Influenza A viruses possess a hemagglutinin (HA) attachment protein that binds sialic acid residues to facilitate infection of target epithelial cells. The HA of human influenza viruses preferentially binds to terminal sialic acid (SA) residues with a2,6 linkages, whereas avian influenza viruses preferentially bind to SA with a2,3 linkages [6] [7] [8] [9] . The prevalence of a2,6 SA but paucity of a2,3 SA in the human respiratory tract has been considered to restrict infection by avian influenza viruses [10] . Recent reports, however, have detected significant levels of a2,3 SA on human airway epithelium both in vitro and ex vivo, including in nasopharyngeal and tracheobronchial tissue [11] [12] [13] [14] . This SA distribution also correlated with avian influenza virus infection in vitro and ex vivo and raised the possibility that avian viruses could infect the upper airways in vivo. Therefore, although it is universally accepted that human-to-human transmission of avian influenza viruses requires adaptation of HA to switch from a2,3 to a2,6 SA usage, the cumulative data published to date indicate that SA linkages and their respective distribution in the human airways are not the sole barrier to avian influenza virus infection [15] [16] [17] . Other host factors and viral genes are likely also important determinants of infectivity.