TY - GEN T1 - In Silico Prediction and Experimental Confirmation of HA Residues Conferring Enhanced Human Receptor Specificity of H5N1 Influenza A Viruses AU - Schmier, Sonja AU - Mostafa, Ahmed AU - Haarmann, Thomas AU - Bannert, Norbert AU - Ziebuhr, John AU - Veljkovic, Veljko AU - Dietrich, Ursula AU - Pleschka, Stephan AB - 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. KW - Animals KW - Humans KW - Genetic Vectors/genetics KW - Phenotype KW - Mutation KW - Cell Line KW - Gene Expression KW - Models Molecular KW - Computer Simulation KW - Virus Replication KW - Models Biological KW - Amino Acids KW - Hemagglutinin Glycoproteins Influenza Virus/chemistry KW - Hemagglutinin Glycoproteins Influenza Virus/genetics KW - Influenza A Virus H5N1 Subtype/genetics KW - Influenza A Virus H5N1 Subtype/metabolism KW - Protein Conformation KW - Receptors Virus/genetics KW - Receptors Virus/metabolism KW - Retroviridae/genetics KW - Virus Attachment KW - 610 Medizin PY - 2015 LA - eng PB - Robert Koch-Institut, Biologische Sicherheit IS - 11434 DO - 10.1038/srep11434 ER -