Heads of Laboratories
Maurice R. and Corinne P. Greenberg Professor
Laboratory of Virology and Infectious Disease
ricec@rockefeller.edu
Globally, an estimated 130 million people are chronically infected with hepatitis C virus (HCV), a major cause of acute hepatitis and chronic liver disease — including cirrhosis and liver cancer. No HCV vaccine is available and treatments are often ineffective. Dr. Rice’s lab focuses on understanding the mechanisms of virus replication, on dissecting pathogen interactions with host immune responses and on developing therapies and vaccines to fight HCV and other infectious diseases such as malaria.
Antiviral drugs that specifically inhibit HCV enzymes or processes have yet to reach the market, and current treatments for HCV infection are often ineffective and have significant side effects. Studies in the Rice lab are under way to pinpoint critical interactions between the host and the virus that may serve as therapeutic targets. Through this work, the Rice lab has identified two receptors involved in HCV entry into cells, defined novel RNA structures within the HCV genome that may interact with viral or cellular components and begun to map factors that influence the spread of viruses. Biochemical and structural analyses of several viral proteins have also revealed unexpected mechanisms and new targets for drug development. Work in the Rice lab continues to dissect the molecular biology of HCV entry, RNA replication and virus assembly and to discover essential interactions with host cell factors.
The Rice lab uses and develops new tools for studying the life cycle of HCV and other viruses. While researchers have been able to dissect the steps of viral RNA replication for years, recent advances have enabled them to recapitulate HCV infection in cell culture for the first time. What remains as a major roadblock to HCV antiviral development and vaccine research is establishing a small animal model in which researchers can study HCV replication, immunogenicity and resulting disease. Recent work in the Rice lab, however, has identified a human protein that allows the virus to enter mouse cells, a finding that represents the clearest path yet for developing such a model. The discovery means that scientists now have the complete list of cellular factors — a total of four — that the virus uses to enter human and nonhuman cells. Success in creating a small animal model for HCV will also have broad implications for developing vaccines for HIV, malaria and other uniquely human pathogens.
The strategies that HCV and other viruses use to escape from host defenses are also of significant interest, as failure of the immune response to combat HCV replication often results in chronic disease. Investigations led by Research Associate Professor Lynn Dustin are focused on B cell responses to HCV as well as immune abnormalities that appear to be caused by the virus. Her recent studies revealed that clonal activation drives B cell proliferation in some patients who have an immune manifestation of HCV termed mixed cryoglobulinemia. As well as escaping the immune system, HCV fights back against drugs that are being developed to block its replication. Studies are under way to learn how HCV evolves under drug selection, information that will be used to guide the construction of future therapeutic regimens. The Rice laboratory is also interested in developing immunotherapeutic and prophylactic vaccines for HCV, and to that end is exploring the development of vectors, based on Sindbis and yellow fever viruses, that can deliver genes from other pathogens into cells.
Exploiting innate cellular factors that block viral entry and replication may be an additional strategy for developing antiviral therapeutics. One such factor, designated the zinc-finger antiviral protein, or ZAP, is able to completely inhibit the replication of multiple members of the Alphavirus genus. Using the prototype alphavirus, Sindbis virus, as a model system, investigators led by Research Associate Professor Margaret MacDonald are currently working to understand this and other such inhibitory factors. Future studies aim to determine the mechanisms by which this inhibition occurs and to identify additional host genes that can interfere with virus growth.
CAREER
Dr. Rice received his Ph.D. in biochemistry in 1981 from the California Institute of Technology, where he was then a postdoctoral
research fellow from 1981 to 1985. Before he joined Rockefeller in 2000, he spent 14 years on the faculty of the Washington
University School of Medicine. Dr. Rice is executive and scientific director of the Center for the Study of Hepatitis C, an interdisciplinary
center established jointly by The Rockefeller University, NewYork-Presbyterian Hospital and Weill Cornell Medical College.
Dr. Rice is a member of the National Academy of Sciences.
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