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Journal of Virology, January 2009, p. 836-846, Vol. 83, No. 2
0022-538X/09/$08.00+0     doi:10.1128/JVI.01388-08
Copyright © 2009, American Society for Microbiology. All Rights Reserved.

Differential Expression of the CXCR3 Ligands in Chronic Hepatitis C Virus (HCV) Infection and Their Modulation by HCV In Vitro {triangledown}

Karla J. Helbig,1,3 Andrew Ruszkiewicz,2 Robert E. Lanford,4 Mark D. Berzsenyi,5 Hugh A. Harley,6 Shaun R. McColl,3 and Michael R. Beard1,3*

Infectious Diseases Laboratories,1 Division of Tissue Pathology, Institute of Medical and Veterinary Science, Adelaide 5000, South Australia,2 School of Molecular and Biomedical Science, University of Adelaide, Adelaide 5005, South Australia,3 Department of Virology and Immunology, Southwest Foundation for Biomedical Research, Southwest National Primate Research Centre, San Antonio, Texas 78227,4 Alfred Hospital, Melbourne 3000, Australia,5 Department of Gastroenterology and Hepatology, Royal Adelaide Hospital, Adelaide 5000, South Australia6

Received 3 July 2008/ Accepted 24 October 2008

To investigate chemokine expression networks in chronic hepatitis C virus (HCV) infection, we used microarray analysis to determine chemokine expression in human infection and in chimpanzees experimentally infected with HCV. The CXCR3 chemokine family was highly expressed in both human and chimpanzee infection. CXCL10 was the only CXCR3 chemokine elevated in the serum, suggesting that it may neutralize any CXCR3 chemokine gradient established between the periphery and liver by CXCL11 and CXCL9. Thus, CXCR3 chemokines may not be responsible for recruitment of T lymphocytes but may play a role in positioning these cells within the liver. The importance of the CXCR3 chemokines, in particular CXCL11, was highlighted by replicating HCV (JFH-1) to selectively upregulate its expression in response to gamma interferon (IFN-{gamma}) and tumor necrosis factor alpha (TNF-{alpha}). This selective upregulation was confirmed at the transcriptional level by using the CXCL11 promoter driving the luciferase reporter gene. This synergistic increase in expression was not a result of HCV protein expression but the nonspecific innate response to double-stranded RNA (dsRNA), as both in vitro-transcribed HCV RNA and the dsRNA analogue poly(I:C) increased CXCL11 expression and promoter activity. Furthermore, we show that CXCL11 is an IRF3 (interferon regulatory factor 3) response gene whose expression is selectively enhanced by IFN-{gamma} and TNF-{alpha}. In conclusion, the CXCR3 chemokines are the most significantly expressed chemokines in chronic hepatitis C and most likely play a role in positioning T cells in the liver. Furthermore, HCV can selectively increase CXCL11 expression in response to IFN-{gamma} and TNF-{alpha} stimulation that may play a role in the pathogenesis of HCV-related liver disease.

* Corresponding author. Mailing address: Department of Molecular Biosciences, The University of Adelaide, North Terrace, Adelaide 5005, South Australia. Phone: 61 08 8303 5522. Fax: 61 08 8303 7532. E-mail: michael.beard{at}adelaide.edu.au

{triangledown} Published ahead of print on 5 November 2008.

Journal of Virology, January 2009, p. 836-846, Vol. 83, No. 2
0022-538X/09/$08.00+0     doi:10.1128/JVI.01388-08
Copyright © 2009, American Society for Microbiology. All Rights Reserved.



This article has been cited by other articles:

  • Miller, M. B., Tang, Y.-W. (2009). Basic Concepts of Microarrays and Potential Applications in Clinical Microbiology. Clin. Microbiol. Rev. 22: 611-633 [Abstract] [Full Text]  


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