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Hepatitis C drug overwhelms virus with flood of mutations - surprising mechanism may improve anti-viral treatments, UCSF study finds

One of the few drugs available to treat hepatitis C has been shown to kill viruses by generating a flood of new mutations that overwhelm the virus - a mechanism known as error catastrophe, according to a new study from researchers at University of California, San Francisco. The newly discovered mechanism for the drug ribavirin should help pharmaceutical companies to create more effective versions of the drug to cure a larger proportion of hepatitis C patients.

That ribavirin destroys viruses by generating excess mutations comes as a big surprise because viruses that the drug attacks, those with RNA as their genetic material, usually profit from their ability to mutate, said Shane Crotty, BS, a graduate student in UCSF's department of microbiology and immunology.

RNA viruses like HIV and the influenza virus use a naturally high mutation rate to avoid and escape most treatments and vaccines, Crotty explained. "These viruses are incredibly clever. They use mutations to get around almost anything. But we now see that ribavirin adds so many extra mutations to the virus, that it is pushed into a kind of genetic meltdown," he said.

Crotty's main co-investigators on the study were Craig Cameron, PhD, assistant professor of biochemistry and molecular biology at Pennsylvania State University, and Raul Andino, PhD, UCSF associate professor of microbiology and immunology.

Previously, researchers had suggested that ribavirin kills viruses by blocking an enzyme necessary to prepare the genetic subunits, known as nucleotides, which the virus uses to copy its genome, Crotty said. But this idea was never very convincing, because more potent inhibitors of this same enzyme were not effective against the same viruses, he said.

The seed for the new experiments, which are published in the December issue of Nature Medicine, came from the demonstration by Penn State's Cameron that the ribavirin molecule can take the place of a nucleotide, meaning
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Contact: Kevin Boyd
kboyd@pubaff.ucsf.edu
415-476-2557
University of California - San Francisco
7-Dec-2000


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