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* Department of Medicine,
Department of Oncology, and
Department of Epidemiology, Johns Hopkins Medical Institutions, Baltimore, MD 21205;
Southwest Hospital, Third Military Medical University, Chongqing, People’s Republic of China;
¶ Medarex Inc., Milpitas, CA 95035; and
|| La Jolla Institute for Allergy and Immunology, San Diego, CA 92121
Hepatitis C virus (HCV) is an important human pathogen that represents a model for chronic infection given that the majority of infected individuals fail to clear the infection despite generation of virus-specific T cell responses during the period of acute infection. Although viral sequence evolution at targeted MHC class I-restricted epitopes represents one mechanism for immune escape in HCV, many targeted epitopes remain intact under circumstances of viral persistence. To explore alternative mechanisms of HCV immune evasion, we analyzed patterns of expression of a major inhibitory receptor on T cells, programmed death-1 (PD-1), from the time of initial infection and correlated these with HCV RNA levels, outcome of infection, and sequence escape within the targeted epitope. We show that the level of PD-1 expression in early HCV infection is significantly higher on HCV-specific T cells from subjects who progress to chronic HCV infection than from those who clear infection. This correlation is independent of HCV RNA levels, compatible with the notion that high PD-1 expression on HCV-specific CD8 T cells during acute infection inhibits viral clearance. Viral escape during persistent infection is associated with reduction in PD-1 levels on the surface of HCV-specific T cells, supporting the necessity of ongoing antigenic stimulation of T cells for maintenance of PD-1 expression. These results support the idea that PD-1 expression on T cells specific for nonescaped epitopes contributes to viral persistence and suggest that PD-1 blockade may alter the outcome of 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 grants from The Damon Runyon Foundation and The Dana Foundation and by United States Public Health Service Grants K08 DA11880, U19 AI040035, and R01 DA024565.
2 A.R. and S.C.R. contributed equally to the work,
3 Address correspondence and reprint requests to Dr. Andrea L. Cox, 855 North Wolfe Street. Suite 530, Johns Hopkins University, Baltimore, MD 21205. E-mail address: acox{at}jhmi.edu
4 Abbreviations used in this paper: HCV, hepatitis C virus; HBV, hepatitis B virus; PD-1, programmed death-1; Flu, influenza; MFI, mean fluorescence intensity.
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  D.-Y. Chang and E.-C. Shin Immune-based therapy for chronic hepatitis C J. Leukoc. Biol., July 1, 2009; 86(1): 33 - 39. [Abstract] [Full Text] [PDF]
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