The goals of this project are to determine if the expression of the hepatitis C virus (HCV) core protein alters the ability of the immune system to cause hepatitis, and results in immune dysfunctions by altering the ability of the immune system to generate effectors.
The first aim i s to determine if expression of the core protein in hepatocytes alters their ability to be recognized by CD8+ and CD4+ immune effectors. This will be accomplished by adoptive transfer of NS5-specific immune effectors into transgenic (TG) mice expressing both NS5 and core protein under the control of a hepatocyte-specific promoter. These mice will be compared to mice expressing the NS5 gene only in hepatocytes.
The second aim i s based on Dr. Lai's data (Project I) showing the interaction(s) of the core protein with members of the tumor necrosis factor receptor family. TG mice expressing the core protein under control of the CMV promoter will be examined for immune defects related to alterations in receptor signaling. The hypothesis of the final aim is based on the findings that HCV infects both PBMC and bone marrow cells. Our hypothesis is that expression of the core protein in either macrophage antigen presenting cells or the T cells themselves leads to immune dysregulation. This ability to alter immune responsiveness facilitates HCV persistence. Tests of this aim hypothesis will initially use bone marrow chimeras to determine if expression of the core protein alters immune responsiveness. It will be pursued by specific expression of the core protein in either macrophages or in T cells using cell type specific promoters. This project will establish a small animal model system for studying the pathogenesis of HCV, which is one of the major goals of this center. This project interacts closely with Project I.

Project Start
1998-08-01
Project End
1999-07-31
Budget Start
1997-10-01
Budget End
1998-09-30
Support Year
3
Fiscal Year
1998
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

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