This application seeks continuing funding for the Hepatitis C Cooperative Research Center (HC-CRC) at the University of Southern California (USC) to coordinate and advance research toward understanding the replication infection. HCV is currently the major cause of chronic hepatitis in this country. Options for therapeutic intervention and prevention are limited. Continued funding will facilitate and expand the long-standing collaborative research activities at the USC HC-CRC. Four specific projects are proposed: 1. Study of the effects of HCV proteins on host functions. Emphasis will be placed on the effects of HCV proteins on the interferon activities, particularly the effect of viral E2 and NS5a proteins on host proteins mediating interferon actions. 2) Study of the immune modulation by the HCV core protein. By using an experimental model of adenovirus infection of mouse, we will study the effects of HCV core protein on TNF signaling, induction of cytotoxic T cells, antigen presentation and NK cell function in the liver. 3) Study of the mechanisms of HCV replication. We will develop in vitro cell culture systems for studying HCV replication. We will also study a novel HCV gene product discovered in Dr. Jing-Hsiung Ou's laboratory. 1) Study of the role of E2 and NS5a sequence variations in interferon resistance in patient populations. Furthermore, we will also study the role of NS5b mutations in the clinical resistance to ribavirin. These projects are expected to contribute to the understanding of viral pathogenesis and further improvement in therapies for HCV.

National Institute of Health (NIH)
National Institute of Allergy and Infectious Diseases (NIAID)
Research Program--Cooperative Agreements (U19)
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Special Emphasis Panel (ZAI1-LIG-M (M1))
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Koshy, Rajen
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University of Southern California
Schools of Medicine
Los Angeles
United States
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Liu, Helene Minyi; Aizaki, Hideki; Machida, Keigo et al. (2012) Hepatitis C virus translation preferentially depends on active RNA replication. PLoS One 7:e43600
Machida, Keigo; McNamara, George; Cheng, Kevin T-H et al. (2010) Hepatitis C virus inhibits DNA damage repair through reactive oxygen and nitrogen species and by interfering with the ATM-NBS1/Mre11/Rad50 DNA repair pathway in monocytes and hepatocytes. J Immunol 185:6985-98
Machida, Keigo; Liu, Jian-Chang; McNamara, George et al. (2009) Hepatitis C virus causes uncoupling of mitotic checkpoint and chromosomal polyploidy through the Rb pathway. J Virol 83:12590-600
Machida, Keigo; Tsukamoto, Hidekazu; Mkrtchyan, Hasmik et al. (2009) Toll-like receptor 4 mediates synergism between alcohol and HCV in hepatic oncogenesis involving stem cell marker Nanog. Proc Natl Acad Sci U S A 106:1548-53
Machida, Keigo; Kondo, Yasuteru; Huang, Jeffrey Y et al. (2008) Hepatitis C virus (HCV)-induced immunoglobulin hypermutation reduces the affinity and neutralizing activities of antibodies against HCV envelope protein. J Virol 82:6711-20
Lai, Chao-Kuen; Jeng, King-Song; Machida, Keigo et al. (2008) Hepatitis C virus NS3/4A protein interacts with ATM, impairs DNA repair and enhances sensitivity to ionizing radiation. Virology 370:295-309
Yu, Guann-Yi; Lee, Ki-Jeong; Gao, Lu et al. (2006) Palmitoylation and polymerization of hepatitis C virus NS4B protein. J Virol 80:6013-23
Aswad, Fred; Dennert, Gunther (2006) P2X7 receptor expression levels determine lethal effects of a purine based danger signal in T lymphocytes. Cell Immunol 243:58-65
Kawamura, Hiroki; Aswad, Fred; Minagawa, Masahiro et al. (2006) P2X7 receptors regulate NKT cells in autoimmune hepatitis. J Immunol 176:2152-60
Machida, Keigo; Cheng, Kevin T-H; Lai, Chao-Kuen et al. (2006) Hepatitis C virus triggers mitochondrial permeability transition with production of reactive oxygen species, leading to DNA damage and STAT3 activation. J Virol 80:7199-207

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