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Journal of Virology, September 2007, p. 9249-9258, Vol. 81, No. 17
0022-538X/07/$08.00+0     doi:10.1128/JVI.00409-07
Copyright © 2007, American Society for Microbiology. All Rights Reserved.

Upregulation of PD-1 Expression on Circulating and Intrahepatic Hepatitis C Virus-Specific CD8+ T Cells Associated with Reversible Immune Dysfunction{triangledown} ,{dagger}

Lucy Golden-Mason,1,2,3 Brent Palmer,3,4 Jared Klarquist,1 John A. Mengshol,1,3 Nicole Castelblanco,1 and Hugo R. Rosen1,2,3*

Division of Gastroenterology and Hepatology, Hepatitis C Center,1 Integrated Program in Immunology,2 Department of Medicine,3 Division of Clinical Immunology, University of Colorado Health Sciences Center and National Jewish Hospital, Denver, Colorado 802624

Received 26 February 2007/ Accepted 30 May 2007

Infection with hepatitis C virus (HCV) is associated with persistence in the majority of individuals. We demonstrate here that the inhibitory molecule programmed death-1 (PD-1) is significantly upregulated on total and HCV-specific CD8+ cytotoxic T lymphocytes (CTLs) in the peripheral blood and livers of patients with chronic infection compared to subjects with spontaneous HCV resolution, patients with nonviral liver disease, and normal controls. PD-1 expression on cytomegalovirus-specific CTLs also varies according to HCV status and is highest in patients with chronic infection. HCV-specific CTLs that are PD-1high express higher levels of the senescence marker CD57 than PD-1low CTLs, and CD57 expression is greater in chronic than in resolved infection. In vitro blockade of PD-1 by monoclonal antibodies specific to its ligands (PD-L1 and PD-L2) results in restoration of functional competence (proliferation and gamma interferon and interleukin-2 secretion) of HCV-specific CTLs, including those residing in the liver. This reversal of CTL exhaustion is evident even in individuals who lack HCV-specific CD4+ T-cell help. Our data indicate that the PD-1/PD-L pathway is critical in persistent HCV infection in humans and represents a potential novel target for restoring function of exhausted HCV-specific CTLs.

* Corresponding author. Mailing address: Division of Gastroenterology/Hepatology, UCHSC GI Division, 4200 East Ninth Ave., #B-158, Denver, CO 80262. Phone: (303) 315-2536. Fax: (303) 315-5711. E-mail: Hugo.Rosen{at}UCHSC.edu

{triangledown} Published ahead of print on 13 June 2007.

{dagger} Supplemental material for this article may be found at http://jvi.asm.org/.

Journal of Virology, September 2007, p. 9249-9258, Vol. 81, No. 17
0022-538X/07/$08.00+0     doi:10.1128/JVI.00409-07
Copyright © 2007, American Society for Microbiology. All Rights Reserved.



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