My most recent two blogs have described the remarkable similarities between the HA protein in the 1918 pandemic flu virus and the 2009 pandemic flu virus. However, it is important to note that this similarity is not due to a general sequence similarity. Indeed, an alignment of the HA proteins from A/South Carolina/1/18 (H1N1) and A/California/04/2009(H1N1) reveal an identity of only 86%, quite low. And yet, figure 3C from the Xu et al paper reveals that:
Antibody 2D1 exhibits strong binding to both 1918 HA and CA04 HA, but not to PR8 and HAs of other influenza subtypes, as tested in ELISA assay.
How to explain the remarkable ability of an antibody from over 90 years ago to specifically recognise another pandemic strain of influenza, but not more recent flu viruses? Physically, this may be due a similar epitope, a short segment of the protein, that is nearly identical between the two viruses. The three dimensional shapes of the HA proteins of the two viruses are also very similar, even though most of the primary sequence is quite different. Although this explains why the 2D1 antibody can recognise both viruses, it does not explain why the two viruses are so similar in this one specific way.
To address this question, we should start without preconceptions. This means that we should not assume that the virus evolved naturally or that it was made in a laboratory. Let us consider each of these possibilities to examine which is more likely. We will, of course, be speculating as there is no evidence that has been presented that conclusively proves either hypothesis.
If the remarkable similarity in 2D1 binding of the 1918 and 2009 pandemic strains was the result of natural processes, I can imagine two possible mechanisms. First, an extremely important epitope (short segment of amino acids) that bound to 2D1, was preserved, by sheer chance, over 90 years and just happened to end up in the 2009 pandemic virus. This seems highly unlikely to me, but was suggested in one of the speculative commentaries on these papers. A second possibility is that the epitope in question was under intense selection. That is, it conferred a very strong benefit to the viruses that carried it. However, this advantage would have to have been in animals that were infected with the virus, most likely pigs, because the same epitopes were not found in human viruses. This advantage would have had to have applied to pig viruses, but not to human viruses, until 2009, when it suddenly appeared in the pandemic 2009 virus, apparently without causing any loss of fitness in this particular human virus. This is possible, but not proven.
The other general possibility, that the virus was produced in a laboratory, is almost never discussed in scientific papers, but should be considered in light of the unusual properties of this virus, imo. How would one explain the low general similarity between the 1918 virus and the 2009 virus but high similarity with respect to 2D1 binding if one posits a lab origin? Rather directly, as it turns out. There is a laboratory technique know as immunoprecipitation. It involves using antibodies to specific epitopes to “pull out” particular proteins. One can imagine someone using an antibody to the 1918 virus to screen a large panel of constructed viruses for strains that resemble the 1918 virus in biology, but not general sequence. If this hypothesis is correct, then the ability of 2D1 to recognise the 2009 pandemic virus is not a coincidence – it is how this virus was selected. This is possible, but not proven.
Which general mechanism, an odd and never-before observed pattern of viral evolution or a laboratory immunoprecipitation assay is the more likely possibility? It is difficult to say, at this point. Perhaps further experiments will provide stronger evidence in favor of a natural evolution of this virus. However, at this time, the mounting number of odd features of the 2009 pandemic flu virus should give open-minded people cause for concern, imo.
Xu et al. (2010) Structural Basis of Preexisting Immunity to the 2009 H1N1 Pandemic Influenza Virus. Science.
Wei et al. (2010) Cross -Neutralization of 1918 and 2009 Influenza Viruses: Role of Glycans in Viral Evolution and Vaccine Design. Science Translational Medicine.
Itoh, et al. (2009) In vitro and in vivo characterization of new swine-origin H1N1 influenza viruses. Nature.
Settembre et al. (2010) H1N1: Can a Pandemic Cycle Be Broken? Science Translational Medicine.