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By using two very low passage clinical isolates (AZD2281 ferret respiratory tree, it is unclear if this difference in proportion of a certain amino acid at position 222 in the quasispecies present in the upper or lower airways was related to differences in viral binding or cell tropism, or rather reflected stochastic processes related to which viral variant predominated in early infection. The other significant finding was that the plaque-purified virus containing the G222 caused the least severe illness in ferrets, again suggesting that it is likely that the 222G mutation is not a sole virulence determinant of severe disease as supported by the nonhuman Hesperadin primate infections described by Watanabe et al. (2011). Interestingly, in the current study, those viral isolates with more diversity at HA position 222 were the most pathogenic, causing the most clinical disease, weight loss, and histopathology as demonstrated by those animals infected by transmission with the BAL isolate. Those animals developed the most severe clinical course, and the viruses isolated from those animals were the most diverse at position 222, particularly in virus isolated from the lungs. Although those animals infected by exposure to the NP isolate also developed considerable diversity at position 222, they developed slightly less overall disease. This difference may have been due to the fact that the virus causing the infection did not contain any detectable G222 variants; suggesting that the G222 mutation Quisinostat ic50 may play a role in enhancing pathogenesis as part of a diverse population. The least diverse viruses were isolated from the animals infected with the plaque-purified G222 isogenic clone, and these animals demonstrated the least clinical disease and pathology compared to the other 2 diverse infections. This difference in pathogenicity may signify that HA receptor-binding region diversity may allow virus to bind to more diverse cell types in the initial infection, thus spreading more easily throughout the upper and lower airways. This is similar to quasispecies diversity determined neurotrophism and pathogenesis of polioviruses as described by Vignuzzi et al., suggesting that diverse quasispecies populations are the unit of selection, rather than individual variants (Vignuzzi et al., 2006). Thus, diversity at this HA receptor-binding site, rather than specific polymorphisms themselves, may be a better determinant of disease progression than a specific amino acid change.