Cut and paste. The full HCV virus (genome at top) doesn't replicate well in the lab; a trimmed and mutated replicon version (bottom) does.

'Replicon' Yields Hepatitis C proteins

The virus that causes hepatitis C (HCV) has frustrated researchers because of its stubborn refusal to grow in the lab. Without a plentiful supply of the virus, researchers have had a tough time figuring out how the virus causes infection and how to combat it with drugs. Now a team has partly overcome this problem: They created an improved viruslike "replicon" that produces HCV proteins efficiently without relying on the virus itself.

Twelve years ago, researchers identified HCV as the elusive pathogen that was causing liver disease in some people who had received blood transfusions. Donated blood is now screened for the virus, reducing the number of new HCV infections. But an estimated 1% of the U.S. population has already been infected with the virus, which can persist in the body for many years. Over time, it can damage the liver and increase the risk of cancer.

Last year, Ralf Bartenschlager of the Johannes-Gutenberg University in Mainz, Germany, and colleagues reported that they'd made a replicon of HCV. In other words, they took the HCV genome apart and then reassembled it, editing out parts and adding new pieces (Science, 2 July 1999, p. 110). They removed genes that enable the virus to infect human cells, for instance, and tucked in other genes that allow the researchers to spot which host cells have taken up the replicon.

The replicon system was inefficient, however, producing HCV proteins in about 1 in a million host cells. To boost production, a team led by Charles Rice at Washington University in St. Louis rebuilt the system. They studied Bartenschlager's data, looking for genetic mutations that might enable the replicon to be more productive. They identified 10 mutations, one of which, called S1179I, was outstanding. Replicons with this mutation produced abundant viral proteins in one out of 10 host cells, the researchers report in the 8 December issue of Science.

The innovation has piqued the interest of both industrial and academic scientists, who are racing to develop treatments for hepatitis C. It should make it possible "for investigators to study the effects of antiviral drugs and host control mechanisms that regulate HCV replication," says Frank Chisari of the Scripps Research Institute in La Jolla, California.