Scientific Method —

WHO takes pandemic alert to 11 6 on misplaced virus

The spread of flu viruses usually slows down during the Northern Hemisphere's …

Earlier today, the World Health Organization held a press conference to announce that the current H1N1 flu outbreak has caused it to raise its pandemic alert to the highest level. Although most seasonal flu tends to settle down in the Northern Hemisphere by now, the bulk of the cases continues to be in North America, although roughly 75 countries have now reported cases. Meanwhile, in an impressive display of the capabilities that were developed to enable genome sequencing and comparisons, researchers are already reconstructing the evolutionary history of the virus, and finding that it's the latest version of a virus that may have been around for a decade.

First up, some nomenclature. Neither swine flu nor H1N1 are very specific to this particular strain, so I'm going to adopt a description used in a paper I'll be discussing later: swine-origin influenza A virus, or S-OIV. That's not especially specific either, but it's not obviously been used to describe a previous strain, and it seems to be in the process of being adopted by a number of organizations, including the CDC.


With that out of the way, we can move on to the WHO's statement on S-OIV. It now counts nearly 30,000 cases in 74 nations, which indicates that this strain is global and entirely uncontainable, so the group has raised the pandemic alert level from five to six. The good news is, in the words of Director General Dr. Margaret Chan, "the overwhelming majority of patients experience mild symptoms and make a rapid and full recovery, often in the absence of any form of medical treatment."

That doesn't mean there is no risk—those with additional conditions seem to handle this flu badly, and symptoms often progress rapidly—but things could clearly have been worse. In fact, there has been some discussion of whether the use of the term "pandemic" might be better reserved for an outbreak that carried unusual health risks, rather than something that was simply new but spreading widely. In any case, Dr. Chan suggested that we've been extremely fortunate: the pandemic has allowed us to track the spread of a disease with unprecedented precision, which will provide invaluable experience should anything more threatening begin to spread.

In the US, the CDC continues to monitor the situation; unfortunately, they update on Fridays using data from the end of the week prior, so the figures will undoubtedly be changed in under 24 hours, replaced by information that's going to be out of date by the time it appears. In any case, S-OIV is now in every state, with Wisconsin getting the worst of it. As of last week, there were 27 confirmed deaths associated with it.

There's every indication that this virus is now permanently part of the human disease landscape. There appears to be a reasonable chance that this virus will eventually settle down into a pattern similar to its seasonal relatives. Until that happens, however, it warrants careful surveillance, as there remains the possibility that it will pick up further mutations or swap pieces with a familiar flu virus to produce something that's far more threatening.

Evolution of the virus

That last prospect is more than a hypothetical, as the initial research indicates that S-OIV is a reassortment of two viruses that were themselves reassorted. As we mentioned in our discussion of influenza biology, it's possible for two viruses to exchange genetic material when they both infect the same cell, and that there is a regular background of these events going on in the wider flu habitat. Since then, two papers—an early one in Science and a more detailed one released by Nature today—have described how S-OIV was put together, and where and when it made the leap into humans.

The reassortment of the S-OIV genome
Image: Garten,, Science

As the diagram here shows, just about all of the genetic material can be traced back to different avian flu strains. Some of those went directly into pigs, some as far back as 1918—one of these spent some time circulating in humans before hopping over to pigs. The key event in the production of the current virus is what's called the "triple reassortment" that brought three of these together in a single virus, first detected in pigs in 1998. The final piece, which also has avian origins, was first detected in Belgian swine in 1979. Since then, it's appeared in various forms of Eurasian flu viruses that appeared in both pigs and humans, but never made the jump to the Americas or Australia.

That leaves the key question of when this combination of segments got together to form S-OIV, and in what species. The Nature paper provides a strong hint as to the answer by including a series of viral DNA sequences that were obtained in Hong Kong back in the early 1990s. These included seven different H1N1 subtypes (as well as eight H1N2s), including the Eurasian and triple reassortment strains, and there is evidence for extensive reassortment among them. For three of the viral genes, these samples have the most closely related sequences to the S-OIV version yet uncovered.

Seven of the eight gene segments in a 2004 Hong Kong isolate appeared to be a sister lineage to S-OIV. The authors calculate that S-OIV last shared a common ancestor with its fellow flu strains between 10 and 17 years ago, which would be consistent with a porcine Hong Kong origin. From there on out, the virus vanished, at least as far as human monitoring is concerned. The current virus has a common ancestor that existed no earlier than August of last year, and possibly as recent as January of this year.

There are a couple of things that can be concluded from this work, some of which the authors don't bother to address. One is that, with the emergence of every new virus, there seems to be a parallel production of conspiracy theorists who pin the blame on nefarious organizations. Everything about this one suggests normal flu evolution, though. The other thing is that many people blamed the initial outbreak of S-OIV on nearby factory farms. The simplest explanation for its low genetic diversity, however, suggests that it jumped to humans only once, and did so months before it made its presence known. It may have done so at a factory farm, but there's absolutely no way to tell from this data.

What the authors do conclude is that the internationalization of the food economy, which apparently brought pigs from distant locations together in places like Hong Kong, does increase the chance that we'll see further reassortments of the type that brought us S-OIV. And, as that's the case, the lack of monitoring of our porcine agricultural migrants might not be in our best interest. After all, it's a bit unnerving that the 21st century's first pandemic is caused by a virus that we misplaced for over a decade.

Science, 2009. DOI: 10.1126/science.1176225
Nature, 2009. DOI: 10.1038/nature08182

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