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2010

Using a Virusís Knack for Mutating to Wipe It Out
The New York Times, January 5, 2010
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Evolution is a virus’s secret weapon. The virus can rapidly slip on new disguises to evade our immune systems, and it can become resistant to antiviral drugs.

But some scientists are turning the virus’s secret weapon against it. They hope to cure infections by forcing viruses to evolve their way to extinction.

Viruses can evolve because of the mistakes they make when they replicate. All living things can mutate, but viruses are especially prone to these genetic errors. In fact, some species of viruses mutate hundreds of thousands of times faster than we do.

Many of the mutations that strike new viruses are fatal. Others only slow down their growth, and still others have no effect at all. A few mutations are beneficial, and the viruses that inherit those good mutations can swiftly dominate a viral population.

Viruses depend on this rapid evolution to infect a host successfully. Poliovirus, for example, enters the body in the gut and then moves into the bloodstream, muscles and, in a small fraction of cases, the nervous system.

Each time the virus moves into a new kind of tissue, natural selection favors those best suited to growing there. “The virus needs to have this genetic flexibility to adapt to its environments,” said Raul Andino, a virologist at the University of California, San Francisco.

But if a virus’s rate of mutation gets too high, mathematical studies suggest, it will suffer. “Most mutations are bad,” said Claus O. Wilke, an evolutionary biologist at the University of Texas. “And so by increasing the amount of mutations, you can decrease the number of good offspring.”

The defective offspring reproduce slower than their ancestors. After enough mutations pile up, the viruses can no longer replace their numbers. The entire population vanishes.

If increasing mutation rates can wipe out viruses, does that mean a mutation-increasing drug could cure a case of the flu? “People have thought about this idea for many years,” said Louis M. Mansky, a virologist at the University of Minnesota.

A decade ago, scientists began running experiments that suggested the idea just might work. In one study, Dr. Lawrence A. Loeb, a University of Washington geneticist, and his colleagues eradicated H.I.V. in vitro by applying a mutation-increasing drug to infected cells. Reporting their results, Dr. Loeb’s group dubbed this kind of attack “lethal mutagenesis.”

Lethal mutagenesis appealed to many scientists at first, because it seemed to be a radically new way to fight viruses. But 10 years after its initial successes, lethal mutagenesis has not made its way to the drug store. Scientists have had to grapple with difficult questions about whether lethal mutagenesis can be safe and effective.

“That’s a common thing in biomedical research,” Dr. Mansky said. “People get ideas, but then there are roadblocks and the excitement dies down.”

One roadblock was the fact that many of the drugs scientists used to cause lethal mutagenesis were too toxic to give to patients. And there was also something inherently risky about the very idea of lethal mutagenesis. After all, a drug that speeds up mutations in a virus might also speed up the mutations in its host cell. As a result, lethal mutagenesis could conceivably raise the risk of cancer.

Another problem with lethal mutagenesis is that viruses may be able to evolve resistance to it. Some studies suggest that viruses can evolve so that mutation-increasing drugs cannot interfere with them.

Dr. Andino and his colleagues have discovered another kind of resistance in polioviruses: they become more careful. These resistant strains have a lower mutation rate because their enzymes make fewer mistakes as they build new genes. “The enzymes take more time at each step,” he said.

A new paper to be published in the journal Genetics shows just how mysterious lethal mutagenesis remains. Researchers at the University of Texas tried to use lethal mutagenesis to kill off a virus called T7, which infects only E. coli. The scientists understand T7 very well thanks to two decades of careful research on the virus. They were able to make precise predictions about the effects of a mutation-increasing drug.

But T7 did not wither away as they had predicted. After evolving for 200 generations in the presence of the drug, the viruses ended up replicating 90 percent faster than their ancestors.

James Bull, a co-author of the new study, thinks it shows how unexpected virus evolution can be under lethal mutagenesis. Whether that evolution could pose a risk to patients is an open question. “I’m on the fence on whether that really is a problem,” Dr. Bull said. “But I think it’s worth looking at.”

Despite these challenges, a number of researchers see reason for optimism about lethal mutagenesis. Dr. Mansky, for example, has been inspired by studies in the last few years that revealed how our own bodies use a natural kind of lethal mutagenesis. People produce proteins, known by the acronym Apobec, that fight off H.I.V. infections. They do so by adding mutations to the viruses as they replicate.

“To me that was important,” Dr. Mansky said. “It said that cells have evolved a mechanism for fending off viruses with lethal mutagenesis.”

In recent years Dr. Mansky has been seeking to overcome one of the big hurdles with lethal mutagenesis: toxic side effects. In November, he and his colleagues reported wiping out H.I.V. in infected cells with a drug called 5-AZC. He chose the drug to test because doctors regularly prescribe it for precancerous blood disorders. Now that Dr. Mansky has demonstrated that an approved drug can cause lethal mutagenesis in H.I.V., he is moving forward with preclinical trials on people.

Other scientists are confident they will be able to find solutions to the other problems with lethal mutagenesis. One way to avoid the risk of cancer, for example, would be to design drugs that interfere only with replicating viruses but not host cells.

To eliminate the threat from evolving viruses, Dr. Wilke, of the University of Texas, advises a swift and brutal attack. “If you hit the virus hard and everything dies out in a couple generations, then everything is fine,” he said.

Lethal mutagenesis would be able to hit viruses even harder, Dr. Wilke argues, if it is part of a one-two punch. He points to studies like one published in November by Estaban Domingo of Autonomous University in Madrid and his colleagues.

Dr. Domingo first treated foot-and-mouth viruses with a drug that slowed their growth. Once the population had shrunk, he and his colleagues then gave the viruses a second drug to set off lethal mutagenesis. The viruses vanished much faster than they did when the scientists used lethal mutagenesis alone.

For Dr. Domingo, who has been studying mutation rates in viruses for more than three decades, the latest results suggest lethal mutagenesis will become a medical reality -- at least someday.

“We’re still really just halfway in the development of all these strategies,” he said. “But I’m hopeful that it can be done.”


Copyright 2010 The New York Times Company. Reprinted with permission.
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