Early alterations of the receptor-binding properties of H1, H2, and H3 avian influenza virus hemagglutinins after their introduction into mammals

Interspecies transmission of influenza A viruses circulating in wild aquati c birds occasionally results in influenza outbreaks in mammals, including h umans, To identify early changes in the receptor binding properties of the avian virus hemagglutinin (HA) after interspecies transmission and to deter mine the amino acid substitutions responsible for these alterations, we stu died the HAs of the initial isolates from the human pandemics of 1957 (H2N2 ) and 1968 (H3N2), the European swine epizootic of 1979 (H1N1), and the sea l epizootic of 1992 (H3N3), all of which were caused by the introduction of avian virus HAs into these species. The viruses were assayed for their abi lity to bind the synthetic sialylglycopolymers 3'SL-PAA and 6'SLN-PAA, whic h contained, respectively, 3'-sialyllactose (the receptor determinant prefe rentially recognized by avian influenza viruses) and 6'-sialyl(N-acetyllact osamine) (the receptor determinant for human viruses), Avian and seat virus es bound 6'SLN-PAA very weakly, whereas the earliest available human and sw ine epidemic viruses bound this polymer with a higher affinity. For the H2 and H3 strains, a single mutation, 226Q --> L, increased binding to 6'SLN-P AA, while among H1 swine viruses, the 190E --> D and 225G --> E mutations i n the EU appeared important for the increased affinity of the viruses for 6 'SLN-PAA, Amino acid substitutions at positions 190 and 225 with respect to the avian virus consensus sequence are also present in H1 human viruses, i ncluding those that circulated in 1918, suggesting that substitutions at th ese positions are important for the generation of Hi human pandemic strains . These results show that the receptor-binding specificity of the HA is alt ered early after the transmission of an avian virus to humans and pigs and, therefore, may be a prerequisite for the highly effective replication and spread which characterize epidemic strains.