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Cutting Edge: Programmed Death-1 Expression Is Increased on Immunocytes in Chronic Hepatitis C Virus and Predicts Failure of Response to Antiviral Therapy: Race-Dependent Differences^1,2

Lucy Golden-Mason^*,,, Jared Klarquist^*, Abdus S. Wahed and Hugo R. Rosen^3,*,,

^* Division of Gastroenterology and Hepatology, Hepatitis C Center, Integrated Program in Immunology, and Department of Medicine, University of Colorado Health Sciences Center and National Jewish Hospital, Aurora, Co 80045; and Department of Biostatistics, Graduate School of Public Health, University of Pittsburgh, Pittsburgh, PA 15261

Up-regulation of programmed death-1 (PD-1) identifies exhausted T cells in various mouse and human viral models including chronic hepatitis C virus (HCV) infection, which is characterized by impaired CTL function. A large proportion of patients fail to eradicate HCV with current IFN-based antiviral therapy; in particular, African Americans are less likely to respond, but the mechanisms for these differences are not fully elucidated. In this study, in 72 treatment-naive patients with persistent HCV we found that PD-1 was significantly up-regulated on CD4⁺ and CD8⁺ T cells, HCV-specific CTLs, and NK cells. Increased PD-1 on HCV-specific CTLs was significantly associated with failed early and sustained virologic response to therapy in African American but not Caucasian American patients. Patients with sustained virologic response showed decreases in PD-1 on total CD4⁺ T cells, HCV-specific CTLs, and the CD56^bright NK subset after therapy completion. Collectively, these data indicate that PD-1 is critical in persistent HCV and successful therapy results in global down-regulation of its expression.

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 is supported by RO1 DK071560 (to H.R.R.). This study was funded as a cooperative agreement by the National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK) and the Intramural Research Program of the National Cancer Institute (NCI) with further support under a Cooperative Research and Development Agreement (CRADA) with Roche Laboratories Inc. A complete listing of participants in the Virahep-C study is given in Ref. 16 . Grant numbers are U01 DK60329, U01 DK60340, U01 DK60324, U01 DK60344, U01 DK60327, U01 DK60335, U01 DK60352, U01 DK60342, U01 DK60345, U01 DK60309, U01 DK60346, U01 DK60349, and U01 DK60341.

² This work was done on behalf of the Virahep-C Study Group.

³ Address correspondence and reprint requests to Dr. Hugo R. Rosen, Division of GI/Hepatology B-158, Academic Office Building 1, 12631 East 17th Avenue, Room 7614, P.O. Box 6511, Aurora, CO 80045. E-mail address: Hugo.Rosen{at}UCHSC.edu

⁴ Abbreviations used in this paper: HCV, hepatitis C virus; AA, African American; CA, Caucasian American; CI, confidence interval; NT, natural T cell; PD-1, programmed death-1; RR, risk ratio; SHP, Src homology region 2 domain-containing phosphatase; SVR, sustained virologic response (defined by lack of detectable serum HCV RNA at least 6 mo after cessation of antiviral therapy); Virahep-C, viral resistance to antiviral therapy in hepatitis C.