Recently, the viral replication complex has been recognized as an important contributor to viral pathogenicity, likely by affecting viral growth. The amino acid at position 627 of the PB2 protein was first described by Subbarao et al
. as a host range determinant, based on cell culture studies46
. Hatta et al
. demonstrated that the respective amino acid change determined the pathogenicity of H5N1 influenza viruses in mice47
. Viruses with lysine at this position were pathogenic in mice, whereas those with glutamic acid were nonpathogenic in these animals47
. Notably, almost all human influenza viruses possess lysine at this position, while most avian viruses (with the exception of the ‘Qinghai Lake’ lineage of H5N1 viruses and their descendants) possess glutamic acid at PB2-627. Lysine at position 627 of PB2 is now recognized as a determinant of viral pathogenicity in several mammalian species.
Several studies have addressed the mechanism by which PB2-627Lys affects virulence. The amino acid change does not affect tissue tropism in mice but viral replicative ability. This may result from an inhibitory activity in mammalian cells that prevents efficient replication by polymerase complexes possessing PB2-627Glu48
, and/or from inefficient interaction of PB2-627Glu with mammalian-type NP protein49
. Viruses possessing PB2-627Lys, but not those possessing PB2-627Glu, grow efficiently in the upper respiratory tract of mammals50
, which may be explained by the fact that PB2-627Lys confers efficient replication at 33°C (the temperature of the upper airway in humans) while PB2-627Glu does not51
. By contrast, both variants mediate efficient replication at 37°C50,51
. Collectively, these findings suggest that PB2-627Lys allows efficient replication not only in the lower, but also in the upper respiratory tract of mammals, a feature that may facilitate transmission. In fact, replacement of PB2-627Lys with Glu reduced the transmissibility of human influenza viruses in a guinea pig model52
The amino acid at position 701 of PB2 has also emerged as a determinant of virulence 53,54
, a role likely related to its facilitation of binding of PB2 to importin α (a cellular nuclear import factor) in mammalian cells55
. The recently emerged S-OIV possess the ‘low pathogenic’-type amino acids at positions 627 and 701 (i.e., Glu and Asp).
Recently, the PB2 and HA proteins of the ‘Spanish influenza’ virus were shown to be critical for droplet transmission13
. The underlying mechanism and the amino acids in PB2 that are critical for this function remain to be determined.
In addition to PB2, other components of the replication complex may contribute to viral pathogenicity as well56
. A recent study also suggested that the replication complex, particularly the PB1 protein, contributes to the virulence of the 1918 pandemic virus in ferrets12
Structural data are now becoming available for the viral polymerase complex which may help in the interpretation of mutational analyses; in fact, two studies57,58
showed that PB2-627Lys is part of a basic groove that is disrupted upon replacement with Glu.