This proposal is focused on the host-virus relationship in hepatitis C virus (HCV)-infected patients. Despite advances in our knowledge of the epidemiology and molecular virology of HCV, the mechanisms of hepatocellular injury and viral control are not well understood. Studies of the immunopathogenesis of HCV in patients with chronic HCV have been difficult. After infection is established, multiple factors influence the host virus interaction, resulting in a unique, individual disease pattern. Viral factors include replication efficiency, nucleotide substitution rates and viral heterogeneity. Host factors may include the competence of the innate immune system, local and systemic cytokine production, and the humoral and adaptive cellular immune responses. In most patients with chronic HCV infection, there is a growing body of evidence that the adaptive T cell immune response plays a major role in controlling HCV infection and contributing to hepatocellular damage. Evidence to date would suggest that the immune response to HCV is significantly impaired in patients chronically infected with HCV. The focus of this proposal is to evaluate the mechanisms of viral-specific T cell function and the factors that regulate them.
In specific aim #1, we will focus on the mechanisms by which CD8+ cells control HCV replication and the potential for viral interference via induction of T cell apoptosis and escape responses in the HCV replicon model. The HCV replicon system represents a unique in-vitro model that will allow detailed immunologic and viral analysis of CD8-hepatocyte interaction.
In specific aim #2, we will evaluate the critical role that CD4+CD25+ T regulatory cells play in viral persistence. We have performed the first detailed analysis of these Treg cells in HCV and believe they represent an important component in viral persistence. The experiments outlined in this proposal seek to evaluate the mechanisms of how Treg cells inhibit the HCV-specific T cell responses and the antigenic specificity of this response. This information will have significant impact on vaccine development strategies.
In specific aim # 3, we hypothesize that hepatitis C virus may alter the function of dendritic cells, leading to viral persistence. It is likely that impaired T cell responses in chronically infected patients may reflect an immunosuppressive mechanism linked to the ability of HCV to establish and maintain persistence after infection. A better understanding of the immunologic factors that determine resolution or persistence of the infection may help in the design of therapies and vaccines for the control of HCV infection.

Agency
National Institute of Health (NIH)
Institute
National Institute of Allergy and Infectious Diseases (NIAID)
Type
Research Project (R01)
Project #
1R01AI061158-01A1
Application #
6928917
Study Section
Special Emphasis Panel (ZRG1-IHD (01))
Program Officer
Koshy, Rajen
Project Start
2005-04-01
Project End
2009-12-31
Budget Start
2005-04-01
Budget End
2005-12-31
Support Year
1
Fiscal Year
2005
Total Cost
$278,269
Indirect Cost
Name
University of Florida
Department
Internal Medicine/Medicine
Type
Schools of Medicine
DUNS #
969663814
City
Gainesville
State
FL
Country
United States
Zip Code
32611
Firpi, Roberto J; Dong, Huijia; Clark, Virginia C et al. (2013) CC genotype donors for the interleukin-28B single nucleotide polymorphism are associated with better outcomes in hepatitis C after liver transplant. Liver Int 33:72-8
Clark, Virginia; Nelson, David R (2012) The role of ribavirin in direct acting antiviral drug regimens for chronic hepatitis C. Liver Int 32 Suppl 1:103-7
Yao, Luyu; Yan, Xiaobo; Dong, Huijia et al. (2011) Expression of an IRF-3 fusion protein and mouse estrogen receptor, inhibits hepatitis C viral replication in RIG-I-deficient Huh 7.5 cells. Virol J 8:445
Yao, L; Dong, H; Zhu, H et al. (2011) Identification of the IFITM3 gene as an inhibitor of hepatitis C viral translation in a stable STAT1 cell line. J Viral Hepat 18:e523-9
Cao, Mengde; Cabrera, Roniel; Xu, Yiling et al. (2011) Different radiosensitivity of CD4(+)CD25(+) regulatory T cells and effector T cells to low dose gamma irradiation in vitro. Int J Radiat Biol 87:71-80
Cao, Mengde; Xu, Yiling; Youn, Je-in et al. (2011) Kinase inhibitor Sorafenib modulates immunosuppressive cell populations in a murine liver cancer model. Lab Invest 91:598-608
Eksioglu, Erika A; Bess, Jennifer; Jones, Graham et al. (2010) Characterization of Anti-HCV Antibodies in IL-10-Treated Patients. Viral Immunol 23:359-68
Cao, Mengde; Cabrera, Roniel; Xu, Yiling et al. (2009) Gamma irradiation alters the phenotype and function of CD4+CD25+ regulatory T cells. Cell Biol Int 33:565-71