Eighteen codons in the HA1 domain of the hemagglutinin genes of human influ
enza A subtype H3 appear to be under positive selection to change the amino
acid they encode. Retrospective tests show that viral Lineages undergoing
the greatest number of mutations in the positively selected codons were the
progenitors of future H3 Lineages in 9 of 11 recent influenza seasons. Cod
ons under positive selection were associated with antibody combining site A
or B or the sialic acid receptor binding site. However, not all codons in
these sites had predictive value. Monitoring new H3 isolates for additional
changes in positively selected codons might help identify the most fit ext
ant viral strains that arise during antigenic drift.