Background: In recent years, avian influenza viruses (AIVs) have seriously threatened human health. Questions such as: why do AIVs infect humans?, how quickly can an AIV become pandemic?, and which virus is the most dangerous? cannot be sufficiently answered using current bioinformatic studies.
Method: Secondary structures and energies of representative 5'-untranslated region (UTR) of the HA gene were calculated. Then their secondary structures and energies were re-calculated after one or two nucleotide substitutions were introduced into the HA 5'-UTR. Phylogenetic trees on the basis of hemagglutinin (HA) and polymerase basic protein 2 (PB2) amino acid sequences and HA 5'-UTR nucleotide sequences were constructed. The connection between the energy and translation efficiency of 5'-UTR was confirmed by in vitro coupled transcription/translation assay.
Results: The simplicity of the secondary structure of the 5'-UTR of the HA gene determines the overall virus replication rate and transmission potential. Point mutation assays show that the 5'-UTR sequences of the HA gene in the influenza subtypes H2N2, H3N2, and H7N9 have greater variation potentials than other virus subtypes.
Conclusion: Some high-virulent strains of avian influenza might emerge in the next two to three years. The H2N2 subtype, once disappeared in humans, may stage a comeback. The current outbreak of H7N9 may become pandemic and cause even more deaths, if one or two bases are substituted in the 5'-UTR sequence of the HA gene.