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Journal of Virology, March 2007, p. 2545-2553, Vol. 81, No. 6
0022-538X/07/$08.00+0     doi:10.1128/JVI.02021-06
Copyright © 2007, American Society for Microbiology. All Rights Reserved.

Liver-Infiltrating Lymphocytes in Chronic Human Hepatitis C Virus Infection Display an Exhausted Phenotype with High Levels of PD-1 and Low Levels of CD127 Expression{triangledown}

Henry Radziewicz,1,2 Chris C. Ibegbu,1 Marina L. Fernandez,1 Kimberly A. Workowski,2 Kamil Obideen,2 Mohammad Wehbi,2 Holly L. Hanson,1 James P. Steinberg,2 David Masopust,1 E. John Wherry,3 John D. Altman,1 Barry T. Rouse,4 Gordon J. Freeman,5 Rafi Ahmed,1 and Arash Grakoui1,2*

Emory Vaccine Center and Department of Microbiology and Immunology,1 Department of Medicine, Emory University School of Medicine, Atlanta, Georgia 30322,2 Immunology Program, The Wistar Institute, Philadelphia, Pennsylvania 19104,3 College of Veterinary Medicine, University of Tennessee, Knoxville, Tennessee 37996,4 Department of Medical Oncology, Dana-Farber Cancer Institute, Department of Medicine, Harvard Medical School, Boston, Massachusetts 021155

Received 15 September 2006/ Accepted 7 December 2006

The majority of people infected with hepatitis C virus (HCV) fail to generate or maintain a T-cell response effective for viral clearance. Evidence from murine chronic viral infections shows that expression of the coinhibitory molecule PD-1 predicts CD8+ antiviral T-cell exhaustion and may contribute to inadequate pathogen control. To investigate whether human CD8+ T cells express PD-1 and demonstrate a dysfunctional phenotype during chronic HCV infection, peripheral and intrahepatic HCV-specific CD8+ T cells were examined. We found that in chronic HCV infection, peripheral HCV-specific T cells express high levels of PD-1 and that blockade of the PD-1/PD-L1 interaction led to an enhanced proliferative capacity. Importantly, intrahepatic HCV-specific T cells, in contrast to those in the periphery, express not only high levels of PD-1 but also decreased interleukin-7 receptor alpha (CD127), an exhausted phenotype that was HCV antigen specific and compartmentalized to the liver, the site of viral replication.

* Corresponding author. Mailing address: Emory University School of Medicine, 954 Gatewood Road, N.E., Atlanta, GA 30329. Phone: (404) 727-5850. Fax: (404) 727-7768. E-mail: arash.grakoui{at}emory.edu.

{triangledown} Published ahead of print on 20 December 2006.

Journal of Virology, March 2007, p. 2545-2553, Vol. 81, No. 6
0022-538X/07/$08.00+0     doi:10.1128/JVI.02021-06
Copyright © 2007, American Society for Microbiology. All Rights Reserved.



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