Influenza A viruses (IAV) are significant human pathogens causing yearly epidemics and occasional pandemics. Past pandemics have resulted in significant morbidity and mortality. The 1918 influenza pandemic was thought to have resulted in the death of at least 675,000 people in the U.S., and 40 million people worldwide. Annual influenza A virus epidemics are also very significant, resulting in up to 49,000 deaths in the U.S. per year. Pandemic strains of influenza emerge periodically and are thought to be derived ultimately from avian influenza A viruses. The recent 2009 pandemic influenza virus emerged by reassortment of two pre-existing swine influenza virus lineages. The first lineage is the Eurasian avian-like swine lineage that emerged from an avian influenza virus in toto. The second lineage is the triple-reassortant H1N2 swine influenza virus containing gene segments derived from avian, human, and classical swine influenza viruses. The natural reservoir of influenza A viruses is thought to be wild waterfowl. Genetically and antigenically diverse influenza A viruses circulate in wild birds and viral strains from this pool can adapt to new hosts, including humans and domestic animals. Influenza A viruses are also significant pathogens for agriculturally important animals like poultry, swine, and horses. Understanding the mechanisms of host switching are very important for surveillance and pandemic preparedness. Understanding the molecular basis underlying the annual evolution of human influenza will aid in vaccine strain selection. The emergence of new pandemic influenza A viruses requires overcoming barriers to cross-species transmission as viruses move from animal reservoirs into humans. This complicated process is driven by both individual gene mutations and genome reassortments. The viral polymerase complex, composed of the proteins PB1, PB2, and PA, is a major factor controlling host adaptation, and reassortment events involving polymerase gene segments occurred with past pandemic viruses. The newly identified PA-X protein, encoded as a frameshifted protein within the polymerase PA gene segment, was shown to be evolutionarily conserved in influenza A viruses. The X-ORFs of diverse influenza A viruses can be divided into two groups that differ in selection pressure and likely function, reflected in the presence of an internal stop codon and a change in synonymous diversity. Notably, truncated forms of PA-X evolved convergently in swine and dogs, suggesting a strong species-specific effect. Influenza A viruses possess RNA genomes that mutate frequently in response to immune pressures. The mutations in the hemagglutinin genes are particularly significant, as the hemagglutinin proteins mediate attachment and fusion to host cells, thereby influencing viral pathogenicity and species specificity. Large-scale influenza A genome sequencing efforts have been ongoing to understand past epidemics and pandemics and anticipate future outbreaks. Sequencing efforts thus far have generated nearly 9,000 distinct hemagglutinin amino acid sequences. Comparative models for all publicly available influenza A hemagglutinin protein sequences were generated using the Rosetta modeling suite. The C-alpha root mean square deviations between a randomly chosen test set of models and their crystallographic templates were less than 2 , suggesting that the modeling protocols yielded high-quality results. The models were compiled into an online resource, the Hemagglutinin Structure Prediction (HASP) server. The HASP server was designed as a scientific tool for researchers to visualize hemagglutinin protein sequences of interest in a three-dimensional context. With a built-in molecular viewer, hemagglutinin models can be compared side-by-side and navigated by a corresponding sequence alignment. The models and alignments can be downloaded for offline use and further analysis.
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