Evolution of highly pathogenic avian H5N1 influenza viruses and the emergence of dominant variants.

Highly pathogenic avian H5N1 viruses have circulated in South-east Asia for more than a decade and have now spread to more than 60 countries. The evolution of these viruses is characterized by frequent reassortment of the so-called 'internal' genes, creating novel genotypes. Additionally, over time, the surface glycoprotein, haemagglutinin (HA), which is the primary target of the adaptive immune response, has evolved by point mutation into 20 genetically and potentially antigenically distinct clades. To investigate the evolution of avian H5N1 influenza viruses, we undertook a high-resolution analysis of the reassortment of internal genes and evolution of HA of 651 avian H5N1 viruses from 2000 to 2008. Our analysis suggested: (i) all current H5N1 genotypes were derived from a single, clearly defined sequence of initial reassortment events; (ii) reassortment of just three of the internal genes had the most importance in avian H5N1 virus evolution; (iii) HA and the constellation of internal genes may be jointly important in the emergence of dominant variants. Further, our analysis led to the identification of evolutionarily significant molecular changes in the internal genes that may be significant for the emergence of these dominant variants.