Abstract
Seasonal influenza virus infections can cause significant morbidity and mortality, but the threat from the emergence of a new pandemic influenza strain might have potentially even more devastating consequences. As such, there is intense interest in isolating and characterizing potent neutralizing antibodies that target the hemagglutinin (HA) viral surface glycoprotein. Here, we use cryo-electron microscopy (cryoEM) to decipher the mechanism of action of a potent HA head-directed monoclonal antibody (mAb) bound to an influenza H7 HA. The epitope of the antibody is not solvent accessible in the compact, prefusion conformation that typifies all HA structures to date. Instead, the antibody binds between HA head protomers to an epitope that must be partly or transiently exposed in the prefusion conformation. The “breathing” of the HA protomers is implied by the exposure of this epitope, which is consistent with metastability of class I fusion proteins. This structure likely therefore represents an early structural intermediate in the viral fusion process. Understanding the extent of transient exposure of conserved neutralizing epitopes also may lead to new opportunities to combat influenza that have not been appreciated previously.
Highlights
Influenza displays three glycoproteins that embroider the viral surface: hemagglutinin (HA), neuraminidase (NA), and Matrix-2 ion channel
Vaccine efforts are hampered by the virus’s naturally high mutation rate, which results in wide variation between influenza strains of the antigens that are produced and recognized by antibodies, in the surface glycoprotein hemagglutinin (HA)
fragment antigen binding (Fab) bound has been deposited to the RCSB database with accession numbers EMD-9139/Protein Data Bank (PDB) 6MLM
Summary
Influenza displays three glycoproteins that embroider the viral surface: hemagglutinin (HA), neuraminidase (NA), and Matrix-2 ion channel. All of these proteins are necessary for the viral replication cycle. HA is a class I viral fusion protein that facilitates viral entry by interacting with sialic acid receptors on the host cell and fusing the viral and cell membranes in acidic endosomal compartments. The HA1 and HA2 domains remain covalently linked by a disulfide bond after cleavage. This cleaved, prefusion conformation is metastable and poised to undergo pHinduced conformational changes but must not do so prematurely
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