Heads of Laboratories

Charles M. Rice, Ph.D.

Maurice R. and Corinne P. Greenberg Professor in Virology
Laboratory of Virology and Infectious Disease
Charles.Rice@rockefeller.edu

Research Lab Members Publications In the News

Faculty Bio

Charles Rice

Globally, an estimated 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. There is currently no HCV vaccine, and although new antiviral drugs were recently approved and are clinically available, more will be needed to combat resistance and target all genotypes. Dr. Rice’s lab focuses on understanding virus replication, host responses to infection and developing new therapies to treat HCV and other viral pathogens.

The Rice lab seeks new ways of blocking HCV infection by studying how the virus replicates. Traditionally, blocking the actions of essential viral enzymes has been key to generating effective antiviral drugs. With collaborators at the University of Missouri, the lab has been studying drug combinations and the mechanisms of drug resistance.  Dr. Rice’s group has also analyzed the biochemistry and structure of a number of HCV proteins, such as the viral helicase, the nonstructural protein NS5A, and the NS2-3 autoprotease. Since all are necessary for virus replication, understanding how they work may help in the design of new inhibitors that target these proteins.

Another of Dr. Rice’s research interests is the development and improvement of systems to propagate viruses in vitro and in vivo.  For example, growing HCV in cell culture has been difficult and restricted to only a few select genotypes and isolates.  Recently, the Rice group found that overexpressing selected host cell proteins allows growth of a broader number of HCV isolates, and studies of the mechanism by which these proteins promote replication are underway.  A collaborative effort with colleagues at the Massachusetts Institute of Technology has resulted in improved methods to infect otherwise healthy human hepatocytes in culture. Unlike previous culture models, which depend on cancerous cells, HCV infection of normal liver cells may more accurately reflect what happens in a patient and yield clues about how the virus causes disease.  More recently, this work has been extended to studies of the viral life cycle in stem cell-derived hepatocytes, which is paving the way toward personalized medicine applications.  Alongside improving culture systems, Dr. Rice’s group has pioneered new methods to concentrate HCV, enabling analysis of its structure and composition with electron microscopy, which in turn, will inform the design of vaccines and new drugs targeting virus particles. Additionally, the Rice lab has been developing an HCV-permissive transgenic mouse model, and also animals engrafted with human liver and immune tissues susceptible to HCV infection and capable of mounting human virus-specific immune responses.

The Rice lab is also interested in developing bioinformatic approaches to study host-virus interactions at a systems level.  Using novel techniques such as HITS-CLIP and RNAseq, the Rice lab is analyzing the role of cellular micro RNAs and RNA-binding proteins in regulating the replication of HCV and other RNA viruses.  Laser-capture microdissection of infected, uninfected, and bystander cells has allowed specific comparisons of the cellular responses at a genetic level.  Because these experiments can be applied in a variety of settings, such as different viruses, chronic vs. acute infection, different genotypes or cell types, they will help to illuminate the complex relationship between host and pathogen in a panoramic and genome-wide view.

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 viruses evade adaptive immunity, innate antiviral mechanisms may limit their replication and spread. Exploiting innate cellular factors that limit viral entry and replication is an additional strategy for developing antiviral therapeutics. The Rice lab 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. Understanding the mechanisms of ISG inhibition is a prerequisite to potential exploitation of these processes to interfere with virus growth, and mechanistic studies are underway. 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.

Together, all these investigations interrogate both sides of the virus-host cell relationship, with the overarching objective of designing efficacious new therapies and vaccines.  Additional studies underway on viral pathogens related to HCV, such as dengue virus, yellow fever virus, and influenza A virus will shed light on the specificities of their interactions with host cells.  They will also be broadly instructive toward novel strategies to tip the balance in the age-old warfare between pathogenic viruses and their hosts.

 

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 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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