Download The Genetic Evolution of H5N1

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,
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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.
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