A recommended numbering scheme for influenza A HA subtypes

Abstract

Comparisons of residues between sub-types of influenza virus is increasingly used to assess the zoonotic potential of a circulating strain and for comparative studies across subtypes. An analysis of N-terminal cleavage sites for thirteen subtypes of influenza A hemagglutinin (HA) sequences, has previously been described by Nobusawa and colleagues. We have expanded this analysis for the eighteen known subtypes of influenza. Due to differences in the length of HA, we have included strains from multiple clades of H1 and H5, as well as strains of H5 and H7 subtypes with both high and low pathogenicity. Analysis of known structures of influenza A HA enables us to define amino acids which are structurally and functionally equivalent across all HA subtypes using a numbering system based on the mature HA sequence. We provide a list of equivalences for amino acids which are known to affect the phenotype of the virus.

Figure 1. Sequence alignment of HA for known sub-types.

Alignment of mature HA sequence for all known HA sub-types. Additional strains have been included for sub-types which show variation in the length of HA. Sequences are ordered according to their phylogenetic classification as group 1 (magenta bar) or group 2 (orange bar) HA. The protein secondary structure elements, α-helices and β-strands, are highlighted with red bars and cyan arrows, respectively. A blue box highlights regions which have high structural variation across all subtypes. Amino acids within these regions should not be defined as equivalent between all sub-types. Each amino acid is coloured according to clustalx2 rules . Briefly, glycine and proline are coloured orange and yellow, respectively. Conserved positively charged residues and negatively charged residues are coloured red and magenta, respectively. Conserved cysteines are coloured pink while conserved serine or threonine residues are in green. The remaining amino acids, if conserved are coloured blue. The sequences representative of each subtype are as follows: H1(A/United Kingdom/1/1933); H1pdm(A/California/04/2009); H2(A/Singapore/1/1957); H3(A/Aichi/2/1968); H4(A/swine/Ontario/01911/2/1999); H5(A/Vietnam/1203/2004); H5c221(A/chicken/Egypt/0915-NLQP/2009); H6(A/chicken/Taiwan/0705/1999); H7(A/Netherlands/219/2003); H8(A/turkey/Ontario/6118/1968); H9(A/swine/HongKong/9/1998); H10(A/mallard/bavaria/3/2006); H11(A/duck/England/1/1956); H12(A/duck/Alberta/60/1976); H13(A/gull/Maryland/704/1977); H14(A/mallard/Astrakhan/263/1982); H15(A/duck/Australia/341/1983); H16(A/black-headed-gull/Turkmenistan/13/1976); H17(A/little-yellow-shouldered-bat/Guatemala/060/2010); H18(A/flat-facedbat/Peru/033/2010).