Current experimental therapies for hepatitis C virus includes ribavirin and alpha-interferon; however, the responses to these therapies are variable. The factors determining the efficacy of the therapies are not known. The finding described in Project I that the HCV core protein interacts with members of tumor necrosis factor receptor (TNFR) family provides a potential basis for determining the efficacy of these therapies in different patients. This project will utilize abundant clinical resources available at USC medical facilities to examine four groups of patients: (1) patients with HCV infection and elevated serum aminotransferase (ALT) level; (2) patients treated with ribavirin; (3) patients treated with alpha-interferon; (4) patients coinfected with HIV and HCV. Liver biopsy specimens derived from these patients will be examined for the expression of various TNFRs, including TNFR I, TNFR II, lymphotoxin-beta receptor and Fas, CD30 and various HCV viral antigens. They will also be examined with respect to the lymphocyte subsets. Sera from these patients will be examined for HCV genotype and RNA level, and the possible presence of soluble CD30 and TNFR. These immunological parameters will be correlated with the patients' clinical status, including ALT level, responsiveness to interferon or ribavirin therapy. This study is linked closely with Project I, and provides clinical confirmation for the in vitro studies proposed in Project I. These studies may form the conceptual basis for the next generation of therapies for hepatitis C virus, which is one of the major goals of the proposed Hepatitis C Cooperative Research Centers. Furthermore, the experience of the P.I. for this project will enable close cooperation with other potential Hepatitis C Research Centers in the country.

Project Start
1999-08-01
Project End
2000-07-31
Budget Start
1997-10-01
Budget End
1998-09-30
Support Year
4
Fiscal Year
1999
Total Cost
Indirect Cost
Name
University of Southern California
Department
Type
DUNS #
041544081
City
Los Angeles
State
CA
Country
United States
Zip Code
90089
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
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
Dennert, Gunther; Aswad, Fred (2006) The role of NKT cells in animal models of autoimmune hepatitis. Crit Rev Immunol 26:453-73

Showing the most recent 10 out of 51 publications