title: In Silico Prediction and Experimental Confirmation of HA Residues Conferring Enhanced Human Receptor Specificity of H5N1 Influenza A Viruses.
abstract: Newly emerging influenza A viruses (IAV) pose a major threat to human health by causing seasonal epidemics and/or pandemics, the latter often facilitated by the lack of pre-existing immunity in the general population. Early recognition of candidate pandemic influenza viruses (CPIV) is of crucial importance for restricting virus transmission and developing appropriate therapeutic and prophylactic strategies including effective vaccines. Often, the pandemic potential of newly emerging IAV is only fully recognized once the virus starts to spread efficiently causing serious disease in humans. Here, we used a novel phylogenetic algorithm based on the informational spectrum method (ISM) to identify potential CPIV by predicting mutations in the viral hemagglutinin (HA) gene that are likely to (differentially) affect critical interactions between the HA protein and target cells from bird and human origin, respectively. Predictions were subsequently validated by generating pseudotyped retrovirus particles and genetically engineered IAV containing these mutations and characterizing potential effects on virus entry and replication in cells expressing human and avian IAV receptors, respectively. Our data suggest that the ISM-based algorithm is suitable to identify CPIV among IAV strains that are circulating in animal hosts and thus may be a new tool for assessing pandemic risks associated with specific strains.
authors.affiliation: Georg-Speyer-Haus, Institute for Tumor Biology and Experimental Therapy, Paul-Ehrlich-Str. 42-44, Frankfurt, Germany.
authors.forename: Sonja
authors.initials: S
authors.lastname: Schmier
authors.affiliation: Institute of Medical Virology, Justus Liebig University Giessen, Schubertstrasse 81, Giessen, Germany.|Center of Scientific Excellence for Influenza Viruses, National Research Centre (NRC), Dokki, Giza, Egypt.
authors.forename: Ahmed
authors.initials: A
authors.lastname: Mostafa
authors.affiliation: Georg-Speyer-Haus, Institute for Tumor Biology and Experimental Therapy, Paul-Ehrlich-Str. 42-44, Frankfurt, Germany.
authors.forename: Thomas
authors.initials: T
authors.lastname: Haarmann
authors.affiliation: Robert-Koch-Institute, Division for HIV and other Retroviruses, Nordufer 20, Berlin, Germany.
authors.forename: Norbert
authors.initials: N
authors.lastname: Bannert
authors.affiliation: Institute of Medical Virology, Justus Liebig University Giessen, Schubertstrasse 81, Giessen, Germany.
authors.forename: John
authors.initials: J
authors.lastname: Ziebuhr
authors.affiliation: Centre for Multidisciplinary Research, Institute of Nuclear Sciences VINCA, Mihaila Petrovica 14, Belgrade, Serbia.
authors.forename: Veljko
authors.initials: V
authors.lastname: Veljkovic
authors.affiliation: Georg-Speyer-Haus, Institute for Tumor Biology and Experimental Therapy, Paul-Ehrlich-Str. 42-44, Frankfurt, Germany.
authors.forename: Ursula
authors.initials: U
authors.lastname: Dietrich
authors.affiliation: Institute of Medical Virology, Justus Liebig University Giessen, Schubertstrasse 81, Giessen, Germany.
authors.forename: Stephan
authors.initials: S
authors.lastname: Pleschka
mesh_terms: D000596:Amino Acids; D000818:Animals; D002460:Cell Line; D003198:Computer Simulation; D015870:Gene Expression; D005822:Genetic Vectors / Q000235:genetics; D019267:Hemagglutinin Glycoproteins, Influenza Virus / Q000737:chemistry* / Q000235:genetics*; D006801:Humans; D053124:Influenza A Virus, H5N1 Subtype / Q000235:genetics* / Q000378:metabolism*; D008954:Models, Biological; D008958:Models, Molecular; D009154:Mutation; D010641:Phenotype; D011487:Protein Conformation; D011991:Receptors, Virus / Q000235:genetics / Q000378:metabolism*; D012190:Retroviridae / Q000235:genetics; D053585:Virus Attachment; D014779:Virus Replication
chemical_list: D000596:Amino Acids; D019267:Hemagglutinin Glycoproteins, Influenza Virus; D011991:Receptors, Virus