The polymerase basic protein 2 (PB2) gene of pandemic H1N1

The first genomic segment of the influenza A virus encodes the polymerase basic 2 protein (PB2) gene. This is the longest genomic segment and is sometimes labeled “segment 1”. This gene produces the PB2 protein. The PB2 subunit works with PB1 and PA subunits to create the viral polymerase. This polymerase is responsible for the transcription and replication of the viral genome.

Like all flu viruses, the pandemic H1N1 originated in viruses that infected birds. One of the questions that arises with a new human pathogen is: what is the source of the virus? Some flu viruses are thought to have adapted directly from birds to humans (the 1918 pandemic virus, H5N1). However, there has been much speculation that pigs served as an intermediary for the new H1N1 virus. To determine the most likely origin of a new virus, it is often useful to align sequences from the new virus with sequences from existing virus. When the BLAST program is used to align A/California/04/2009(H1N1) PB2 with sequences from GenBank, both the nucleotide sequence and protein sequence most closely match viruses that were collected from North American birds. Specifically, the PB2 nucleotide sequence was 96% similar to A/mallard/South Dakota/Sg-00128/2007 (H3N2), A/mallard/South Dakota/Sg-00127/2007(H3N2), A/mallard/South Dakota/Sg-00125/2007(H3N2) and A/northern pintail/South Dakota/Sg-00126/2007(H3N2). The PB2 protein was 98% identical to the same four avian virus sequences. Thus, for the PB2 genomic segment, the best match is with viruses that were collected in North American ducks two years ago. The nucleotide matches are not particularly close, so it is unlikely that these birds were the source of the pandemic virus. The lack of a close match suggests that the origin of segment 1 from the new H1N1 virus is currently unknown.

The PB2 gene is reported to be key in the adaptation of a virus that infects birds to one that infects humans. In particular, it has been reported that the amino acid at position 627 is critical for this adaptation (Van Hoeven et al. 2009). Viruses that infect birds typically have a glutamic acid (E) in this position. Flu A viruses that are fully adapted to humans usually have a lysine (K) at this position. This same position in PB2 appears to be key in determining the lethality of flu viruses (Hatta et al. 2001). In the 1918 pandemic and H5N1 viruses, a lysine in this position is associated with a higher level of lethality. The presence of a lysine at position 627 appears to permit flu viruses to replicate in both the lungs and nose and thus spread more easily from person to person.

A/California/04/2009(H1N1) has a glutamic acid at position 627. Thus, it still has an “avian” signature at this position. It is possible, perhaps likely, that as pandemic H1N1 adapts to humans, a mutation will occur that will create a lysine in position 627 in this virus. If so, will the virus become more virulent? At this point, it is difficult to say. On the one hand, “seasonal” flu viruses that are not considered particularly lethal have a lysine at position 627. On the other hand, a change from glutamic acid, when the virus is infecting birds, to a lysine, when the virus is starts to infect humans, is associated with much greater virulence. How to reconcile these apparently contradictory facts? It may be that the change to a lysine is initially associated much greater virulence due to interactions with other proteins. As the virus moves through the human population immune responses are triggered. Thus, a year or two after a pandemic begins, the virus comes under selection to escape immune system detection. This selection may result in the preferential propagation of new versions of other proteins which no longer interact with PB2 to create a more lethal virus. In this scenario, a mutation at position 627 from gluatamic acid to lysine will initially create a more lethal virus, but, as the virus is “tamed” by the immune system selection, this mutation will utlimately be insufficient to sustain a high degree of lethality.

Given that human-adapted flu A viruses tend to have a lysine at position 627, it seems likely that the new pandemic H1N1 will eventually lose its “avian” glutamic acid and acquire a lysine at this position. There have already been sporadic instances of this. If/when this occurs in a strain that spreads widely, it would not be surprising if it becomes more lethal.

References

Van Hoeven et al. (2009) Human HA and polymerase subunit PB2 proteins confer transmission of an avian influenza virus through the air. PNAS. 106: 3366 – 3371.

Watanabe (2009) Viral RNA polymerase complex promotes optimal growth of 1918 virus in the lower respiratory tract of ferrets. PNAS. 106: 588–592.

Hatta et al. (2007) Growth of H5N1 Influenza A Viruses in the Upper Respiratory Tracts of Mice. PLoS Pathog. 3(10): e133.

Hatta et al. (2001) Molecular Basis for High Virulence of Hong Kong H5N1 Influenza A Viruses. Science. 293: 1840-1842.

Hiromoto et al. (2000) Phylogenetic analysis of the three polymerase genes (PB1, PB2 and PA) of influenza B virus. J. Gen. Virol. 81: 929–937.

Perales and Orten (1997) The Influenza A Virus PB2 Polymerase Subunit Is Required for the Replication of Viral RNA. J. Virol. 71: 1381–1385.

Perales et al. (1996) Mutational Analysis Identifies Functional Domains in the Influenza A Virus PB2 Polymerase Subunit. J. Virol. 70: 1678–1686.

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