FORGET survival of the fittest. For viruses, the winning mantra may be closer to survival of the sloppiest. An experiment with polio viruses suggests that being too good at copying genes can be a pathogen鈥檚 undoing.
Viruses that carry their genes as RNA rather than DNA have no equipment for proof-reading their genome when it is copied. The RNA polymerase enzymes that do the copying make mistakes, so whenever they infect an organism and replicate, they also produce a swarm of mutant virus particles.
Virologists suggested in the 1990s that instead of being a burden, this swarm of 鈥渜uasi-species鈥� might help the virus if it produces individuals with a variety of methods for defeating host defences. This has been modelled mathematically, but never shown experimentally. Now Raul Andino at the University of California, San Francisco, and his colleagues have done just that.
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They discovered a strain of polio virus with a high-fidelity RNA polymerase, which makes three to four times fewer mistakes than the average for polio. It is not very good at infecting mice, and can鈥檛 even cross the tissue barrier that keeps intruders in the blood from entering the brain and spinal cord. This is where polio replicates most successfully and is what paralyses polio victims.
When the team restored the genetic haphazardness of the virus artificially by treating it with a mutagenic drug, it was restored to full virulence. The team then took samples of the virus from the mice鈥檚 brains, and used them to infect more mice. This time, without the boost of artificial mutation but still saddled with a sternly proficient polymerase, it was once again reduced to a wimp. But when they gave mice that wimp, plus ordinary polio, both strains entered the brain (Nature, DOI: 10.1038/nature04388).
鈥淰iruses can be seen as communities with diverse talents, like humans or ants鈥�
鈥淭his is the first time anyone has managed to manipulate the diversity of the virus on its own,鈥� says team member Marco Vignuzzi. 鈥淚nstead of the concept of the fittest virus, we see an army of different individuals with different roles that together allow the virus to move on.鈥�
鈥淰iruses can be envisaged as communities with diverse talents, like humans or ants,鈥� says Andino. He says the community must defeat numerous host defences simultaneously in order to move through the body, replicate and jump to a new host. One virus might decoy elements of the immune system such as macrophages, he speculates, while another causes an inflammation that opens the blood-brain barrier.
But this vision of a cooperative viral attack not only revolutionises our understanding of how viruses operate 鈥� it might also help us defeat them. For example, Vignuzzi suggests equipping the live, weakened viruses used for vaccines with high-fidelity polymerases to make them less able to mutate back into dangerous forms.
Meanwhile, some antiviral drugs employ the opposite tactic. If viruses are overly sloppy during RNA replication, they generate too many defunct progeny to survive. Drugs that produce extra mutations can push viruses with high mutation rates over the edge. The polio study suggests that these drugs may have the double benefit of creating a selection pressure for viruses that make fewer mistakes 鈥� and are also less aggressive. If an infection evolves in this direction, it might lose the diversity it needs to continue.
The work has important implications for other viruses such as flu, which has resisted efforts to pinpoint the specific mutations that make some strains more deadly. Perhaps, suggests Vignuzzi, it isn鈥檛 specific mutations per se that matter, but the ability to generate lots of them in the course of an infection.
Recent studies have credited polymerases with all or part of the deadliness of the Asian H5N1 flu and the 1918 pandemic flu. It is possible, says Andino, that their virulence came from sloppy copying.
