There is an urgent need to understand the molecular properties that contribute sellckchem to the transmission and host range of these viruses for their effective surveillance and containment. The transmissibility and pathogenicity of influenza A viruses, including the H5N1 subtype, in avian and mammalian species are determined by both viral and host factors (8, 39). One key factor is the multifunctional hemagglutinin (HA) protein. During viral entry, the HA protein binds to sialic acid-containing receptors on host cells; the virus then undergoes endocytosis, and its HA protein is activated at a low pH to cause the fusion of the viral and endosomal membranes (11, 41). The host range of influenza A viruses depends in large part on the receptor specificity of the HA protein.

Avian influenza viruses generally bind to ��(2,3) sialosides with greater affinity, while human influenza viruses usually bind to ��(2,6) sialosides with greater affinity (4, 37). The receptor binding affinities and specificities of HA proteins also depend on internal linkages and modifications of inner oligosaccharides, and glycan microarray profiling has revealed differences in receptor binding between seasonal human influenza viruses and H5N1 viruses (23, 45, 46). Thus, the natural distribution of various sialosides in different tissues of different species helps to determine both tissue tropism and species specificity (31, 40, 50, 58). The posttranslational cleavability of the HA0 precursor protein into the fusion-capable HA1-HA2 complex is a critical determinant of the virulence of influenza viruses (16, 22, 55).

The presence of a polybasic cleavage site in H5 and H7 influenza viruses allows HA protein cleavage in the trans-Golgi network by ubiquitous furin-like enzymes and is a marker of high pathogenicity (12, 38, 55). During entry into host cells, influenza viruses are exposed to increasingly lower pHs until a threshold is reached at which HA protein trimers undergo irreversible conformational changes that promote membrane fusion (11, 41). Threshold pH values differ among influenza viruses, and a change in the pH of fusion of the HA protein can help influenza viruses to adapt to different cell lines (5, 25) and host species (13) or to the higher endosomal pH induced by Entinostat high concentrations of the antiviral drug amantadine (6, 9, 42-44). In general, a high pH of HA protein activation could result in influenza virus inactivation in the environment or during transport to the cell surface for intracellularly cleaved HA proteins (2, 44). On the other hand, a low pH of HA protein activation could result in degradation in the lysosome as the pH of the endocytic pathway decreases from early endosomes to late endosomes to lysosomes (61).