Hepatitis C virus (HCV) infection in humans is remarkably efficient in the establishment of persistent infection by evading host immune surveillance. HCV persistent infection is a major risk factor for the development of hepatocellular carcinoma and autoimmune disease. The high incidence of persistent infection with HCV suggests that this virus has evolved one or more mechanisms to evade and possibly suppress the host immune response. Indeed, HCV core protein, one of HCV viral proteins, has been reported to contain the immunomodulatory function. Human hepatocyte cell line expressing HCV core protein has been reported to upregulate HLA-E, ligand of NK inhibitory receptor, possibly leading to NK dysfunction. However, the mechanism of HCV core-mediated NK cell dysregulation in vivo is yet to be defined. To dissect the molecular mechanism of immune modulation by HCV core, we have developed a murine model of Core-Tg mice by directing the expression of HCV core protein in hepatocytes. In our prior studies, we demonstrated that anti-viral CD8+ T cell function was impaired in Core-Tg mice following Ad-LacZ infection. In addition, the in vivo depletion of NK cells recovered impaired CD8+ T cell function in core-Tg mice. Based on these findings, we hypothesize that HCV core-expressing hepatocytes induce NK inhibitory function to impair antiviral CD8+ T cell responses via NK-mediated alteration of DC activation. In order to test this hypothesis and further investigate the mechanism of NK-mediated inhibition of antiviral CD8+ T cell responses, we will first determine the kinetics of NK cell recruitment and their differentiation in the liver of Core- Tg mice. Second, we will characterize the signaling event involved in the inhibitory NK function in Core-Tg mice. Lastly, we will explore the mechanism for impaired CD8+ T cell responses by NK-DC crosstalk in Core-Tg mice.

Public Health Relevance

This project will identify the role of host NK cells in regulating anti-viral activity of CD8 T cells that is critical for clearing viral infection. It focuses on suppression of CD8 T cell responses by HCV viral product, core protein in the liver environment. In addition, our studies will elucidate a potential mechanism for HCV-mediated suppression of CD8 T cell responses. HCV infection is a major problem for human health worldwide and is remarkably efficient in establishing persistent infection. It is believed that the high rate of HCV persistent infection is possibly due to the impaired CD8 T cell responses. Thus, understanding the mechanism of HCV-mediated suppression of CD8 T cell responses will lead to better HCV treatment and vaccines. 1

Agency
National Institute of Health (NIH)
Institute
National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK)
Type
Research Project (R01)
Project #
5R01DK063222-07
Application #
7795259
Study Section
Innate Immunity and Inflammation Study Section (III)
Program Officer
Doo, Edward
Project Start
2003-06-01
Project End
2012-03-31
Budget Start
2010-04-01
Budget End
2011-03-31
Support Year
7
Fiscal Year
2010
Total Cost
$254,975
Indirect Cost
Name
University of Virginia
Department
Microbiology/Immun/Virology
Type
Schools of Medicine
DUNS #
065391526
City
Charlottesville
State
VA
Country
United States
Zip Code
22904
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Krueger, Peter D; Kim, Taeg S; Sung, Sun-Sang J et al. (2015) Liver-resident CD103+ dendritic cells prime antiviral CD8+ T cells in situ. J Immunol 194:3213-22
Ely, Kenneth H; Matsuoka, Mitsuo; DeBerge, Matthew P et al. (2014) Tissue-protective effects of NKG2A in immune-mediated clearance of virus infection. PLoS One 9:e108385
Dolina, Joseph S; Braciale, Thomas J; Hahn, Young S (2014) Liver-primed CD8+ T cells suppress antiviral adaptive immunity through galectin-9-independent T-cell immunoglobulin and mucin 3 engagement of high-mobility group box 1 in mice. Hepatology 59:1351-65
Dolina, Joseph S; Sung, Sun-Sang J; Novobrantseva, Tatiana I et al. (2013) Lipidoid Nanoparticles Containing PD-L1 siRNA Delivered In Vivo Enter Kupffer Cells and Enhance NK and CD8(+) T Cell-mediated Hepatic Antiviral Immunity. Mol Ther Nucleic Acids 2:e72
Tosello-Trampont, Annie-Carole; Landes, Susan G; Nguyen, Virginia et al. (2012) Kuppfer cells trigger nonalcoholic steatohepatitis development in diet-induced mouse model through tumor necrosis factor-? production. J Biol Chem 287:40161-72
Krueger, Peter D; Lassen, Matthew G; Qiao, Huihong et al. (2011) Regulation of NK cell repertoire and function in the liver. Crit Rev Immunol 31:43-52
Lassen, Matthew G; Lukens, John R; Dolina, Joseph S et al. (2010) Intrahepatic IL-10 maintains NKG2A+Ly49- liver NK cells in a functionally hyporesponsive state. J Immunol 184:2693-701
Lukens, John R; Dolina, Joseph S; Kim, Taeg S et al. (2009) Liver is able to activate naïve CD8+ T cells with dysfunctional anti-viral activity in the murine system. PLoS One 4:e7619
Lukens, John R; Cruise, Michael W; Lassen, Matthew G et al. (2008) Blockade of PD-1/B7-H1 interaction restores effector CD8+ T cell responses in a hepatitis C virus core murine model. J Immunol 180:4875-84

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