Identification, Characterization, and Natural Selection of Mutations Driving Airborne Transmission of A/H5N1 Virus

Cell (Impact Factor: 32.24). 04/2014; 157(2):329-39. DOI: 10.1016/j.cell.2014.02.040
Source: PubMed


Recently, A/H5N1 influenza viruses were shown to acquire airborne transmissibility between ferrets upon targeted mutagenesis and virus passage. The critical genetic changes in airborne A/Indonesia/5/05 were not yet identified. Here, five substitutions proved to be sufficient to determine this airborne transmission phenotype. Substitutions in PB1 and PB2 collectively caused enhanced transcription and virus replication. One substitution increased HA thermostability and lowered the pH of membrane fusion. Two substitutions independently changed HA binding preference from α2,3-linked to α2,6-linked sialic acid receptors. The loss of a glycosylation site in HA enhanced overall binding to receptors. The acquired substitutions emerged early during ferret passage as minor variants and became dominant rapidly. Identification of substitutions that are essential for airborne transmission of avian influenza viruses between ferrets and their associated phenotypes advances our fundamental understanding of virus transmission and will increase the value of future surveillance programs and public health risk assessments.

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Available from: Jan Baumann, Sep 12, 2014
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    • "To promote quality of comparison between ferret and human studies, we only included data from ferret studies that tested one or more wild-type human isolates. While avian and other animal isolates maintain close sequence homology with human isolates (Claas et al., 1998), the transmission of animal isolates into humans is associated with genetic bottlenecks (Zaraket et al., 2015) and considerable within-host adaptation (Linster et al., 2014). These evolutionary barriers lead to avian precursors that have lower mortality in mice, less morbidity in ferrets, and lower viral titers in human epithelial cells (Belser et al., 2013; Watanabe et al., 2014; Zaraket et al., 2015). "
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