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Inside the new flu virus

By Richard Knox — NPR's Morning Edition, May 7, 2009

A crash effort to analyze the genes of the swine flu virus has revealed that it first emerged in humans last year — most likely last fall.

"The consistent range we're getting out is the second half of last year — between June and December," says Oliver Pybus of Oxford University. "The best estimate is the middle of that range, kind of September."

That means the newly recognized virus has been hiding in plain sight for the past eight months or so. Researchers say it probably had been circulating in Mexico and causing disease there, but its presence was masked by cases of regular flu and the absence of lab tests to identify the newcomer.

A Dizzyingly Complex Virus
Genetic analysis of the swine flu virus is proceeding at a furious pace, abetted by the Internet. The research is not only yielding early insights about the virus's lineage and age, but scientists say the work will also be crucial in tracking how the virus is evolving and what sort of threat it may represent over the coming months.

Pybus is one of 11 scientists around the world who've been digging through genetic data on thousands of animal and human flu viruses and sharing it with each other on a new swine flu wiki. This is the fastest a new flu virus has ever been identified and placed on a family tree that's dizzyingly complex.

"This has got to be the way this happens from this point forward," says Michael Worobey of the University of Arizona, another member of the spontaneous new collaboration, which includes groups from Hong Kong to Edinburgh and Tucson, Ariz., to Gainesville, Fla.

Where Did The Virus Come From?
The effort has already shed considerable light on where the new-found virus came from and over what period it evolved. Its great-grand-daddy was what flu scientists call a "triple reassortant" a three-fer virus made up of genes from a seasonal human flu virus of the H3N2 family, a North American bird virus and a classic swine virus.

The three separate viruses got together in a pig somewhere. When all three ancestor viruses infected the same pig cell, that enabled them to swap genes, a trick flu viruses specialize in.

"Pigs are special because they are easily infected with swine viruses, avian viruses and human viruses," says Joan Nichols of the University of Texas in Galveston. "That makes pigs a mixing pot." The pot keeps boiling, genetically speaking, because flu viruses are notoriously mistake-prone as they replicate within a bird or mammalian "host."

"This virus doesn't have a proof-reading mechanism, so it makes a lot of sloppy little mistakes along the way," Nichols says. Some viruses with those "mistakes" survive and thrive because the mutations allow them to spread more efficiently or infect another species. Other mutations cause more severe disease in the virus's hosts.

A Flu Stew
Scientists say the swap meet that gave rise to the newly discovered swine flu virus happened 10 or 20 years ago. That "triple reassortant" spread among swine for years, but it wasn't yet able to spread among people. It acquired that ability only last year, when the old "triple reassortant" combined again with two other pig viruses that circulated in North American and Eurasian swine.

That created the virus that's currently bedeviling the world. The new collaborative group calls it A/California/04/2009 because it was first identified near San Diego in April 2009. It is, in fact, mostly a swine virus with human and bird elements.

Pybus says it really should be called the "gallimaufry" virus. That's a 16th century French word that means "stew" or "hodgepodge."

Finding Clues For Next Flu Season
Scientists will track genetic changes and correlate them with the kinds of disease it causes in the Southern Hemisphere, where the flu season begins this month. So far the swine flu virus has begun to turn up in Costa Rica, Colombia, El Salvador and Guatemala.

"We're going to be actively monitoring what it does as it moves through the population," says Joan Nichols. "As it turns around and comes back to us in the fall, we'll know much more about it."

If it starts causing severe and fatal disease at a high rate in the Southern Hemisphere, that will be obvious enough. Scientists will quickly analyze viruses from such cases to see if they can identify the genetic changes that correlate with increase virulence.

But unfortunately, the absence of such an obvious signal this summer may not mean the virus won't evolve into a pandemic killer in the fall. That's because researchers know relatively little about the genes that confer virulence.

Jeffrey Taubenberger of the National Institute of Allergy and Infectious Diseases knows as much about virulence in flu viruses as anyone. He led an effort to reconstruct the killer virus of 1918, which has enabled scientists to probe what made it so dangerous.

Taubenberger says virulence doesn't appear to reside in a particular gene mutation. Instead it comes from the interaction of still-unknown genetic elements, which he calls "a constellation effect."

"Virulence and other behaviors are totally dependent on the overall makeup of the virus," Taubenberger says.

Nichols says the only solution is to watch the newly discovered virus obsessively in the coming months. "Remember," she says, "this virus hasn't stopped. It's just begun."

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