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Journal of Virology, June 2007, p. 5537-5546, Vol. 81, No. 11
0022-538X/07/$08.00+0     doi:10.1128/JVI.01741-06
Copyright © 2007, American Society for Microbiology. All Rights Reserved.

Poly(I:C) and Lipopolysaccharide Innate Sensing Functions of Circulating Human Myeloid Dendritic Cells Are Affected In Vivo in Hepatitis C Virus-Infected Patients{triangledown}

Ian Gaël Rodrigue-Gervais,1,2,3 Loubna Jouan,1,5 Geneviève Beaulé,1,3 Dominike Sauvé,1,3 Julie Bruneau,1,4 Bernard Willems,1,5 Rafick-Pierre Sékaly,1,2,3 and Daniel Lamarre1,2,5,6*

Centre Hospitalier de l'Université de Montréal,1 INSERM U743, Hôpital Saint-Luc, Montréal, Québec, Canada H2X 1P1,2 Département de Microbiologie et Immunologie,3 Département de Médecine Familiale,4 Département de Médecine,5 Institut de Recherche en Immunologie et en Cancérologie, Faculté de Médecine, Université de Montréal, Québec, Canada H3C 3J76

Received 11 August 2006/ Accepted 11 March 2007

The role of peripheral dendritic cells (DCs) in hepatitis C virus (HCV) infection is unclear. To determine if persistent infection exerts an inhibitory pressure on HCV-specific innate responses, we analyzed DC function in blood through quantification of cell-associated HCV RNA levels in conjunction with multiparametric flow cytometry analysis of pathogen recognition receptor-induced cytokine expression. Independently of the serum viral load, fluorescence-activated cell sorter-purified total DCs had a wide range of cell-associated HCV genomic RNA copy numbers (mean log10, 5.0 per 106 cells; range, 4.3 to 5.8). Here we report that for viremic patients with high viral loads in their total DCs, the myeloid DC (MDC) subset displayed impaired expression of interleukin-12 (IL-12) and tumor necrosis factor alpha (TNF-{alpha}) but normal IL-6 or chemokine CCL3 expression in response to poly(I:C) and lipopolysaccharide (LPS). IL-6-expressing cells from this subgroup of viremic patients demonstrated a significant increase (sixfold more) in TNF-{alpha}– IL-12– cell frequency compared to healthy donors (mean, 38.8% versus 6.5%; P < 0.0001), indicating a functional defect in a subpopulation of cytokine-producing MDCs (~6% of MDCs). Attenuation of poly(I:C) and LPS innate sensing was HCV RNA density dependent and did not correlate with viremia or deficits in circulating MDC frequencies in HCV-infected patients. Monocytes from these patients were functionally intact, responding normally on a per-cell basis following stimulation, independent of cell-associated HCV RNA levels. Taken together, these data indicate that detection of HCV genomic RNA in DCs and loss of function in the danger signal responsiveness of a small proportion of DCs in vivo are interrelated rather than independent phenomena.

* Corresponding author. Mailing address: Centre Hospitalier de l'Université de Montréal, Hôpital Saint-Luc, 264 Boul. René-Lévesque Est, Rm. EA-312, Montréal, Québec, Canada H2X 1P1. Phone: (514) 890-8000, ext. 35258. Fax: (514) 412-7314. E-mail: daniel.lamarre{at}umontreal.ca

{triangledown} Published ahead of print on 21 March 2007.

Journal of Virology, June 2007, p. 5537-5546, Vol. 81, No. 11
0022-538X/07/$08.00+0     doi:10.1128/JVI.01741-06
Copyright © 2007, American Society for Microbiology. All Rights Reserved.



This article has been cited by other articles:

  • Liu, B., Woltman, A. M., Janssen, H. L. A., Boonstra, A. (2009). Modulation of dendritic cell function by persistent viruses. J. Leukoc. Biol. 85: 205-214 [Abstract] [Full Text]  


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