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Journal of Virology, April 1999, p. 3184-3189, Vol. 73, No. 4
Department of Pathobiological Sciences,
School of Veterinary Medicine, University of Wisconsin
Received 25 September 1998/Accepted 23 December 1998
An H5N1 avian influenza A virus was transmitted to humans in Hong
Kong in 1997. Although the virus causes systemic infection and is
highly lethal in chickens because of the susceptibility of the
hemagglutinin to furin and PC6 proteases, it is not known whether it
also causes systemic infection in humans. The clinical outcomes of
infection in Hong Kong residents ranged widely, from mild respiratory
disease to multiple organ failure leading to death. Therefore, to
understand the pathogenesis of influenza due to these H5N1 isolates, we
investigated their virulence in mice. The results identified two
distinct groups of viruses: group 1, for which the dose lethal for 50%
of mice (MLD50) was between 0.3 and 11 PFU, and group 2, for which the MLD50 was more than 103 PFU. One
day after intranasal inoculation of mice with 100 PFU of group 1 viruses, the virus titer in lungs was 107 PFU/g or 3 log
units higher than that for group 2 viruses. Both types of viruses had
replicated to high titers (>106 PFU/g) in the lungs by day
3 and maintained these titers through day 6. More importantly, only the
group 1 viruses caused systemic infection, replicating in
nonrespiratory organs, including the brain. Immunohistochemical
analysis demonstrated the replication of a group 1 virus in brain
neurons and glial cells and in cardiac myofibers. Phylogenetic analysis
of all viral genes showed that both groups of Hong Kong H5N1 viruses
had formed a lineage distinct from those of other viruses and that
genetic reassortment between H5N1 and H1 or H3 human viruses had not
occurred. Since mice and humans harbor both the furin and the PC6
proteases, we suggest that the virulence mechanism responsible for the
lethality of influenza viruses in birds also operates in mammalian
hosts. The failure of some H5N1 viruses to produce systemic infection
in our model indicates that multiple, still-to-be-identified, factors contribute to the severity of H5N1 infection in mammals. In addition, the ability of these viruses to produce systemic infection in mice and
the clear differences in pathogenicity among the isolates studied here
indicate that this system provides a useful model for studying the
pathogenesis of avian influenza virus infection in mammals.
0022-538X/99/$04.00+0
Copyright © 1999, American Society for Microbiology. All rights reserved.
Biological Heterogeneity, Including Systemic
Replication in Mice, of H5N1 Influenza A Virus Isolates from Humans
in Hong Kong
Madison,
Madison, Wisconsin 53706,1 and
Laboratory of Microbiology,
*
Corresponding author. Mailing address: Department of
Pathobiological Sciences, School of Veterinary Medicine, University of Wisconsin
Madison, 2015 Linden Dr. West, Madison, WI 53706. Phone: (608) 265-4925. Fax: (608) 265-5622. E-mail:
kawaokay{at}svm.vetmed.wisc.edu.
Journal of Virology, April 1999, p. 3184-3189, Vol. 73, No. 4
0022-538X/99/$04.00+0
Copyright © 1999, American Society for Microbiology. All rights reserved.
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