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Journal of Virology, February 2005, p. 2230-2239, Vol. 79, No. 4
0022-538X/05/$08.00+0     doi:10.1128/JVI.79.4.2230-2239.2005
Copyright © 2005, American Society for Microbiology. All Rights Reserved.

Hepatitis C Virus Core Protein Induces an Anergic State Characterized by Decreased Interleukin-2 Production and Perturbation of Mitogen-Activated Protein Kinase Responses

Sara Sundström,1 Seisuke Ota,1 Lina Y. Dimberg,2 Maria G. Masucci,1 and Anders Bergqvist1*

Microbiology and Tumor Biology Centre, Karolinska Institutet, Stockholm,1 Department of Medical Biochemistry and Microbiology, Biomedical Centre, Uppsala University, Uppsala, Sweden2

Received 17 June 2004/ Accepted 29 September 2004

Alterations of cytokine responses are thought to favor the establishment of persistent hepatitis C virus (HCV) infections, enhancing the risk of liver cirrhosis and hepatocellular carcinoma. Here we demonstrate that the expression of the HCV core (C) protein in stably transfected T cells correlates with a selective reduction of interleukin-2 (IL-2) promoter activity and IL-2 production in response to T-cell receptor triggering, whereas the activation of IL-4, IL-10, gamma interferon, and tumor necrosis factor alpha was moderately increased. This altered cytokine expression profile was associated with a perturbation of mitogen-activated protein (MAP) kinase responses. Extracellular regulated kinase and p38 were constitutively phosphorylated in C-expressing cells, while triggering of the costimulatory c-Jun N-terminal kinase (JNK) signaling cascade and activation of the CD28 response element within the IL-2 promoter appeared to be impaired. The perturbations of MAP kinase phosphorylation could be eliminated by cyclosporine A-mediated inhibition of nuclear factor of activated T cells, suggesting that the inactivation of JNK signaling and hyporesponsiveness to IL-2 induction were downstream consequences of C-induced Ca2+ flux in a manner that mimics the induction of clonal anergy.

* Corresponding author. Mailing address: MTC, Karolinska Institutet, Box 280, SE-171 77 Stockholm, Sweden. Phone: 46-8-52487149. Fax: 46-8-331399. E-mail: anders.bergqvist{at}mtc.ki.se.

Journal of Virology, February 2005, p. 2230-2239, Vol. 79, No. 4
0022-538X/05/$08.00+0     doi:10.1128/JVI.79.4.2230-2239.2005
Copyright © 2005, American Society for Microbiology. All Rights Reserved.



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  • Dominguez-Villar, M., Munoz-Suano, A., Anaya-Baz, B., Aguilar, S., Novalbos, J. P., Giron, J. A., Rodriguez-Iglesias, M., Garcia-Cozar, F. (2007). Hepatitis C virus core protein up-regulates anergy-related genes and a new set of genes, which affects T cell homeostasis. J. Leukoc. Biol. 82: 1301-1310 [Abstract] [Full Text]  
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