The PB2-E627K Mutation Attenuates Viruses Containing the 2009 H1N1 Influenza Pandemic Polymerase

Abstract

The swine-origin H1N1 influenza A virus emerged in early 2009 and caused the first influenza pandemic in 41 years. The virus has spread efficiently to both the Northern and the Southern Hemispheres and has been associated with over 16,000 deaths. Given the virus’s recent zoonotic origin, there is concern that the virus could acquire signature mutations associated with the enhanced pathogenicity of previous pandemic viruses or H5N1 viruses with pandemic potential. We tested the hypothesis that mutations in the polymerase PB2 gene at residues 627 and 701 would enhance virulence but found that influenza viruses containing these mutations in the context of the pandemic virus polymerase complex are attenuated in cell culture and mice.

Naturally Occurring Swine Influenza A Virus PB1-F2 Phenotypes That Contribute to Superinfection with Gram-Positive Respiratory Pathogens

“…In fact, other influenza virus genes can contribute to the virulence associated with primary influenza virus infection, including PB2 (10,28,43) and NS1 (6,22,41,49). Viruses used in the current study were selected based on PB1-F2 genotype, without consideration for other viral genes expressed by these viruses.…”

The M Segment of the 2009 New Pandemic H1N1 Influenza Virus Is Critical for Its High Transmission Efficiency in the Guinea Pig Model

“…Interestingly, triplereassortant classical swine virus infections in humans had been sporadically reported and mostly self-limiting until this time (4,22,29). Even though several studies have determined the viral virulence factors for the 2009 pandemic influenza virus (8,9,12,19,26), the viral factor(s) contributing to the sustained transmission in humans, a most intriguing question about this virus, remains unresolved.…”

Combination of PB2 271A and SR Polymorphism at Positions 590/591 Is Critical for Viral Replication and Virulence of Swine Influenza Virus in Cultured Cells and In Vivo

“…The three amino acid substitutions in PB2 seem not to affect interactions with host factors because the triple-mutated virus exhibited a similar replication capacity in canine, swine, and human cell lines. Recent studies showed that the PB2 E627K or D701N substitution in 2009 pH1N1 did not lead to enhanced virulence in mice (5, 21) and ferrets (5) or enhanced transmission in ferrets (5); these substitutions actually cause the attenuation of a reassortant virus that contains the 2009 pH1N1 influenza polymerase and NP and the remaining four genes from a recent seasonal H1N1 (A/New York/312/2001) virus in culture cells and mice (6). These findings suggest that the pH1N1 and currently circulating triple-reassortant SIVs use different strategies to achieve efficient replication and adaptation to mammals without the signature PB2 627K or 701N residue.…”