Complete structure of A/duck/Ukraine/63 influenza hemagglutinin gene: animal virus as progenitor of human H3 Hong Kong 1968 influenza hemagglutinin

We have explored the possibility that an animal viral reservoir contained a direct ancestor gene for the H3 hemagglutinin type present in influenza A viruses in humans since 1968. For this purpose, the duck/Ukraine/1/63 hemagglutinin gene was cloned and sequenced. From the comparison of its complete primary structure with that of several human H3 hemagglutinins as well as those of an H2 and an H7 hemagglutinin, we conclude that the duck/Ukraine/63 hemagglutinin sequence fully corroborates its previous identification by immunological and other methods as belonging to the H3 subtype. Moreover, the duck/Ukraine/63 amino acid sequence is more closely related structurally and presumably antigenically to the human Aichi/68 hemagglutinin, which formed the beginning of the H3N2 pandemic in humans, than to that of Victoria/75, which has undergone an additional 7 year drift period in humans. This observation could best be explained by a common ancestor hemagglutinin gene for duck/Ukraine/63 and human Aichi/68. On the basis of silent, accumulated base changes, we estimate that the strain carrying this postulated common progenitor hemagglutinin gene was circulating in the period 1949–1953 in the animal reservoir. This relatively recent divergence, as well as the closer kinship between the duck/Ukraine/63 and the human Aichi/68 hemagglutinin, as compared with the later Victoria/75, strongly suggests that the influenza A virus of the H3N2 subtype circulating in the human population since 1968 has derived its hemagglutinin gene from a strain in the animal reservoir. Undoubtedly, this occurred by reassortment between previously present human H2N2 virus and this animal strain. These results provide support at the molecular level for the general idea that the wide variety of influenza viruses known to be present in animals can serve as a gene reservoir for human influenza A viruses.