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Journal of Virology, August 2003, p. 8299-8309, Vol. 77, No. 15
0022-538X/03/$08.00+0     DOI: 10.1128/JVI.77.15.8299-8309.2003
Copyright © 2003, American Society for Microbiology. All Rights Reserved.

Upregulation of Major Histocompatibility Complex Class I on Liver Cells by Hepatitis C Virus Core Protein via p53 and TAP1 Impairs Natural Killer Cell Cytotoxicity{dagger}

Kerstin Herzer,1 Christine S. Falk,2 Jens Encke,3 Sören T. Eichhorst,4 Axel Ulsenheimer,5 Barbara Seliger,6 and Peter H. Krammer1*

Division of Immunogenetics, German Cancer Research Center (DKFZ), D-69120 Heidelberg,1 Department of Medicine IV, University of Heidelberg, D-69115 Heidelberg,3 Institute for Molecular Immunology, GSF National Research Center for the Environment and Health,2 Department of Medicine II, Klinikum Grosshadern, Ludwig-Maximilians University,4 Institute of Immunology, University of Munich, D-81377 Munich,5 Johannes Gutenberg University, Department of Internal Medicine III, D-55131 Mainz, Germany6

Received 10 January 2003/ Accepted 15 May 2003

The mechanisms of immune evasion and the role of the early immune response in chronic infection caused by hepatitis C virus (HCV) are still unclear. Here, we present evidence for a cascade of molecular events that the virus initiates to subvert the innate immune attack. The HCV core protein induced p53-dependent gene expression of TAP1 (transporter associated with antigen processing 1) and consecutive major histocompatibility complex (MHC) class I upregulation. Moreover, in p53-deficient liver cell lines, only reconstitution with wild-type p53, but not mutated p53 lacking DNA binding capacity, showed this effect. As a consequence of increased MHC class I expression, a significantly downregulated cytotoxic activity of natural killer (NK) cells against HCV core-transfected liver cells was observed, whereas lysis by HCV-specific cytotoxic T cells was not affected. These results demonstrate a way in which HCV avoids recognition by NK cells that may contribute to the establishment of a chronic infection.

* Corresponding author. Mailing address: German Cancer Research Center (DKFZ), Division of Immunogenetics (D030), Im Neuenheimer Feld 280, D-69120 Heidelberg, Germany. Phone: 49-6221-423718. Fax: 49-6221-411715. E-mail: P.Krammer{at}dkfz.de.

{dagger} This report is dedicated to Harald zur Hausen on the occasion of his retirement as head of the German Cancer Research Center with gratitude and appreciation for 20 years of leadership.

Journal of Virology, August 2003, p. 8299-8309, Vol. 77, No. 15
0022-538X/03/$08.00+0     DOI: 10.1128/JVI.77.15.8299-8309.2003
Copyright © 2003, American Society for Microbiology. All Rights Reserved.



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