BioEd Online

Influenza resistance to a powerful group of antiviral drugs, the adamantane family, has worryingly jumped from 2% to 90% in recent years around the world. This dramatic shift was initially attributed to drug selection pressure: throwing adamantane drugs at viruses should select for influenza strains that evade those drugs. But a new study hints that this isn't the cause of the increased resistance; instead it seems viruses developed the resistance on their own accord.

The result suggests that strategies to beat down emerging resistance through careful drug use might not always work. And it serves as a potent reminder to researchers of just how naturally adaptable viruses can be.

Under most circumstances, physicians would expect to see an antiviral drug function very effectively during early days of introduction. As viruses susceptible to the drug are beaten down, only the resistant strains remain, and it would be normal for the drug's effectiveness to begin to wane as resistant viruses proliferate. But this isn't what happened with adamantane.

When researchers at the US Centers for Disease Control and Prevention took a close look at adamantane resistance two years ago, they expected to find high levels of resistance in the United States, where an average of 1.5 million adamantane dosages were prescribed annually, and low levels in countries where adamantane has been rarely administered, such as New Zealand and Japan. Instead, they were shocked to discover adamantane resistance everywhere¹.

Single trick

To better understand this, a team of researchers led by the National Institutes of Health (NIH) in Bethesda, Maryland, examined a large international collection of viral genomes. They found that a single type of mutation was responsible for every case of resistance they studied. "If pressure from admantane use was behind this, we would have expected to see all possible resistance point mutations appear, but we only saw one," says Lone Simonsen, an epidemiologist at the National Institute of Allergy and Infectious Diseases.

By looking in detail at the full genomes of multiple viruses, the NIH team determined that this resistance-conferring mutation had hitch-hiked along with other genes that allowed the virus to escape immunologic detection. So the evolution of resistance to adamantane seemed to be an accidental by-product of the virus becoming better at its job, they report in Molecular Biology and Evolution².

The abrupt rise in resistance to 90% "does seem surprising", says Simonsen. But, she adds, it is in line with our understanding of how influenza evolves in bursts, through a series of 'bottlenecks' that restrict the populations' ability to survive.

Plan for it

There is no doubt that the selective pressure generated from drugs still plays a significant role in the emergence of drug resistance. But the adamantane case is a strong reminder that other forces are also at play.

Those factors will have to be accounted for in our disease-management strategies, says Edwin D. Kilbourne, emeritus professor of microbiology and immunology at New York Medical College. "This paper has great practical implications for planning for future pandemics, if they occur," he says.

Mark Miller, at the Fogarty International Center for Advanced Study in the Health Sciences in Bethesda agrees. And he adds that the work is also an important example of how useful it can be to share influenza data. "Virologists the world over have had a lot of difficulty sharing viral genomes," he notes. "This publication illustrates the power of a multinational collaboration where viruses and their whole genomes are shared to advance public health."