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.

Download full-text


Available from: Jan Baumann, Sep 12, 2014
56 Reads
  • [Show abstract] [Hide abstract]
    ABSTRACT: The looming threat of a new influenza virus pandemic has fueled ambitious efforts to devise more predictive parameters for assessing the risks associated with emergent virus strains. At the same time, a comprehensive understanding of critical factors that can accurately predict the outcome of vaccination is sorely needed in order to improve the effectiveness of influenza virus vaccines. Will new studies aimed at identifying adaptations required for virus transmissibility and systems-level analyses of influenza virus vaccine responses provide an improved framework for predictive models of viral adaptation and vaccine efficacy?
    Cell 04/2014; 157(2):294-9. DOI:10.1016/j.cell.2014.03.023 · 32.24 Impact Factor
  • [Show abstract] [Hide abstract]
    ABSTRACT: Human and other mammalian influenza viruses emerge from a large gene pool provided by avian influenza viruses. Two recent studies (Watanabe et al., 2014; Linster et al., 2014) show that adaptation to a mammalian host depends on a limited number of mutations that allow airborne transmission, a specific trait of the mammalian viruses.
    Cell Host & Microbe 06/2014; 15(6):653-654. DOI:10.1016/j.chom.2014.05.019 · 12.33 Impact Factor
  • Source
    [Show abstract] [Hide abstract]
    ABSTRACT: The direct precursors of the A/Goose/Guangdong/1/1996 (GS/GD) virus lineage and its reassortants have been established geographically and ecologically. To investigate the variation and evolutionary dynamics of H5N1 viruses, whole-genome viral sequences (n = 164) were retrieved from the NCBI Influenza Virus Resource. Here, we present phylogenetic evidence for intrasubtype reassortments among H5N1 viruses isolated from China during 1996-2012. On the basis of phylogenetic analysis, we identified four major groups and further classified the reassortant viruses into three subgroups. Putative mosaic structures were mostly found in the viral ribonucleoprotein (vRNP) complexes and 91.0% (10/11) mosaics were obtained from terrestrial birds. Sequence variability and selection pressure analyses revealed that both surface glycoproteins (HA and NA) and nonstructural protein 1 (NS1) have higher dN/dS ratio and variability than other internal proteins. Furthermore, we detected 47 positively selected sites in genomic segments with the exception of PB2 and M1 genes. Hemagglutinin (HA) and neuraminidase (NA) are considered highly variable due to host immune pressure, however, it is not known what drives NS1 variability. Therefore, we performed a thorough analysis of the genetic variation and selective pressure of NS1 protein (462 available NS1 sequences). We found that most of positively selected sites and variable amino acids were located in the C-terminal effector domain (ED) of NS1. In addition, we focused on the NS1-RNA and NS1-protein interactions that were involved in viral replication mechanisms and host immune response. Transcriptomic analysis of H5N1-infected monkey lungs showed that certain PI3K-related genes were up-regulated.
    PLoS ONE 07/2014; 9(7):e101384. DOI:10.1371/journal.pone.0101384 · 3.23 Impact Factor
Show more