Featured Article - June 2014
Short description: Structural studies of antibody F045–092 explain its ability to neutralize all H3-subtype influenza strains.
Each year seasonal flu infects millions of people worldwide, with severe health and economic consequences. Although vaccination can be effective in preventing the spread of the flu, the constantly changing virus requires annual reformulation of the vaccine. Part of this challenge comes from the hyper-variable influenza's hemagglutinin (HA) surface glycoprotein, which initiates infection by binding to sialic acid glycans on host cells. A small number of neutralizing antibodies show broad activity in inhibiting HA-receptor interaction across many HA subtypes. Antibody F045–092, for example, has neutralizing activity against all H3N2 strains from 1968 to 2004, as well as against certain H1N1, H2N2 and H5N1 viruses.
To understand the structural basis for the broad activity of F045–092, Wilson and colleagues used the JCSG crystallization pipeline and solved the crystal structures of its fragment antigen-binding (Fab) in complex with HAs from two H3 subtypes: A/Victoria/3/1975 (Vic1975/H3; PDB 4O58) and A/Victoria/361/2011 (Vic2011/H3; PDB 4O5I). These structures show that the F045–092 complementarity determining region loop HCDR3 consists of four residues that chemically resemble sialic acid and form the same network of hydrogen bonds used by HA to recognize its cellular target. Alanine scanning mutagenesis of HCDR3 abolished binding of the F045–092 Fab to nearly all H3 strains tested, suggesting that the antibody's mimicry of sialic acid is crucial in the recognition of H3 HA.
In addition to its direct interactions with the sialic acid-binding pocket, F045–092 makes contacts with residues that are absolutely conserved in all H3 HAs (namely Ser136 and Trp153), helping explain the antibody's specificity for the H3 subtype. Notably, F045–092 does not make contact with any of the N-linked glycosylation sites on the Vic1975/H3 or Vic2011/H3 heads, which have seven and twelve glycans, respectively. The avoidance of these sites allows the antibody to maintain binding efficacy within the H3 subtype, despite the evolutionary accretion of glycosylation sites over time.
Overall, these structures show how a single antibody can neutralize many HA targets from the same subfamily, and may allow for the development of small-molecule inhibitors or immunogens against all H3 viruses.
P.S. Lee et al. Receptor mimicry by antibody F045–092 facilitates universal binding to the H3 subtype of influenza virus.
Nat Commun. 5, 3614 (2014). doi:10.1038/ncomms4614