The work in Dr. Rice’s laboratory is directed at understanding major questions about the viral lifecycle, how the host fights back and how the virus counters the host response. The Rice lab uses several new tools for these studies, including a robust system for recapitulating HCV infection in cell culture; replicon systems, which allow dissection of the steps in viral RNA replication and protein processing; and animal and/or cell culture models for each virus. Studies in the Rice lab are under way to identify receptors involved in cell attachment and entry by HCV and to identify steps in cell entry for HCV, bovine viral diarrhea virus, yellow fever virus and alphaviruses, with the goal of pinpointing critical interactions that may serve as therapeutic targets.

Biochemical analyses of the viral proteins, their structures and functions, performed in the Rice lab, have revealed several unexpected mechanisms and new targets for drug development. In addition, the mechanisms of viral polyprotein processing are under study and Dr. Rice aims to identify new targets for therapeutic intervention in this arena. Finally, the lab identified novel viral RNA structures that may interact with HCV proteins or RNA, or with cellular structures important in viral replication.

In addition, Dr. Rice is working to identify host factors that block viral entry or replication. Led by Research Associate Professor Margaret MacDonald, investigators are using the prototype alphavirus, Sindbis virus, as a model viral system to identify inhibitory factors and are currently studying the mechanism by which exogenous expression of 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. Future studies will be directed at identifying additional host genes or viral sequences that can interfere with alphavirus replication and determining the mechanism by which this inhibition occurs.

A major roadblock in HCV antiviral development and vaccine research is establishing a small animal model where HCV replication, immunogenicity and pathogenesis can be studied. The Rice lab is working with an international consortium, funded by a Gates Foundation Grand Challenges grant, on methods to implant human liver cells and immune cells in mice. Success in creating such an animal model for HCV will have broad implications for developing vaccines for HIV, malaria and other uniquely human pathogens.

A group led by Research Associate Professor Lynn Dustin is studying the B cell response and extrahepatic manifestations of HCV infection. Studies of lymphocytes from HCV-infected patients and normal controls, as well as in vitro models, are under way in order to learn how HCV infection affects B lymphocyte function. The Rice laboratory is also interested in developing immunotherapeutic and prophylactic vaccines, and to that end researchers in the lab are exploring opportunities to develop and use Sindbis and yellow fever virus vectors for gene expression and gene delivery applications in vitro and in vivo.

Dr. Rice also is interested in learning what strategies HCV and other viruses use to escape the immune system and the host response. Because HCV also fights back against drugs developed to block HCV replication, studies are under way to learn how HCV evolves under selection by antiviral drugs. A goal of these studies is to predict what changes HCV will manifest during drug treatment, and to use this information to guide the development of future antiviral drugs.

CAREER

Dr. Rice received his Ph.D. in biochemistry in 1981 from the California Institute of Technology, and then was a postdoctoral research fellow at the institute 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 scientific director of the Center for the Study of Hepatitis C, an interdisciplinary center established jointly by The Rockefeller University, New York-Presbyterian Hospital and Weill Medical College of Cornell University in New York City. Dr. Rice is a member of the National Academy of Sciences.