Researchers show laboratory hepatitis C strain is also infections in animal models

An important step in developing a treatment for viral diseases is for scientists to culture live viruses from infected patients, but the hepatitis C virus (HCV), a major cause of chronic and sometimes fatal liver disease, has proven to be particularly wily. For many years scientists have struggled with an inability to efficiently culture HCV in the laboratory. Now, researchers at Rockefeller University have overcome several obstacles and successfully shown that a strain of HCV they created in the laboratory, which can efficiently be cultured in vitro, is also infectious in animals. The findings, reported in the March 7 issue of the Proceedings of the National Academy of Sciences, will enable scientists to study the life cycle of HCV at the molecular level and develop better treatments for this disease.

The researchers, led by Brett Lindenbach at Rockefeller and Philip Meuleman at Ghent University in Belgium, used a cell-culture version of HCV, developed by Lindenbach and colleagues at Rockefeller, called HCVcc. HCVcc, which was the first infectious cell-culture version of hepatitis C, was used to infect two chimpanzees as well as mice bearing human liver grafts. The researchers found that in both the chimpanzees and the mice, hepatitis C infection lasted for as long as 15 weeks. Also, the infections raised in the mice could be passed to other mice. Samples of the test tube-cultured strain could be recovered from infected animals and was easily recultured in vitro, unlike most other strains of HCV isolated from infected animals or people.

“The ability to study a genetically defined virus in the test tube and in living animals allows us to completely dissect the HCV life cycle,” says senior author Charles Rice, Maurice R. and Corinne P. Greenberg Professor and head of the Laboratory of Virology and Infectious Disease at Rockefeller.

The chimpanzees, which are housed at the Southwest National Primate Research Center in San Antonio, Texas, were previously used for studies of HIV and other strains of hepatitis, and were not infected with HCV before being inoculated with HCVcc. The mouse experiments, which took place at Ghent University, involved a strain of mice called uPA-SCID, which lack an immune system and mimic the liver failure that can accompany chronic hepatitis C infection in people.

In addition, the researchers found that the virus recovered from the experimentally infected animals had a higher infectivity than the original HCVcc. They also found that virus particles with a lower buoyant density — a measure of how well they float — had increased infectivity, suggesting that differences in the physical properties of the viruses grown in vitro and in vivo are important for biological activity.

These results show that it should be possible to culture HCV from clinical samples and provide a useful positive control to help isolate additional strains that grow in cell culture, Lindenbach and Rice say.

Proceedings of the National Academy of Sciences: 103(10): 3805-3809 (March 7, 2006)