.:Center for Hepatitis Research: .

STANLEY M. LEMON, M.D.

Professor of Microbiology & Immunology and Internal Medicine
Molecular virology and pathogenesis of hepatitis C and hepatitis A virus infections

Phone: (409) 747.6500 | Fax: (409) 747.6514 | E-mail: smlemon@utmb.edu
Websites: http://www.utmb.edu/ihii | http://www.utmb.edu/gnl

"The research in my lab focuses on the molecular pathogenesis of hepatitis C . We are interested in understanding the mechanisms of viral RNA replication and infectious particle assembly, the molecular basis of liver injury in the context of viral replication, and the mechanisms by which the virus eludes the innate immune system to achieve persistent virus infection. "

RESEARCH INTERESTS

The research in our lab focuses on the molecular pathogenesis of hepatitis C. We are interested in defining the structure of the RNA segments that control the initiation of translation as well as those that are recognized by the replicase complex to initiate viral RNA synthesis. We are thus dissecting the mechanisms of hepatitis C virus RNA replication, and the process of infectious particle assembly. Toward that end, we have developed robust, cell-culture based hepatitis C virus RNA and, more recently, virus replication systems, that allow structure-function correlates to be studied using reverse molecular genetics. We are also interested in mechanisms of hepatocellular injury in chronic hepatitis C. We have developed transgenic mouse models of hepatitis C-related liver injury, including hepatocellular carcinoma, and have constructed hepatoma-derived and other cell lines with conditional expression of hepatitis C virus proteins. We are using these cells and our infectious virus systems to study the effects of hepatitis C virus protein expression on post-transcriptional regulation of the retinoblastoma tumor suppressor protein and its effect on host cell proliferation and chromosomal stability. We are also interested in the mechanisms by which hepatitis C virus evades intrahepatic innate cellular immune defenses. We have shown that the NS3/4A serine protease directs the cleavage of a key Toll-like receptor adaptor protein, TRIF, resulting in an effective blockade of dsRNA-induced activation of the transcription factors interferon regulatory factor 3 (IRF-3) and NF-kB and their cognate gene targets. The protease recognizes TRIF through a unique molecular interaction that differs from its recognition of natural viral polyprotein substrates, and also cleaves IPS-1, a recently recognized signaling protein, thereby disrupting a second, TRIF-independent pathway leading to interferon synthesis that is initiated by and dependent upon the cellular DExH(D) RNA helicase, RIG-I. We interact closely with Dr. Kui Li in the Center in studying interactions of hepatitis C virus with the innate immune system,; with Dr. Steve Weinman in investigating the role of hepatitis C core protein expression in mitochondrial injury in hepatitis C, and with Drs. Tehsheng Chan and Jiaren Sun in the construction and evaluation of inducible transgenic mouse models in which cellular responses to hepatitis C virus proteins can be studied.

PUBLICATIONS

E. Foy, K. Li, C. Wang, R. Sumpter, Jr., M. Ikeda, S.M. L emon, and M. Gale, Jr. Inhibition of interferon regulatory factor-3 activation by the hepatitis C virus serine protease. Science 300: 1145-1148, 2003.
K. Li, E. Foy, J. C. Ferreon, M. Nakamura, A. C. M. Ferreon, M. Ikeda, S. C. Ray, M. J. J. Gale, and S. M. Lemon. Immune evasion by hepatitis C virus NS3/4A protease-mediated proteolysis of the TLR adaptor protein TRIF. Proc. Nat’l. Acad. Sci. USA 102:2992-7. 2005.
J.C. Ferreon, A. C. M. Ferreon, K. Li, and S. M. Lemon. Molecular determinants involved in TRIF proteolysis by the hepatitis C virus NS3/4A protease. J. Biol. Chem. 280:20483-92, 2005
C.L. Jopling, M.Y. Yi, A.M. Lancaster, S.M. Lemon, and P. Sarnow. Modulation of hepatitis C virus RNA abundance by a liver-specific microRNA. Science 309:1577-1581, 2005
T. Munakata, Y. Liang, M. Nakamura, K. Li, and S. M. Lemon. Down regulation of the Rb tumor suppressor by the hepatitis C virus NS5B RNA-dependent RNA polymerase. Proc. Nat’l Acad. Sci. USA, in revision, 2005.

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