The researchers also used a technique in which they compared different types of mutations - those that do cause antiviral resistance and others that don't have that effect - to see which type of mutation is more common.

"We look at the ratio of mutations that do confer resistance vs. those that don't, and if the ratio is higher than 1, it means that change is being promoted by natural selection rather than chance. Something is driving the evolution of drug resistance," Janies said. "We could see that happening in seasonal influenza and in the data we have so far for pandemic influenza, as well.

"A Darwinian would say that something changed that made the Tamiflu-resistant strain more fit than the wild type," he said.

The group also examined mutations that alter these two strains of H1N1 viruses' responses to Relenza. Resistance to that drug is relatively rare, Janies said, which could be attributed to less frequent use of the drug or to the possibility that mutations leading to resistance to Relenza aren't tolerated by the virus itself, so those strains die off.

Janies noted that there is another phenomenon with flu that could further make the pandemic strains difficult to treat. In at least 50 geographic regions identified by the analysis, both seasonal and pandemic H1N1 viruses are co-circulating, including Tamiflu-resistant strains. Because the flu virus in general is not precise when it makes copies of itself, this means that a drug-susceptible pandemic strain might exchange a gene with a drug-resistant viral strain and add it to the new genome.

"And then we would have drug-resistant pandemic influenza without any mutation. It's a random swap of the whole gene," Janies said of this phenomenon, which is called reassortment.

"That's how we got into this situation with pandemic influenza. We have something that's called pandemic H1N1, but all of its internal genes are different. It underwent a few rounds of reassortment and it's a virus we've never seen before because its genome is highly reshuffled compared to seasonal H1N1. This same process could confer resistance to a drug," he said.

The researchers have plotted areas where pandemic influenza and drug-resistant seasonal influenza circulate together into Google Earth using software called Pointmap. Regions in the United States and Japan are among those in which pandemic flu isolates carry the Tamiflu-resistant mutation.

Source: Ohio State University