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Blockade of PD-1/B7-H1 Interaction Restores Effector CD8⁺ T Cell Responses in a Hepatitis C Virus Core Murine Model¹

Beirne Carter Center for Immunology Research, Department of Microbiology, University of Virginia, Charlottesville, VA 22908

The impaired function of CD8⁺ T cells is characteristic of hepatitis C virus (HCV) persistent infection. HCV core protein has been reported to inhibit CD8⁺ T cell responses. To determine the mechanism of the HCV core in suppressing Ag-specific CD8⁺ T cell responses, we generated a transgenic mouse, core(+) mice, where the expression of core protein is directed to the liver using the albumin promoter. Using a recombinant adenovirus to deliver Ag, we demonstrated that core(+) mice failed to clear adenovirus-LacZ (Ad-LacZ) infection in the liver. The effector function of LacZ-specific CD8⁺ T cells was particularly impaired in the livers of core(+) mice, with suppression of IFN-, TNF-, and granzyme B production by CD8⁺ T cells. In addition, the impaired CD8⁺ T cell responses in core(+) mice were accompanied by the enhanced expression of the inhibitory receptor programmed death-1 (PD-1) by LacZ-specific CD8⁺ T cells and its ligand B7-H1 on liver dendritic cells following Ad-LacZ infection. Importantly, blockade of the PD-1/B7-H1 inhibitory pathway (using a B7-H1 blocking antibody) in core(+) mice enhanced effector function of CD8⁺ T cells and cleared Ad-LacZ-infection as compared with that in mice treated with control Ab. This suggests that the regulation of the PD-1/B7-H1 inhibitory pathway is crucial for HCV core-mediated impaired T cell responses and viral persistence in the liver. This also suggests that manipulation of the PD-1/B7-H1 pathway may be a potential immunotherapy to enhance effector T cell responses during persistent HCV infection.

The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked advertisement in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

¹ This work was supported by National Institutes of Health Grants (DK063222 to Y.S.H.) and Training Fellowship Grant 5T32AI10749608.

² Address correspondence and reprint requests to Dr. Young S. Hahn, Carter Immunology Center, University of Virginia, P.O. Box 801386, Charlottesville, VA 22908. E-mail address: ysh5e{at}virginia.edu

³ Abbreviations used in this paper: HCV, hepatitis C virus; Ad-LacZ, adenovirus-LacZ; Alb, albumin; βgal, β-galactosidase; β₂M, β₂-microglobulin; DC, dendritic cell; MFI, mean fluorescence intensity; p.i., post infection; PD-1, programmed death-1; rAD, recombinant adenovirus; X-gal, 5-bromo-4-chloro-3-indolyl-β- D-galactopyranoside.