Giuseppe
Emeritus
J Virol. 2008 Oct 1. [Epub ahead of print]
Experimental evolution of Human Influenza H3 hemagglutinin in the mouse lung identifies adaptive regions in HA1 and HA2.
Keleta L, Ibricevic A, Bovin NV, Brody SL, Brown EG. - Department of Biochemistry, Microbiology and Immunology, Faculty of Medicine, University of Ottawa, Ontario, Canada; and Department of Internal Medicine, Washington University School of Medicine, St. Louis, MO, U.S.A.; Shemyakin-Ovchinnikov Institute of Bioorganic Chemistry, Moscow V-437, 117997, Russia.
The genetic basis for virulence and host switching in influenza A viruses (FLUAV) is largely unknown.
Because the hemagglutinin (HA) protein is a determinant of these properties HA evolution was mapped in the experimental model of mouse lung adaptation.
Variants of prototype A/Hong Kong/1/68 (H3N2) (HK-wt) human virus were selected in both longitudinal and parallel studies of lung adaptation.
Mapping of HA mutations found in 11 independently derived mouse-adapted populations of HK-wt, identified 27 mutations that clustered within two distinct regions in or near the globular frameworks of the HA1 and HA2 subunits.
The adaptive mutations demonstrated multiple instances of convergent evolution involving 4 amino acid positions; HA1: 162, 210, 218 and HA2: 154.
Using reverse genetics, convergent HA mutations were shown to affect cell tropism by enhancing infection and replication in primary mouse tracheal epithelial cells in vitro and mouse lung tissue in vivo.
Adaptive HA mutations were multifunctional affecting both the median pH of fusion and receptor specificity.
Specific mutations within both adaptive regions were shown to increase virulence in a mouse lung model.
The occurrence of mutations in the HA1 and HA2 adaptive regions of natural FLUAV host range and virulent variants of avian and mammalian viruses is discussed.
This study has identified adaptive sites and regions within the HA1 and HA2 subunits that may guide future studies of viral adaptation and evolution in nature.
PMID: 18829764 [PubMed - as supplied by publisher
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Experimental evolution of Human Influenza H3 hemagglutinin in the mouse lung identifies adaptive regions in HA1 and HA2.
Keleta L, Ibricevic A, Bovin NV, Brody SL, Brown EG. - Department of Biochemistry, Microbiology and Immunology, Faculty of Medicine, University of Ottawa, Ontario, Canada; and Department of Internal Medicine, Washington University School of Medicine, St. Louis, MO, U.S.A.; Shemyakin-Ovchinnikov Institute of Bioorganic Chemistry, Moscow V-437, 117997, Russia.
The genetic basis for virulence and host switching in influenza A viruses (FLUAV) is largely unknown.
Because the hemagglutinin (HA) protein is a determinant of these properties HA evolution was mapped in the experimental model of mouse lung adaptation.
Variants of prototype A/Hong Kong/1/68 (H3N2) (HK-wt) human virus were selected in both longitudinal and parallel studies of lung adaptation.
Mapping of HA mutations found in 11 independently derived mouse-adapted populations of HK-wt, identified 27 mutations that clustered within two distinct regions in or near the globular frameworks of the HA1 and HA2 subunits.
The adaptive mutations demonstrated multiple instances of convergent evolution involving 4 amino acid positions; HA1: 162, 210, 218 and HA2: 154.
Using reverse genetics, convergent HA mutations were shown to affect cell tropism by enhancing infection and replication in primary mouse tracheal epithelial cells in vitro and mouse lung tissue in vivo.
Adaptive HA mutations were multifunctional affecting both the median pH of fusion and receptor specificity.
Specific mutations within both adaptive regions were shown to increase virulence in a mouse lung model.
The occurrence of mutations in the HA1 and HA2 adaptive regions of natural FLUAV host range and virulent variants of avian and mammalian viruses is discussed.
This study has identified adaptive sites and regions within the HA1 and HA2 subunits that may guide future studies of viral adaptation and evolution in nature.
PMID: 18829764 [PubMed - as supplied by publisher
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