"Now, if you've got a second mutation that fixes this problem in H274Y mutants," Bloom says, "you'll have a virus that grows very well and is resistant to Tamiflu. And that's bad-for us, not the virus."

The researchers discovered just such a secondary mutation-two of them, in fact-in the neuraminidase gene of Tamiflu-resistant seasonal flu strains dating from the 2007-2008 flu season.

Interestingly, an examination of flu sequences showed that the two secondary mutations had cropped up before the H274Y mutation had begun to spread. The existence of these "pre-adaptive mutations," say the researchers, permitted the survival and spread of subsequent occurrences of the H274Y mutation.

Genetic changes that set the stage for later adaptations may represent a fairly common event in evolution.

"This study shows how combining an understanding of molecular mechanisms underlying evolution with the extensive sequencing data on historical isolates of influenza virus can bring about a deeper understanding of the challenge that this virus presents to the human population," says Baltimore. "Only by marshaling a wide range of available information was it possible to understand why the virus could suddenly tolerate mutations that were previously deleterious. It shows that mutations are not necessarily 'good' or 'bad,' but that their effects may depend on the context in which they appear."

So far, the H274Y mutation has not become widespread in either the avian H5N1 influenza or the recent swine-origin influenza pandemic, although it has cropped up in isolated cases. "We hope that understanding the basis of the evolution of Tamiflu resistance in seasonal H1N1 might help in understanding what might be needed for H274Y to spread widely in these other strains as well," Bloom says.

Source: California Institute of Technology