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

December 07, 2000

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 a virus would mistakenly insert ribavirin into newly formed copies of its RNA genome, Crotty said.

Crotty and his colleagues then found that this insertion of ribavirin into the virus' RNA created genetic mutations in a culture of the virus growing in cells in a petri dish. The more drug they added, the more mutations were generated, and as the number of mutations increased, fewer and fewer viruses survived, Crotty said. At the highest ribavirin concentrations tested, only one out of every ten million virus particles survived.

The idea of error catastrophe is not new, Crotty said, but this is the first time it has been demonstrated as a mechanism for a working drug.

Two pharmaceutical companies have already begun working with the study findings to develop a more effective form of ribavirin. Currently, ribavirin is prescribed together with the immune boosting drug interferon-alpha for patients who have hepatitis C, but it cures only about one-third of these cases.

The drug is also used to treat severe infections of newborns with the respiratory syncytial virus, which is the most common infection of the lower respiratory tract in children.

The companies will be searching for ribavirin-like molecules that generate mutations, but that also have different chemical features that could boost their effectiveness against hepatitis C, Crotty said. And because ribavirin's mechanism is unique among anti-viral drugs, companies will be searching for similar drugs that might work against other RNA viruses, Crotty said. "This paper shows that mutagenesis is a valuable anti-viral drug strategy. And it's reasonable to assume that there are other drugs like this out there, but until now we haven't known the right way to look for them," he said.
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Other investigators on the study were David Maag and Jamie Arnold, both graduate students in the department of biochemistry and molecular biology at Pennsylvania State University; Weidong Zhong, PhD, Johnson Lau, MD, and Zhi Hong, PhD, all from Schering-Plough Research Institute.

This study was supported by grants from the National Cancer Institute, the National Institute of Allergy and Infectious Disease. Shane Crotty is a Howard Hughes Medical Institute doctoral fellow.

University of California - San Francisco

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