Heads of Laboratories
Globally, at least 130 million people are 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, dissecting host responses to infection and developing new therapies and vaccines to fight HCV and other infectious diseases.
Although the first generation of specific anti-HCV inhibitors is poised to enter the clinic, additional drugs will be needed to combat resistance and target all genotypes. By mapping out the details of how HCV replicates, the Rice lab hopes to uncover new ways of stopping the infection. Traditionally, blocking the actions of essential enzymes has been key to generating effective antiviral drugs. The Rice lab analyzed the biochemistry and structure of several HCV proteins and revealed unexpected insights. A series of molecular “snapshots” has captured the viral helicase at work; understanding the mechanism of this important enzyme may facilitate efforts to block it. Critical interactions between the virus and host may also serve as therapeutic targets. The lab has pinpointed several such associations, including the identification of two receptors involved in HCV entry into cells. The Rice lab has also developed methods of watching HCV infection spread through a culture in real time, which may speed the identification of new therapeutics. Remarkably, collaborative efforts in the last years with investigators at Columbia University have led to the discovery of HCV-related viruses in horses and rodents. These new viruses offer intriguing opportunities for studying hepacivirus species restriction and tissue tropism.
A major roadblock to HCV antiviral drug and vaccine development is the lack of model systems that accurately mimic the complex environment of the human liver. In collaboration with researchers at the Massachusetts Institute of Technology, investigators in the Rice lab have shown that HCV can infect otherwise healthy human hepatocytes in culture. Unlike previous culture models, which depend on cancerous cells, studying HCV infection of normal liver cells may yield clues about how the virus causes disease. More recently, this work has been extended to studies of the viral life cycle in stem cellderived hepatocytes, which is paving the way toward personalized medicine approaches. Lab members have also identified a human protein that allows the virus to enter mouse cells. Based on this discovery, the group has developed small animal models that allow researchers to study HCV infection in vivo. Additional mouse models under development — including animals engrafted with human liver and immune tissues — will have broad implications for studies of HIV and other uniquely human pathogens.
The strategies that viruses use to escape from host defenses are of significant interest, as failure of the immune response can result in chronic disease. Even as the virus evades adaptive immunity, innate antiviral mechanisms may limit HCV replication and spread. The group has identified some of the cytokines and antiviral pathways that become activated in primary liver cells following HCV infection. The Rice laboratory is also interested in developing immunotherapeutic and prophylactic vaccines for HCV.
Exploiting innate cellular factors that block viral entry and replication is an additional strategy for developing antiviral therapeutics. The Rice laboratory has recently reported a comprehensive screen for antiviral activities of naturally occurring cellular defense proteins, termed interferon-stimulated genes (ISGs). Interestingly, unique combinations of these genes, or “ISG profiles,” were found to target different viruses. The lab aims to determine the mechanisms of ISG inhibition and to use these findings to interfere with virus growth.The zinc-finger antiviral protein (ZAP) is an ISG that potently inhibits the replication of members of the Alphavirus genus. Using the prototype alphavirus, Sindbis virus, as a model system, investigators led by Research Associate Professor Margaret R. MacDonald are working to understand ZAP’s mechanism and how it functions in concert with other ISGs. Dr. MacDonald is also investigating the role of cellular chaperone proteins in flavivirus RNA replication.
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 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 Cornell Medical College. Dr. Rice is a member of the National Academy of Sciences.
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