Molecular correlates of influenza A H5N1 virus pathogenesis in mice

Background: In 1997, highly pathogenic avian influenza A H5N1 viruses caused 18 human cases of respiratory illness and six deaths in Hong Kong. The genes of the H5N1 viruses isolated from humans were derived from avian influenza viruses, with no evidence of reassortment with human influenza viruses. The molecular determinants of human pathogenesis were not evident. Methods: The BALB/c mouse was used as a mammalian model to evaluate the biological and molecular basis of human H5N1 virus pathogenesis. Molecular correlates of H5N1 virus pathogenicity for mice were sought by analyzing the nucleotide sequence of human H5N1 viruses. Results: Based on high and low lethality for mice, the pathogenicity phenotype of 15 human H5N1 viruses was characterized; nine viruses displayed a high, five a low, and one an intermediate pathogenicity phenotype. H5N1 viruses with a high pathogenicity phenotype replicated in multiple solid organs and caused depletion of peripheral blood leukocytes. Sequence analysis determined that five specific amino acids in four proteins correlated with pathogenicity in mice, Conclusions: Alone or in combination, these specific residues are the likely determinants of virulence of human H5N1 influenza viruses in this mammalian model. Published by Elsevier Science B.V.