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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.
- Cell 2019 v.177 no.5 pp. 1136-1152.e18
- Influenza A virus, antibodies, disease control, epitopes, hemagglutinins, humans, influenza, mice, therapeutics, vaccines, viruses
- 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.