|SUBBARAO, K - CTR FOR DIS CNTRL-ATLANTA
|LU, X - CTR FOR DIS CNTRL-ATLANTA
|SMITH, C - CTR FOR DIS CNTRL-ATLANTA
|SHAW, M - CTR FOR DIS CNTRL-ATLANTA
|KATZ, J - CTR FOR DIS CNTRL-ATLANTA
Submitted to: Options for the Control of Influenza Conference
Publication Type: Proceedings
Publication Acceptance Date: 8/9/2001
Publication Date: 12/19/2001
Interpretive Summary: In 1997 in Hong Kong, 18 human cases of respiratory illness were caused by an avian influenza A H5N1 virus. The H5N1 viruses are the only highly pathogenic avian viruses that have caused an outbreak of respiratory disease in humans. The H5N1 viruses isolated from humans during the 1997 outbreak had avian virus genomes. This outbreak created a new awareness that avian influenza viruses could spread directly from poultry to humans and cause severe respiratory disease in humans. However, the molecular basis of the H5N1 virus virulence in humans was not evident. The molecular determinants and related mechanisms that make certain influenza viruses highly pathogenic for mammalian species, including humans, are poorly understood. In this study, we investigated the molecular determinants that distinguish the viruses of high and low pathogenicity in mice and found a few likely determinants of virulence of the H5N1 viruses.
Technical Abstract: During 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. 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. Based on lethality for mice, the pathogenicity phenotype of 15 human H5N1 viruses was characterized; 9 viruses displayed a high, 5 a low, and 1 an intermediate pathogenicity phenotype. H5N1 viruses with a high pathogenicity phenotype replicated in multiple solid organs and caused depletion of peripheral blood leukocytes. Utilizing sequence analysis we determined that five specific amino acids i four proteins correlated with pathogenicity in mice. Alone or in combination, these specific residues are the likely determinants of virulence of human H5N1 influenza viruses in this mammalian model.