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Cell. 2019 May 16;177(5):1136-1152.e18. doi: 10.1016/j.cell.2019.04.011.

A Site of Vulnerability on the Influenza Virus Hemagglutinin Head Domain Trimer Interface.

Author information

1
Department of Pathology, Microbiology and Immunology, Vanderbilt University Medical Center, Nashville, TN 37232, USA.
2
Department of Integrative Structural and Computational Biology, The Scripps Research Institute, La Jolla, CA 92037, USA.
3
Department of Microbiology, Icahn School of Medicine at Mount Sinai, New York, NY 10029, USA; Global Health and Emerging Pathogens Institute, Icahn School of Medicine at Mount Sinai, New York, NY 10029, USA.
4
Department of Microbiology and Immunology, Peter Doherty Institute for Infection and Immunity, University of Melbourne, Melbourne, Victoria, Australia.
5
The Vanderbilt Vaccine Center, Vanderbilt University Medical Center, Nashville, TN 37232, USA.
6
Department of Microbiology, Icahn School of Medicine at Mount Sinai, New York, NY 10029, USA; Global Health and Emerging Pathogens Institute, Icahn School of Medicine at Mount Sinai, New York, NY 10029, USA; Department of Medicine, Icahn School of Medicine at Mount Sinai, New York, NY 10029, USA.
7
Department of Medicine and Biomedical Sciences, School of Medicine, University of California, San Diego, CA 92093, USA.
8
Department of Integrative Structural and Computational Biology, The Scripps Research Institute, La Jolla, CA 92037, USA; The Skaggs Institute for Chemical Biology, The Scripps Research Institute, La Jolla, CA 92037, USA. Electronic address: wilson@scripps.edu.
9
Department of Pathology, Microbiology and Immunology, Vanderbilt University Medical Center, Nashville, TN 37232, USA; The Vanderbilt Vaccine Center, Vanderbilt University Medical Center, Nashville, TN 37232, USA; Department of Pediatrics, Vanderbilt University Medical Center, Nashville, TN 37232, USA. Electronic address: james.crowe@vanderbilt.edu.

Abstract

Here, we describe the discovery of a naturally occurring human antibody (Ab), FluA-20, that recognizes a new site of vulnerability on the hemagglutinin (HA) head domain and reacts with most influenza A viruses. Structural characterization of FluA-20 with H1 and H3 head domains revealed a novel epitope in the HA trimer interface, suggesting previously unrecognized dynamic features of the trimeric HA protein. The critical HA residues recognized by FluA-20 remain conserved across most subtypes of influenza A viruses, which explains the Ab's extraordinary breadth. The Ab rapidly disrupted the integrity of HA protein trimers, inhibited cell-to-cell spread of virus in culture, and protected mice against challenge with viruses of H1N1, H3N2, H5N1, or H7N9 subtypes when used as prophylaxis or therapy. The FluA-20 Ab has uncovered an exceedingly conserved protective determinant in the influenza HA head domain trimer interface that is an unexpected new target for anti-influenza therapeutics and vaccines.

KEYWORDS:

B-lymphocytes; antibodies; antibody-dependent cell cytotoxicity; antigen-antibody reactions; hemagglutinin glycoproteins; influenza A virus; influenza virus; monoclonal; viral

PMID:
31100268
DOI:
10.1016/j.cell.2019.04.011

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