ABSTRACT Researchers have been searching for molecular features that could make avian H5N1 influenza transmissible among people since the first report of human infections with this virus in 1997. A recent study surprisingly demonstrated that only five mutations, fewer than previously estimated, are needed to make avian H5N1 influenza transmissible between ferrets through the air, raising fears that a human pandemic is possible if this virus escapes from the lab. Of the five mutations found, four of them are located in the HA gene that is responsible for the viral entry into the host cells. A crucial step for avian influenza to go across the species boundary to infect humans is the switch of its receptor binding specificity from avian to human types. The first task of this study was to quantify the individual as well as the collective effect of the known HA mutations from the previous research on receptor binding selection. Our second task was to identify new combinations of HA mutations that could change the receptor binding preference of H5N1 from avian to human types. Our findings thus deepened our understanding of the previous research and also extended its results by discovering new combinations of mutations that could enhance the binding of avian H5N1 to human type receptors while reduce that to avian types.
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