Abstract
Two amino acids (lysine at position 627 or asparagine at position 701) in the polymerase subunit PB2 protein are considered critical for the adaptation of avian influenza A viruses to mammals. However, the recently emerged pandemic H1N1 viruses lack these amino acids. Here, we report that a basic amino acid at position 591 of PB2 can compensate for the lack of lysine at position 627 and confers efficient viral replication to pandemic H1N1 viruses in mammals. Moreover, a basic amino acid at position 591 of PB2 substantially increased the lethality of an avian H5N1 virus in mice. We also present the X-ray crystallographic structure of the C-terminus of a pandemic H1N1 virus PB2 protein. Arginine at position 591 fills the cleft found in H5N1 PB2 proteins in this area, resulting in differences in surface shape and charge for H1N1 PB2 proteins. These differences may affect the protein's interaction with viral and/or cellular factors, and hence its ability to support virus replication in mammals.
Highlights
Influenza viruses pose an ongoing threat to human health, as underscored by the current H1N1 influenza pandemic and the sporadic transmission of highly pathogenic avian H5N1 influenza viruses to humans [1,2]
We report that a basic amino acid at position 591 of PB2 can compensate for the lack of PB2-627K and allows efficient replication of highly pathogenic H5N1 and pandemic H1N1 viruses in mammalian species
We present the X-ray crystal structure of the C-terminal portion of a pandemic H1N1 PB2 protein
Summary
Influenza viruses pose an ongoing threat to human health, as underscored by the current H1N1 influenza pandemic and the sporadic transmission of highly pathogenic avian H5N1 influenza viruses to humans [1,2]. Replacement of the aspartic acid at position 701 of PB2 (PB2-701D) found in most avian influenza viruses with asparagine (PB2-701N) conferred high pathogenicity to an H5N1 influenza virus in mice [5] These mammalian-type amino acids (i.e., PB2-627K and PB2-701N) are found in some H5N1 (http://www.flu.lanl.gov) or H7N7 [6] influenza viruses isolated from humans, are selected during replication of H5N1 viruses in humans [7], and facilitate virus transmission in ferret [8] and guinea pig models [9]. These results have led to the concept that PB2-627K or PB2-701N are critical for efficient influenza virus replication in mammalian species. The pandemic H1N1 viruses and some H5N1 influenza viruses isolated from humans do not possess these
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