TO BEAT off invading viruses, our cells may unleash a bizarre weapon – a “mutator protein” that sneaks inside certain viruses and riddles their genome with mutations when they attempt to replicate in another cell.
“We think this protein amounts to an ancient and previously undiscovered part of the immune system,” says Reuben Harris of the MRC Laboratory of Molecular Biology in Cambridge, UK. The AIDS virus, unfortunately, has evolved an effective defence. But the discovery could lead to drugs or vaccines that tip the balance back in favour of the body.
The researchers were trying to solve a persistent mystery about HIV: the function of a protein called virion infectivity factor, or Vif. “Without it HIV can’t infect cells,” says Hui Zhang of Thomas Jefferson University in Philadelphia. “Yet after a decade of research no one really knew why.”
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But last year, a clue came when researchers isolated an antiviral factor from human cells called APOBEC3G, whose sequence suggested it was related to proteins that can mutate DNA and RNA. Genetic studies showed that APOBEC3G (also called CEM15) attacks DNA by transforming one letter of the DNA code, cytosine or C, into another normally found only in RNA, uracil or U. While HIV’s genome is made of RNA, when it infects cells the virus creates a DNA copy to insert into the host’s genome.
This implied that Vif’s purpose is to counteract this mutational attack on the DNA copy of HIV. Sure enough, in mid-May a French group announced that in the absence of Vif, HIV did suffer from “hypermutation” (Science, vol 300, p 1112).
But that did not prove that APOBEC3G was responsible for the hypermutation. Now three teams – Harris’s team in the UK, Zhang’s team in the US and a Swiss group – have created cells with and without APOBEC3G to prove that hypermutation of HIV occurs only when the mutator protein is present (Cell, vol 113, p 803; Nature, DOI: 10.1038/nature01707 and DOI: 10.1038/nature01709).
The mutator protein also targets other viruses related to HIV, suggesting it is a ubiquitous defence mechanism. The protein’s ability to morph cytosine into uracil not only scrambles gene sequences in viruses, but may slow their replication. This suggests that drugs that boost the mutator’s activity could help treat many viral infections.
Conversely, blocking its activity could also be an effective strategy against HIV. The AIDS virus is famous for its ability to mutate quickly and develop resistance to drugs. But Zhang’s work suggests that these mutations are created by APOBEC3G molecules whose action has been toned down by Vif. “HIV hijacks the cell’s DNA mutator weapon to serve its own purpose,” he says.
The discovery also has implications for gene therapy. If viruses designed to deliver genes are grown in cells that produce mutator proteins, Harris says, many of the viruses could be rendered useless or deliver scrambled versions of the desired genes.