title: Structural determinants for naturally evolving H5N1 hemagglutinin to switch its receptor specificity.
abstract: Of the factors governing human-to-human transmission of the highly pathogenic avian-adapted H5N1 virus, the most critical is the acquisition of mutations on the viral hemagglutinin (HA) to "quantitatively switch" its binding from avian to human glycan receptors. Here, we describe a structural framework that outlines a necessary set of H5 HA receptor-binding site (RBS) features required for the H5 HA to quantitatively switch its preference to human receptors. We show here that the same RBS HA mutations that lead to aerosol transmission of A/Vietnam/1203/04 and A/Indonesia/5/05 viruses, when introduced in currently circulating H5N1, do not lead to a quantitative switch in receptor preference. We demonstrate that HAs from circulating clades require as few as a single base pair mutation to quantitatively switch their binding to human receptors. The mutations identified by this study can be used to monitor the emergence of strains having human-to-human transmission potential.
authors.affiliation: Department of Biological Engineering, Koch Institute of Integrative Cancer Research, Infectious Diseases Interdisciplinary Research Group, Singapore-MIT Alliance for Research and Technology, Massachusetts Institute of Technology, 77 Massachusetts Avenue, Cambridge, MA 02139, USA.
authors.forename: Kannan
authors.initials: K
authors.lastname: Tharakaraman
authors.forename: Rahul
authors.initials: R
authors.lastname: Raman
authors.forename: Karthik
authors.initials: K
authors.lastname: Viswanathan
authors.forename: Nathan W
authors.initials: NW
authors.lastname: Stebbins
authors.forename: Akila
authors.initials: A
authors.lastname: Jayaraman
authors.forename: Arvind
authors.initials: A
authors.lastname: Krishnan
authors.forename: V
authors.initials: V
authors.lastname: Sasisekharan
authors.forename: Ram
authors.initials: R
authors.lastname: Sasisekharan
mesh_terms: D000595:Amino Acid Sequence; D000818:Animals; D001717:Birds; D019143:Evolution, Molecular; D019267:Hemagglutinin Glycoproteins, Influenza Virus / Q000737:chemistry* / Q000235:genetics* / Q000378:metabolism; D058507:Host Specificity; D006801:Humans; D053124:Influenza A Virus, H5N1 Subtype / Q000737:chemistry* / Q000472:pathogenicity / Q000502:physiology; D005585:Influenza in Birds / Q000821:virology*; D007251:Influenza, Human / Q000453:epidemiology / Q000635:transmission* / Q000821:virology*; D008958:Models, Molecular; D008969:Molecular Sequence Data; D009154:Mutation; D019158:N-Acetylneuraminic Acid / Q000378:metabolism; D010802:Phylogeny; D011991:Receptors, Virus / Q000737:chemistry / Q000378:metabolism; D016415:Sequence Alignment
chemical_list: D019267:Hemagglutinin Glycoproteins, Influenza Virus; D011991:Receptors, Virus; C109963:hemagglutinin, avian influenza A virus; D019158:N-Acetylneuraminic Acid