Influenza virus-specific CD4+ T-helper cells were cloned that recognized a virus strain isolated in 1981, but that failed to recognize more recent strains. The HLA-DR*1601-restricted epitope recognized was located in the hemagglutinin (HA(99-113)) and the naturally occurring A-->V substitution at position 106 was responsible for abrogating the recognition by HA(99-113)-specific CD4+ T-cells. This amino acid substitution was found in influenza A/H3N2 viruses that circulated between 1999 and 2005 and did not affect recognition by virus-specific antibodies. It was speculated that influenza viruses could evade recognition by virus-specific CD4+ T-cells, at least temporarily.