A site of vulnerability on the influenza virus hemagglutinin head domain trimer interface

Bangaru, Sandhya;Lang, Shanshan;Schotsaert, Michael;Vanderven, Hillary A.;Zhu, Xueyong;Kose, Nurgun;Bombardi, Robin;Finn, Jessica A.;Kent, Stephen J.;Gilchuk, Pavlo;Gilchuk, Iuliia;Turner, Hannah L.;García-Sastre, Adolfo;Li, Sheng;Ward, Andrew B.;Wilson, Ian A.;Crowe, James E.

Hillary Vanderven

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.

Journal

Cell

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Volume

177

ISBN/ISSN

1097-4172

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Publisher

Cell Press

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DOI

10.1016/j.cell.2019.04.011