Differential expression of the CXCR3 ligands in chronic hepatitis C virus (HCV) infection and their modulation by HCV in vitro

Karla J. Helbig, Andrew Ruszkiewicz, Robert E. Lanford, Mark D. Berzsenyi, Hugh A. Harley, Shaun R. McColl, Michael R. Beard

Research output: Contribution to journalArticle

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Abstract

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-γ) and tumor necrosis factor alpha (TNF-α). 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-γ and TNF-α. 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-γ and TNF-α stimulation that may play a role in the pathogenesis of HCV-related liver disease.

Original languageEnglish (US)
Pages (from-to)836-846
Number of pages11
JournalJournal of Virology
Volume83
Issue number2
DOIs
StatePublished - Jan 2009
Externally publishedYes

Fingerprint

chronic hepatitis C
Hepatitis C virus
Chronic Hepatitis C
Virus Diseases
chemokines
Chemokines
Hepacivirus
Ligands
infection
double-stranded RNA
interferons
Pan troglodytes
Double-Stranded RNA
liver
Interferons
T-lymphocytes
Liver
promoter regions
Up-Regulation
Interferon Regulatory Factor-3

ASJC Scopus subject areas

  • Immunology
  • Virology

Cite this

Helbig, K. J., Ruszkiewicz, A., Lanford, R. E., Berzsenyi, M. D., Harley, H. A., McColl, S. R., & Beard, M. R. (2009). Differential expression of the CXCR3 ligands in chronic hepatitis C virus (HCV) infection and their modulation by HCV in vitro. Journal of Virology, 83(2), 836-846. https://doi.org/10.1128/JVI.01388-08

Differential expression of the CXCR3 ligands in chronic hepatitis C virus (HCV) infection and their modulation by HCV in vitro. / Helbig, Karla J.; Ruszkiewicz, Andrew; Lanford, Robert E.; Berzsenyi, Mark D.; Harley, Hugh A.; McColl, Shaun R.; Beard, Michael R.

In: Journal of Virology, Vol. 83, No. 2, 01.2009, p. 836-846.

Research output: Contribution to journalArticle

Helbig, KJ, Ruszkiewicz, A, Lanford, RE, Berzsenyi, MD, Harley, HA, McColl, SR & Beard, MR 2009, 'Differential expression of the CXCR3 ligands in chronic hepatitis C virus (HCV) infection and their modulation by HCV in vitro', Journal of Virology, vol. 83, no. 2, pp. 836-846. https://doi.org/10.1128/JVI.01388-08
Helbig, Karla J. ; Ruszkiewicz, Andrew ; Lanford, Robert E. ; Berzsenyi, Mark D. ; Harley, Hugh A. ; McColl, Shaun R. ; Beard, Michael R. / Differential expression of the CXCR3 ligands in chronic hepatitis C virus (HCV) infection and their modulation by HCV in vitro. In: Journal of Virology. 2009 ; Vol. 83, No. 2. pp. 836-846.
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