Hepatitis C virus (HCV) infection in humans is almost invariably associated with viral persistence and chronic hepatitis. Chronic hepatitis C is a major risk factor for the development of hepatocellular carcinoma. The high incidence of HCV persistence suggests that this virus has evolved one or more mechanisms to evade and possibly suppress T lymphocyte responsiveness. To understand the mechanism(s) involved in the establishment of HCV persistence, we have identified HCV core protein as an immunomodulatory molecule capable of suppressing host immune response. To investigate a molecular basis of HCV core-mediated immune suppression, we identified a gene encoding the C1q complement receptor, gC1qR as a host target, which binds HCV core protein by the yeast two hybrid in our initial attempt to search for a host protein(s) capable of association with HCV core. Evidence has been obtained that this association is highly specific. C1q is a ligand of gC1qR and is involved in the early defense against infection and regulation of adaptive immunity. Like C1q, HCV core can inhibit the human T lymphocyte proliferative response. These observations lead to a hypothesis that the HCV core/gC1qR-mediated inhibition of T cell function may play a critical role in the establishment of HCV persistent infection. This proposal is to investigate the underlying mechanism for HCV core-mediated suppression of T cell function and analyze a structural basis for HCV core and gC1qR interaction. First, we will elucidate the mechanism involved in the inhibition of T lymphocyte proliferative response by HCV core. Second, we will further define and characterize the molecular interaction between HCV core protein and gC1qR. Lastly, we will characterize the inhibition of T cell function by core proteins from acute and persistent infection. The proposed studies will help to understand the mechanism for the establishment of HCV persistence. In addition, they will provide a basis for the rational design of vaccines and novel therapeutic agents to block the action of HCV core/gC1qR on suppression of T cell function.

Agency
National Institute of Health (NIH)
Institute
National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK)
Type
Research Project (R01)
Project #
5R01DK066754-03
Application #
7056219
Study Section
Special Emphasis Panel (ZRG1-GMA-2 (50))
Program Officer
Doo, Edward
Project Start
2004-07-01
Project End
2009-04-30
Budget Start
2006-05-01
Budget End
2007-04-30
Support Year
3
Fiscal Year
2006
Total Cost
$296,736
Indirect Cost
Name
University of Virginia
Department
Pathology
Type
Schools of Medicine
DUNS #
065391526
City
Charlottesville
State
VA
Country
United States
Zip Code
22904
Tang, Xi; Wagoner, Jessica; Negash, Amina et al. (2010) Functional characterization of core genes from patients with acute hepatitis C virus infection. J Infect Dis 201:912-22
Park, Sung-Jae; Hahn, Young S (2010) Regulation of host innate immunity by hepatitis C virus: crosstalk between hepatocyte and NK/DC. Rev Infect 1:151-157
Kassel, Rachel; Cruise, Michael W; Iezzoni, Julia C et al. (2009) Chronically inflamed livers up-regulate expression of inhibitory B7 family members. Hepatology 50:1625-37
Cummings, Kara L; Rosen, Hugo R; Hahn, Young S (2009) Frequency of gC1qR+CD4+ T cells increases during acute hepatitis C virus infection and remains elevated in patients with chronic infection. Clin Immunol 132:401-11
Cummings, Kara L; Waggoner, Stephen N; Tacke, Robert et al. (2007) Role of complement in immune regulation and its exploitation by virus. Viral Immunol 20:505-24
Yao, Zhi Qiang; Shata, Mohamed Tarek; Tricoche, Nancy et al. (2006) gC1qR expression in chimpanzees with resolved and chronic infection: potential role of HCV core/gC1qR-mediated T cell suppression in the outcome of HCV infection. Virology 346:324-37
Yao, Zhi Qiang; Waggoner, Stephen N; Cruise, Michael W et al. (2005) SOCS1 and SOCS3 are targeted by hepatitis C virus core/gC1qR ligation to inhibit T-cell function. J Virol 79:15417-29
Eisen-Vandervelde, Audrey L; Waggoner, Stephen N; Yao, Zhi Qiang et al. (2004) Hepatitis C virus core selectively suppresses interleukin-12 synthesis in human macrophages by interfering with AP-1 activation. J Biol Chem 279:43479-86
Yao, Zhi Qiang; Eisen-Vandervelde, Audrey; Waggoner, Stephen N et al. (2004) Direct binding of hepatitis C virus core to gC1qR on CD4+ and CD8+ T cells leads to impaired activation of Lck and Akt. J Virol 78:6409-19