Abstract
The hemagglutinin (HA) of A/H3N2 pandemic influenza viruses (IAVs) of 1968 differed from its inferred avian precursor by eight amino acid substitutions. To determine their phenotypic effects, we studied recombinant variants of A/Hong Kong/1/1968 virus containing either human-type or avian-type amino acids in the corresponding positions of HA. The precursor HA displayed receptor binding profile and high conformational stability typical for duck IAVs. Substitutions Q226L and G228S, in addition to their known effects on receptor specificity and replication, marginally decreased HA stability. Substitutions R62I, D63N, D81N and N193S reduced HA binding avidity. Substitutions R62I, D81N and A144G promoted viral replication in human airway epithelial cultures. Analysis of HA sequences revealed that substitutions D63N and D81N accompanied by the addition of N-glycans represent common markers of avian H3 HA adaptation to mammals. Our results advance understanding of genotypic and phenotypic changes in IAV HA required for avian-to-human adaptation and pandemic emergence.
Highlights
Wild aquatic birds represent the major natural reservoir of influenza viruses (IAVs), which occasionally transmit, adapt and circulate for prolonged periods of time in domestic birds and mammals [1,2]
We studied phenotypic effects of eight amino acid substitutions that accompanied evolution of the HA of the 1968 pandemic IAV from its inferred avian precursor
We showed that two substitutions were primarily responsible for increased HA binding to human-type receptors and, in addition, marginally decreased stability of the HA, whereas three other substitutions reduced binding avidity of the HA
Summary
Wild aquatic birds represent the major natural reservoir of IAVs, which occasionally transmit, adapt and circulate for prolonged periods of time in domestic birds and mammals [1,2]. HAs of the previous pandemic IAVs differed from avian HAs by one or two amino acid substitutions in the conserved positions of the receptor-binding site (RBS). These substitutions were found to be essential for the switch of the HA receptor specificity from preferential binding to Neu5Acα23Gal-terminated glycans (avian-type receptors) to preferential binding to Neu5Acα2-6Gal-terminated glycans (human-type receptors). In the case of H1N1/1918 and H1N1/2009 IAVs, this role was played by substitutions E190D and G225D/E (for recent reviews, see [9,10]) It remains unexplored whether other substitutions in the HA of pandemic IAVs were required for adaptation to receptors in humans, for example, by adjusting HA interactions with sub-terminal oligosaccharide parts of the receptors and/or modulating binding avidity
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