Abstract
BackgroundInfluenza virus undergoes rapid evolution by both antigenic shift and antigenic drift. Antibodies, particularly those binding near the receptor-binding site of hemagglutinin (HA) or the neuraminidase (NA) active site, are thought to be the primary defense against influenza infection, and mutations in antibody binding sites can reduce or eliminate antibody binding. The binding of antibodies to their cognate antigens is governed by such biophysical properties of the interacting surfaces as shape, non-polar and polar surface area, and charge.MethodsTo understand forces shaping evolution of influenza virus, we have examined HA sequences of human influenza A and B viruses, assigning each amino acid values reflecting total accessible surface area, non-polar and polar surface area, and net charge due to the side chain. Changes in each of these values between neighboring sequences were calculated for each residue and mapped onto the crystal structures.ResultsAreas of HA showing the highest frequency of pairwise changes agreed well with previously identified antigenic sites in H3 and H1 HAs, and allowed us to propose more detailed antigenic maps and novel antigenic sites for H1 and influenza B HA. Changes in biophysical properties differed between HAs of different subtypes, and between different antigenic sites of the same HA. For H1, statistically significant differences in several biophysical quantities compared to residues lying outside antigenic sites were seen for some antigenic sites but not others. Influenza B antigenic sites all show statistically significant differences in biophysical quantities for all antigenic sites, whereas no statistically significant differences in biophysical quantities were seen for any antigenic site is seen for H3. In many cases, residues previously shown to be under positive selection at the genetic level also undergo rapid change in biophysical properties.ConclusionsThe biophysical consequences of amino acid changes introduced by antigenic drift vary from subtype to subtype, and between different antigenic sites. This suggests that the significance of antibody binding in selecting new variants may also be variable for different antigenic sites and influenza subtypes.
Highlights
Influenza virus undergoes rapid evolution by both antigenic shift and antigenic drift
Prediction of novel sites in potential antigenic sites in hemagglutinin subtype 1 (H1) and B HA Neutralizing antigenic sites have been described for human H1 [23,25], hemagglutinin subtype 3 (H3) [7,26], and influenza B [24] HA
Residues in each of the previously described H3 HA antigenic sites (A-E) are represented in the residues with the highest Δabs values (Figure 1a, Table 2), suggesting that pairwise sequence analysis for determining frequencies of change is a useful method for predicting residues that may be evolving in response to antibody selection
Summary
Influenza virus undergoes rapid evolution by both antigenic shift and antigenic drift. Influenza virus undergoes rapid evolution in nature by both genetic shift, where one (or more) of the eight gene segments is exchanged from one virus into another [1], and genetic drift, whereby mutations accumulate in viral genes [2], presumably due to the relatively error-prone replication of the viral RNA. This presents a significant challenge for vaccine design, as new vaccines must be produced almost every year in order to provide the best match with viruses. It should be noted the total number of antibody/antigen pairs that have been analyzed at the biophysical level remains small, so any generalization must be made with caution
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