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Influenza A virus is unique among human viruses in its capacity to alter the antigenic phenotype with relative ease and evade neutralizing antibodies. This property is ascribed to the accumulation of a series of amino acid changes in the antigenic regions of hemagglutinin (HA) molecule. Neutralizing antibodies against HA prevent the early stage of infection, whereas neuraminidase (NA) antibodies mediate the antiviral effect by restricting spread of viruses in the host cells after infection. Thus the understanding of antigenic structure on those protective antigen is significant. Sequence analysis of natural variants and escape mutants selected by monoclonal antibodies allowed us to assign each antigenic sites and epitopes to a particular region on the three dimensional structure of HA and NA molecules.

The hemagglutinin(HA) of influenza virus is a major glycoprotein and plays a crucial role in the early stage of virus infection: HA is responsible for binding of the virus to cell surface receptors, and it mediates liberation of the viral genome into the cytoplasm through membrane fusion. The essential component of the receptor for influenza viruses has been considered to be the sialic acid. Influenza A and B viruses recognize N-acetylneuraminic acid, whereas influenza C virus specifically recognizes N-acetyl-9-O-acetylneuraminic acid as the receptor. Influenza A viruses are subdivided into 15 subtypes by their antigenic differences, but several amino acid residues composing functional domains (receptor binding site and fusion peptide) are shown to be conserved among HAs.

Influenza A viruses are suitable for the analysis of virus evolution because the genes of the viruses are well analyzed. The origin of the present human influenza A viruses are deduced to be direct descendent of the viruses which caused Spanish flu in 1918. The analysis of NS gene shows the branching point between avian and human viruses are early 1900. By comparison of the amino acid sequences, HA serotypes could be divided into two groups, i.e., an H1 and an H3 groups. The branching between subtypes H1 and H2 occurred fairly recently. The HA genes of influenza A viruses evolve causing two kinds of antigenic variation, saift and drift, which are caused by different mechanisms.