despite significant sequence differences between H1 and H3 HAs. Both antibodies potently inhibit receptor binding, but only HC63 can block the pH-induced conformational changes in HA that drive membrane fusion. Contacts within the RBS suggested that 1F1 may be sensitive to changes that alter HA receptor binding activity. Affinity assays confirmed that sequence changes that switch the HA to avian receptor specificity affect binding of 1F1 and a mAb possessing a closely related heavy chain, 1I20. To characterize 1F1 cross-reactivity, additional escape mutant selection and site-directed mutagenesis were performed. Residues 190 and 227 in the 1F1 epitope were found to be critical for 1F1 reactivity towards 1918, 1943 and 1977 HAs, as well as for 1I20 reactivity towards the 1918 HA. Therefore, 1F1 heavy-chain interactions with conserved RBS residues likely contribute to its ability to inhibit divergent HAs.



    Author Summary

    Influenza infection kills thousands of people every year and causes major pandemics every few decades. The most lethal outbreak of influenza known was the 1918 H1N1 influenza pandemic that killed an estimated 20 to 100 million people. The 1918 virus was likely introduced into the human population from birds. We previously described five human neutralizing antibodies from survivors of the 1918 pandemic that bind the hemagglutinin (HA) surface antigen. Here, we define the binding sites of antibodies 1F1 and 1I20 on the 1918 HA and demonstrate that these overlap with the glycan receptor binding site. The glycan specificity differs between human and avian viruses for the linkages of the sialylated sugar receptors [human (α2?6) or avian (α2?3)]. 1F1 and 1I20 binds viruses that contain HA residues that mediate preference for α2?6 sialylated sugars. Three other control antibodies were not affected by preferences for the linkages of the sialylated sugar receptors because they bind elsewhere. Since the receptor-binding site is relatively conserved, this may explain the cross-reactivity of 1F1 and the enhanced binding of 1F1 and 1I20 to HAs with human receptor specificity.



    Citation: Tsibane T, Ekiert DC, Krause JC, Martinez O, Crowe JE Jr, et al. (2012) Influenza Human Monoclonal Antibody 1F1 Interacts with Three Major Antigenic Sites and Residues Mediating Human Receptor Specificity in H1N1 Viruses. PLoS Pathog 8(12): e1003067. doi:10.1371/journal.ppat.1003067

    Editor: Andrew Pekosz, Johns Hopkins University - Bloomberg School of Public Health, United States of America

    Received: May 17, 2012; Accepted: October 6, 2012; Published: December 6, 2012

    Copyright: ? 2012 Tsibane et al. This is an open-access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.

    Funding: This work was supported by NIH grants P01 AI058113 and R21 AI085306, NIH Contract HHSN272200900047C and DoD grant HDTRA1-10-1-0067. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.

    Competing interests: The authors have declared that no competing interests exist.

    * E-mail: james.crowe@vanderbilt.edu (JEC); wilson@scripps.edu (IAW); chris.basler@mssm.edu (CFB)

    # These authors contributed equally to this work.
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