The evolution of influenza hemagglutinin: structural numbering and receptor binding sites of influenza viruses capable of infecting humans

Influenza virus antigenic drift and shift have shaped seasonal epidemics and pandemics. Amino acid changes in the surface glycoprotein hemagglutinin (HA) are primarily responsible for these antigenic changes, with neutralizing antibodies focusing on the HA molecule. This review examines the structure, function, and antigenic evolution of influenza virus HA, along with the organization of antigenic sites across multiple influenza A subtypes (H1, H2, H3, H5, H7) and influenza B lineages. The structural features governing the specificity for the HA receptor-binding domain (RBD) and the key amino acid substitutions that drive host adaptation and transmissibility are described, as are the mutations and glycosylation changes within these HA regions that facilitate immune escape. HA sequence alignments highlight a functional balance between the HA1 and HA2 regions. The HA2 stem is structurally constrained and highly conserved, preserving the core mechanisms required for viral entry. In contrast, the HA1 globular head is evolutionarily flexible, allowing the virus to escape host antibodies and maintain survival and transmissibility. An evaluation of the changes in vaccine strain selections for H1N1, H3N2, and influenza B viruses further illustrate the ongoing challenge of matching vaccines to rapidly evolving strains. Collectively, this review underscores the importance of integrating structural, genetic, and antigenic data to improve influenza surveillance, vaccine design, and pandemic preparedness.