Transmission of Influenza Virus in a Mammalian Host Is Increased by PB2 Amino Acids 627K or 627E/701N

Abstract

Since 2003, more than 380 cases of H5N1 influenza virus infection of humans have been reported. Although the resultant disease in these cases was often severe or fatal, transmission of avian influenza viruses between humans is rare. The precise nature of the barrier blocking human-to-human spread is unknown. It is clear, however, that efficient human-to-human transmission of an antigenically novel influenza virus would result in a pandemic. Influenza viruses with changes at amino acids 627 or 701 of the PB2 protein have been isolated from human cases of highly pathogenic H5 and H7 avian influenza. Herein, we have used the guinea pig model to test the contributions of PB2 627 and 701 to mammalian transmission. To this end, viruses carrying mutations at these positions were generated in the A/Panama/2007/99 (H3N2) and A/Viet Nam/1203/04 (H5N1) backgrounds. In the context of either rPan99 or rVN1203, mutation of lysine 627 to the avian consensus residue glutamic acid was found to decrease transmission. Introduction of an asparagine at position 701, in conjunction with the K627E mutation, resulted in a phenotype more similar to that of the parental strains, suggesting that this residue can compensate for the lack of 627K in terms of increasing transmission in mammals. Thus, our data show that PB2 amino acids 627 and 701 are determinants of mammalian inter-host transmission in diverse virus backgrounds.

Prevalence, genetics, and transmissibility in ferrets of Eurasian avian-like H1N1 swine influenza viruses

“…Several amino acid changes in PB2 are important for the replication or virulence of influenza viruses in mammals (22)(23)(24)(25)(26)(27)(28)(29)(30). A detailed comparison of the amino acid differences among the EAH1N1 SIVs indicated that all of these viruses have mammalian-adapting mutations in their PB2 genes (SI Appendix, Table S3).…”

Adaptive strategies of the influenza virus polymerase for replication in humans

“…Discrete mutations within the polymerase have also been associated with an extended host range. A notable example is the species-specific preference for lysine at PB2 position 627 resulting in high levels of viral replication and/or polymerase activity in animal models and human cells (5,(7)(8)(9)(10)(11)(12)(13)(14)(15)(16). Other changes within PB2, such as the D701N mutation, are associated with increased host range, polymerase activity, and pathogenicity in mammalian systems and humans (33)(34)(35).…”

“…PB2 derived from human viral isolates almost exclusively possesses a lysine at position 627 (K627), whereas glutamic acid (E627) at this position predominates in avian viruses (6). PB2 K627 correlates with enhanced polymerase activity, virus replication, transmission, and in certain cases, pathogenicity and mortality in mammals (5,(7)(8)(9)(10)(11)(12)(13)(14)(15)(16). PB2 K627 also correlates with moderately enhanced influenza virus replication in pigs, consistent with pigs serving as an intermediary viral reservoir between birds and humans (17).…”

“…The polymerase from this virus has been identified as a virulence determinant, and PB2 E627 correlates with reduced pathogenicity and transmissibility in animal models, and possibly humans (7,8,10,15). Yet, the current mortality rate for confirmed H5N1 infections is 59.3%*.…”

Minimal molecular constraints for respiratory droplet transmission of an avian–human H9N2 influenza A virus

“…4F and when comparing the viral titers and length of shedding in respiratory droplet contacts from RCP10 and 2RCP10:6M98. The internal genes have been implicated in transmission not only within avian species (20)(21)(22) but also from avian to mammalian species (23,24). A complete set of viruses tested and their transmission phenotype are listed (Table 4 and supporting information (SI) Fig.…”