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Cross-neutralization of influenza A viruses mediated by a single antibody loop

Author

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  • Damian C. Ekiert

    (The Scripps Research Institute, 10550 North Torrey Pines Road, La Jolla, California 92037, USA
    Present addresses: Department of Microbiology and Immunology, University of California-San Francisco, 600 16th Street, San Francisco, California 94143, USA (D.C.E.); Genentech Inc., 1 DNA Way, South San Francisco, California 94080, USA (M.A.D.); Novartis Institutes for Biomedical Research, 4560 Horton Street, Emeryville, California 94608, USA (R.E.O.); Department of Microbiology and Immunology, Emory University School of Medicine, 3103 Rollins Research Center, 1510 Clifton Road, 194-001-1AD, Atlanta, Georgia 30322, USA (J.S.).)

  • Arun K. Kashyap

    (Sea Lane Biotechnologies, 2450 Bayshore Parkway)

  • John Steel

    (Mount Sinai School of Medicine, 1 Gustave Levy Place, New York, New York 10029-6574, USA
    Present addresses: Department of Microbiology and Immunology, University of California-San Francisco, 600 16th Street, San Francisco, California 94143, USA (D.C.E.); Genentech Inc., 1 DNA Way, South San Francisco, California 94080, USA (M.A.D.); Novartis Institutes for Biomedical Research, 4560 Horton Street, Emeryville, California 94608, USA (R.E.O.); Department of Microbiology and Immunology, Emory University School of Medicine, 3103 Rollins Research Center, 1510 Clifton Road, 194-001-1AD, Atlanta, Georgia 30322, USA (J.S.).)

  • Adam Rubrum

    (St Jude Children’s Research Hospital, 262 Danny Thomas Place, Memphis, Tennessee 38105, USA)

  • Gira Bhabha

    (The Scripps Research Institute, 10550 North Torrey Pines Road, La Jolla, California 92037, USA)

  • Reza Khayat

    (The Scripps Research Institute, 10550 North Torrey Pines Road, La Jolla, California 92037, USA)

  • Jeong Hyun Lee

    (The Scripps Research Institute, 10550 North Torrey Pines Road, La Jolla, California 92037, USA)

  • Michael A. Dillon

    (Sea Lane Biotechnologies, 2450 Bayshore Parkway
    Present addresses: Department of Microbiology and Immunology, University of California-San Francisco, 600 16th Street, San Francisco, California 94143, USA (D.C.E.); Genentech Inc., 1 DNA Way, South San Francisco, California 94080, USA (M.A.D.); Novartis Institutes for Biomedical Research, 4560 Horton Street, Emeryville, California 94608, USA (R.E.O.); Department of Microbiology and Immunology, Emory University School of Medicine, 3103 Rollins Research Center, 1510 Clifton Road, 194-001-1AD, Atlanta, Georgia 30322, USA (J.S.).)

  • Ryann E. O’Neil

    (Sea Lane Biotechnologies, 2450 Bayshore Parkway
    Present addresses: Department of Microbiology and Immunology, University of California-San Francisco, 600 16th Street, San Francisco, California 94143, USA (D.C.E.); Genentech Inc., 1 DNA Way, South San Francisco, California 94080, USA (M.A.D.); Novartis Institutes for Biomedical Research, 4560 Horton Street, Emeryville, California 94608, USA (R.E.O.); Department of Microbiology and Immunology, Emory University School of Medicine, 3103 Rollins Research Center, 1510 Clifton Road, 194-001-1AD, Atlanta, Georgia 30322, USA (J.S.).)

  • Aleksandr M. Faynboym

    (Sea Lane Biotechnologies, 2450 Bayshore Parkway)

  • Michael Horowitz

    (Sea Lane Biotechnologies, 2450 Bayshore Parkway)

  • Lawrence Horowitz

    (Sea Lane Biotechnologies, 2450 Bayshore Parkway)

  • Andrew B. Ward

    (The Scripps Research Institute, 10550 North Torrey Pines Road, La Jolla, California 92037, USA)

  • Peter Palese

    (Mount Sinai School of Medicine, 1 Gustave Levy Place, New York, New York 10029-6574, USA)

  • Richard Webby

    (St Jude Children’s Research Hospital, 262 Danny Thomas Place, Memphis, Tennessee 38105, USA)

  • Richard A. Lerner

    (The Scripps Research Institute, 10550 North Torrey Pines Road, La Jolla, California 92037, USA
    The Skaggs Institute for Chemical Biology, The Scripps Research Institute, 10550 North Torrey Pines Road, La Jolla, California 92037, USA)

  • Ramesh R. Bhatt

    (Sea Lane Biotechnologies, 2450 Bayshore Parkway)

  • Ian A. Wilson

    (The Scripps Research Institute, 10550 North Torrey Pines Road, La Jolla, California 92037, USA
    The Skaggs Institute for Chemical Biology, The Scripps Research Institute, 10550 North Torrey Pines Road, La Jolla, California 92037, USA)

Abstract

Immune recognition of protein antigens relies on the combined interaction of multiple antibody loops, which provide a fairly large footprint and constrain the size and shape of protein surfaces that can be targeted. Single protein loops can mediate extremely high-affinity binding, but it is unclear whether such a mechanism is available to antibodies. Here we report the isolation and characterization of an antibody called C05, which neutralizes strains from multiple subtypes of influenza A virus, including H1, H2 and H3. X-ray and electron microscopy structures show that C05 recognizes conserved elements of the receptor-binding site on the haemagglutinin surface glycoprotein. Recognition of the haemagglutinin receptor-binding site is dominated by a single heavy-chain complementarity-determining region 3 loop, with minor contacts from heavy-chain complementarity-determining region 1, and is sufficient to achieve nanomolar binding with a minimal footprint. Thus, binding predominantly with a single loop can allow antibodies to target small, conserved functional sites on otherwise hypervariable antigens.

Suggested Citation

  • Damian C. Ekiert & Arun K. Kashyap & John Steel & Adam Rubrum & Gira Bhabha & Reza Khayat & Jeong Hyun Lee & Michael A. Dillon & Ryann E. O’Neil & Aleksandr M. Faynboym & Michael Horowitz & Lawrence H, 2012. "Cross-neutralization of influenza A viruses mediated by a single antibody loop," Nature, Nature, vol. 489(7417), pages 526-532, September.
    • Handle: RePEc:nat:nature:v:489:y:2012:i:7417:d:10.1038_nature11414
    DOI: 10.1038/nature11414
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