The Rockefeller University » Hospital Centennial

Dissecting the Molecular Virology of Hepatitis C and Identifying New Targets for Therapies

Rice, Charles

In 1989 researchers discovered a new type of hepatitis virus. Initially called non-A non-B hepatitis, it contaminated the blood supply and caused liver disease in people who had received tainted transfusions. Tests to screen out infected blood were quickly put in place and, when scientists produced a clone of the virus's genetic material, it was presumed that studying the pathogen and developing effective therapies would be straightforward tasks. Unfortunately, the usual techniques did not work. Scientists couldn't coax the virus, now called hepatitis C (HCV), to replicate in laboratory-grown cells, and it didn't infect the standard animal models. In humans, the virus slowly damages the liver over many years, often leading to cirrhosis and then cancer. The difficulties of growing and studying the virus in the laboratory have made it much more difficult to develop an HCV vaccine and alternatives to current, frequently ineffective, therapies have not been found.

Over the last two decades, Rockefeller virologist Charles Rice (1952- ) and his team have begun to overcome these hurdles and made a series of ground-breaking advances that have pioneered techniques for growing this intractable virus, so that today it can be studied in laboratories around the world. In addition, Rice and colleagues have worked to clarify how HCV enters cells, replicates, and moves on to its next target. This research has established the basis for new therapies, providing hope for the 130 million people infected with HCV, 4 million of them in the United States.

Culturing a virus in cells in the laboratory makes it possible for scientists to study its life cycle, an essential step toward developing treatments. Rice and colleagues made an important discovery in 1996 when they identified a highly conserved sequence at the 3' end of the genome—an essential RNA element and potential therapeutic target. A year later, they created a chimpanzee-infectious molecular clone of the virus and subsequently an HCV replicon—an edited version of the virus's genome-that could replicate and produce HCV proteins efficiently in the laboratory. Another breakthrough came in 2005, when Rice and coworkers constructed a full-length HCV genome using another isolate, called JFH: for the first time, they could study HCV as it replicated and produced viral particles in cell culture. The next year they showed that this version of HCV could infect laboratory animals, and that virus isolated from these animals also was infectious.

With this genetically defined virus, scientists in the Rice laboratory are now combining genetic analyses in cell culture with biochemical techniques, structural biology, and research in animal models in order to understand every aspect of HCV biology and develop new means of preventing and treating the disease. In addition to HCV, Rice studies other viruses of the family Flaviviridae, including those that cause yellow fever, West Nile, and dengue fever, as well as animal pathogens such as bovine viral diarrhea virus. Rice has conducted pioneering work on a variety of RNA viruses, such as showing that flaviviruses belong to a separate family than alphaviruses, reporting the first nucleotide sequence of a yellow fever virus genome, and elucidating the mechanisms of replication and transcription of the alphavirus Sindbis virus.

Charles M. Rice received his BS from the University of California at Davis (1974) and PhD from the California Institute of Technology (1981). He was a postdoctoral research fellow at Caltech from 1981 to 1985. He joined the faculty of the Washington University School of Medicine in 1986. In 2000 Rice moved to Rockefeller, where he is Maurice R. and Corinne P. Greenberg Professor, Head of the Laboratory of Virology and Infectious Disease, and Scientific and Executive Director of the Center for the Study of Hepatitis C, an interdisciplinary center established jointly by The Rockefeller University, NewYork-Presbyterian Hospital, and Weill Medical College of Cornell University in New York City. Rice is an elected member of the U.S. National Academy of Sciences (2005).

Selected Publications

Grakoui A, McCourt DW, Wychowski C, Feinstone S, and Rice CM. Characterization of the hepatitis C virus-encoded serine proteinase: determination of proteinase-dependent polyprotein cleavage sites. J Virol, 1993, 67: 2832-2843
http://jvi.asm.org/cgi/reprint/67/5/2832

Grakoui A, McCourt DW, Wychowski C, Feinstone S, and Rice CM. A second hepatitis C virus-encoded proteinase. Proc Natl Acad Sci USA, 1993, 90: 10583-10587
http://www.pnas.org/content/90/22/10583.full.pdf+html

Kolykhalov AA, Feinstone SM and Rice CM. Identification of a highly conserved sequence element at the 3' terminus of hepatitis C virus genome RNA. J. Virol. 1996, 70: 3363-3371.
http://jvi.asm.org/cgi/reprint/71/10/7345

Kolykhalov AA, Agapov EV, Blight KJ, Mihalik K, Feinstone SM, and Rice CM. Transmission of hepatitis C by intrahepatic inoculation with transcribed RNA. Science, 1997, 277: 570-574

Blight KJ, Kolykhalov AA, and Rice CM. Efficient initiation of HCV RNA replication in cell culture. Science, 2000, 290: 1972-1974.

Lindenbach BD, Evans MJ, Syder AJ, Wölk B, Tellinghuisen TL, Liu CC, Maruyama T, Hynes RO, Burton DR, McKeating JA, and Rice CM. Complete replication of hepatitis C virus in cell culture. Science, 2005, 309: 623-626

Lindenbach, BD, Meuleman P, Ploss A, Vanwolleghem T, Syder AJ, McKeating JA, Lanford RE, Feinstone SM, Major ME, Leroux-Roels G, and Rice CM. Cell culture-grown hepatitis C virus is infectious in vivo and can be recultured in vitro. Proc Natl Acad Sci USA, 2006, 103: 3805-3809
http://www.pnas.org/content/103/10/3805.full.pdf+html

Evans MJ, von Hahn T, Tscherne DM, Syder AJ, Panis M, Wölk B, Hatziioannou T, McKeating JA, Bieniasz PD, Rice CM. Claudin-1 is a hepatitis C virus co-receptor required for a late step in entry. Nature, 2007, 446: 801-805

Ploss A, Evans MJ, Panis M, You H, de Jong Y, Gayinskaya V, and Rice CM. Human occludin is a hepatitis C virus entry factor required for infection of mouse cells. Nature, 2009, 457: 882-886

Links

Charles M. Rice, Laboratory of Virology and Infectious Disease
http://www.rockefeller.edu/research/abstract.php?id=143

Center for the Study of Hepatitis C
http://www.hepccenter.org/

The Life Cycle of the Hepatitis C Virus
http://www.rockefeller.edu/labheads/rice/abouthcv.php

Hepatitis C Virus: Twenty Years Later
http://www.mc.vanderbilt.edu/discoveryseries/speaker.html?sid=54&yearvar=2009

Hospital Centennial

Dissecting the Molecular Virology of Hepatitis C and Identifying New Targets for Therapies

Selected Publications

Further Reading

Links