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Vol 52(2018) N 4 p. 556-569; DOI 10.1134/S0026893318040052 Full Text

A.S. Gambaryan1*, N.F. Lomakina1,2, E.Y. Boravleva1, L.V. Mochalova3, G.K. Sadykova2 , A.G. Prilipov2, T.Y. Matrosovich4 , M.N. Matrosovich4

Mutations in Hemagglutinin and Polymerase Alter the Virulence of Pandemic A(H1N1) Influenza Virus

1Chumakov Federal Scientific Center for Research and Development of Immune-and-Biological Products, Russian Academy of Sciences, Moscow, 108819 Russia
2Gamaleya Scientific Research Institute of Epidemiology and Microbiology, Ministry of Health of the Russian Federation, Moscow, 123098 Russia
3All-Russia Institute for Scientific and Technical Information (VINITI), Russian Academy of Sciences, Moscow, 125315 Russia
4Institute of Virology, Philipps University, Marburg, 35043 Germany

*al.gambaryan@gmail.com
Received - 2017-10-30; Accepted - 2017-12-12

To study the pathogenicity factors of the pandemic A(H1N1) influenza virus, a number of mutant variants of the A/Hamburg/5/2009 (H1N1)pdm09 strain were obtained through passage in chicken embryos, mouse lungs, and MDCK cell culture. After 17 lung-to-lung passages of the A/Hamburg/5/2009 in mice, the minimum lethal dose of the derived variant decreased by five orders of magnitude compared to that of the parental virus. This variant differed from the original virus by nine amino acid residues in the following viral proteins: hemagglutinin (HA), neuraminidase (NA), and components of the polymerase complex. Additional passaging of the intermediate variants and cloning made it possible to obtain pairs of strains that differed by a single amino acid substitution. Comparative analysis of replicative activity, receptor specificity, and virulence of these variants revealed two mechanisms responsible for increased pathogenicity of the virus for mice. Thus, (1) substitutions in HA (Asp225Gly or Gln226Arg) and compensatory mutation decreasing the charge of HA (Lys123Asn, Lys157Asn, Gly158Glu, Asn159Asp, or Lys212Met) altered viral receptor-binding specificity and restored the functional balance between HA and NA; (2) Phe35Leu substitution in the PA protein increased viral polymerase activity.

pandemic A(H1N1) influenza virus, pathogenicity factors



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