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Title: PATHOGENESIS OF AND IMMUNITY TO AVIAN INFLUENZA A H5 VIRUSES

Author
item KATZ,, JACQUELINE - CDC - ATLANTA, GA
item LU,, XIUHUA - CDC - ATLANTA, GA
item FRACE,, MICHAEL - CDC - ATLANTA, GA
item MORKEN,, TIMOTHY - CDC - ATLANTA, GA
item ZAKI,, SHERIF - CDC - ATLANTA, GA
item Tumpey, Terrence

Submitted to: Biomedicine and Pharmacotherapy
Publication Type: Peer Reviewed Journal
Publication Acceptance Date: 2/1/2000
Publication Date: 5/1/2000
Citation: N/A

Interpretive Summary: In 1997 in Hong Kong, 18 human cases of respiratory illness were caused by an avian influenza A H5N1 virus. Although avian influenza viruses had not previously been known to cause respiratory illness in humans, the H5N1 viruses caused severe illness and death, primarily in individuals aged greater than 12 years. The introduction of H5N1 viruses into humans raised dconcerns about the potential of these viruses to cause a pandemic. We hav used the BALB/c mouse to better understand the pathogenesis of and immunity to the H5N1 viruses in a mammalian model. It was determined that there were two general types of H5N1 viruses, high and low lethality for mice. The highly lethal viruses not only replicated in respiratory tissue but also in other organs such as the brain. The immunization of mice with a low lethal H5 virus or a purified hemagglutinin H5 protein resulted in protection against lethal challenge and was dependent on the presence of specific antibody. The identification of low and high lethal viruses should provide an excellent model system to study genetic diffences between the different viruses.

Technical Abstract: We have used the BALB/c mouse to better understand the pathogenesis of and immunity to the avian H5N1 viruses in a mammalian model. Two general phenotypes of pathogenicity of H5N1 viruses, based on high and low lethality for mice, were observed. We demonstrate that in addition to a lethal outcome, H5N1 viruses with a high pathogenicity phenotype exhibit additional features that include the rapid and uncontrolled replication in the lungs of infected mice, dissemination and replication of virus in other organs, and depletion of peripheral blood leukocytes. The BALB/c mouse model was also used to better understand the parameters of protective immunity to the H5N1 viruses. Prior infection of H5N1 viruses of low pathogenicity or an antigenically related non-pathogenic H5N3 virus protected mice from death by infection with a highly pathogenic HK/483 virus. Immunization of mice with baculovirus-expressed recombinant H5 hemagglutinin protein or a previously defined H5-specific synthetic peptid induced MHC class II restricted CTL activity. Mice that had CTL activity but no serum hemagglutination-inhibition antibody were not protected from a lethal challenge with H5N1 virus. These results suggest that antibody is required for protection of mice against lethal challenge with H5N1 viruses of the high pathogenicity phenotype.