Cultured HCV Infects Cells and Primate Model

Abstract

In what may be a landmark year for hepatitis C virology, scientists reporting in the journal Nature Medicine have demonstrated for the first time that high levels of hepatitis C virus grown in cell culture can infect both cells and primates. The new report appeared less than 1 week after online publications from 2 other laboratories, one led by Dr. Frank Chisari of Scripps Research Institute and the other by Dr. Charles Rice of Rockefeller University, offering evidence of cell culture systems that can grow relatively high levels of HCV, which can infect cells. “Our paper clearly demonstrates that the virus produced in tissue culture can be infectious in chimpanzees,” said Dr. T. Jake Liang, Chief, Liver Disease Branch at the National Institute of Diabetes and Digestive and Kidney Diseases. According to Liang, the paper was a collaborative effort between his group at NIDDK and groups in Japan and Germany, led respectively by Dr. Takaji Wakita of the Tokyo Metropolitan Institute for Neuroscience and Dr. Ralph Bartenschlager of the University of Heidelberg. “One could say that our paper is the complete study, in that that it shows what we produced in tissue culture, this particular clone, is infectious both in tissue culture and in animals,” Liang says. In their successful findings, the 3 papers exploited the same HCV isolate. In 2001, Wakita et al published a report in the Journal of Medical Virology describing an HCV isolate from an HCV-infected patient who developed fulminant hepatitis and then, unexpectedly, cleared the virus. Wakita’s group soon showed that a replicon (so-named because it carries all the information needed to copy itself) made from the nonstructural regions of this virus worked in cell lines, as well as replicons developed previously that had adaptive mutations. In the Nature Medicine report, Wakita et al note that earlier attempts to infect a human hepatoma cell line (Huh7) with sera from infected individuals had not been successful. “But recombinant viral particles have a homogeneous density, whereas HCV in human sera shows much lower and heterogeneous densities, suggesting an association with cellular components, especially lipoproteins, that may interfere with infection,” the authors state. According to the report, recombinant viral particles have a density of about 1.15–1.17 g/mL and a spherical morphology with an average diameter of about 55 nm. While secreted virus was infectious for Huh7 cells, the authors say infectivity can be neutralized by CD81-specific antibodies and by immunoglobulins from chronically infected individuals (Figure 1). They add that further studies are required, “to analyze the mechanism underlying the different infectivities of recombinant and serum-derived virus particles, especially using the serum from JH1 virus-infected chimpanzee.” “This system is a powerful tool for studying the viral life cycle and for developing antiviral strategies,” the report concludes. For more details, see Nature Medicine 2005;11(July 2005) Proceedings of the National Academy of Sciences (PNAS) Early Edition; http://www.sciencemag.org/cgi/content/abstract/1114016