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Human and Avian Influenza Viruses 流感及禽流感病毒的病毒學 Yun-Wei Hsu2 (許芸瑋) and Jen-Ren Wang1,2 (王貞仁) Department of Medical Laboratory Science and Biotechnology, College of Medicine, National Cheng Kung University1; NHRI Tainan Virology Laboratory for Diagnosis and Research, Division of Clinical Research, National Health Research Institutes 2 H5N1 avian influenza was initially confined to poultry, but in recent years it has emerged as a highly fatal infectious disease in the human population. In 1997 in Hong Kong, H5N1 crossed the avian-human species barrier for the first time. Highly pathogenic H5N1 influenza A viruses have spread relentlessly across the globe since 2003, and they are associated with widespread death in poultry. There were 387 reported infections with a mortality rate of 63% to date, most reported human infections with influenza H5N1 viruses resulted from poultry-to-human transmission. Several viral genes and gene products have been identified that may be responsible for the host restriction and pathogenesis of H5N1 influenza. The HPAI (highly pathogenic avian influenza) phenotypes are primarily related to mutations with the multiple basic amino acids in the cleavage site between hemagglutinin 1 (HA1) and HA2 domains of the HA0 precursor protein. This property enables the HA to be cleaved by ubiquitous intracellular proteases which allow viruses to be replicated in multiple organs resulting in systemic infections with high mortality. The receptor specificity of HA is responsible for the host-range restriction of influenza virus. The RNA polymerase (PB2) protein has also been recognized as a critical factor in host range restriction, avian influenza viruses typically have Glu627 in the PB2 (polymerase basic 2) gene, while human viruses have Lys627. Lys627 of PB2 enhances pathogenicity and promotes replication in cells of the upper respiratory tract at lower temperatures. The PB1-F2 gene is under strong positive selection pressure in avian influenza isolates, serine at position 66 of PB2-F1 increases virulence. In addition, the nonstructural 1 (NS1) protein is known to play a role in the host innate immune responses. Glutamic acid at position 92 of NS1 confers resistance to TNF-α (tumor necrosis factor) and interferons. NS1 of most HPAI contains postsynaptic density protein-95, disc-large tumor suppressor protein, zonula occludes-1 (PDZ) ligand motifs including GLu-Pro-Glu-Val (EPEV) and GLu-Ser-Glu-Val (ESEV) motifs at the C-terminus of NS1. Binding of NS1 to PDZ domain-containing proteins may affect cell signaling pathways and modulate pathogenicity including those regulate protein traffic, maintain cell morphology and organization. Furthermore, 1 neuraminidase and matrix proteins both are associated with drug resistance. Histidine to tyrosine substitution at position 274 of neuraminidase (NA) and serine to asparagine substitution at position 31 of M2 confer resistance to oseltamivir and amantadine, respectively. Long-term surveillance and viral molecular characterizations will help in detection of human infection and person-to-person transmission. . 2