Article

Hepatitis C Virus (HCV) Core Protein-Induced, Monocyte-Mediated Mechanisms of Reduced IFN-α and Plasmacytoid Dendritic Cell Loss in Chronic HCV Infection

University of Massachusetts Medical School, Department of Medicine, Worcester, MA 01605, USA.
The Journal of Immunology (Impact Factor: 5.36). 12/2006; 177(10):6758-68. DOI: 10.4049/jimmunol.177.10.6758
Source: PubMed

ABSTRACT IFN-alpha production by plasmacytoid dendritic cells (PDCs) is critical in antiviral immunity. In the present study, we evaluated the IFN-alpha-producing capacity of PDCs of patients with chronic hepatitis C virus (HCV) infection in treatment-naive, sustained responder, and nonresponder patients. IFN-alpha production was tested in PBMCs or isolated PDCs after TLR9 stimulation. Treatment-naive patients with chronic HCV infection had reduced frequency of circulating PDCs due to increased apoptosis and showed diminished IFN-alpha production after stimulation with TLR9 ligands. These PDC defects correlated with the presence of HCV and were in contrast with normal PDC functions of sustained responders. HCV core protein, which was detectable in the plasma of infected patients, reduced TLR9-triggered IFN-alpha and increased TNF-alpha and IL-10 production in PBMCs but not in isolated PDCs, suggesting HCV core induced PDC defects. Indeed, addition of rTNF-alpha and IL-10 induced apoptosis and inhibited IFN-alpha production in PDCs. Neutralization of TNF-alpha and/or IL-10 prevented HCV core-induced inhibition of IFN-alpha production. We identified CD14+ monocytes as the source of TNF-alpha and IL-10 in the HCV core-induced inhibition of PDC IFN-alpha production. Anti-TLR2-, not anti-TLR4-, blocking Ab prevented the HCV core-induced inhibition of IFN-alpha production. In conclusion, our results suggest that HCV interferes with antiviral immunity through TLR2-mediated monocyte activation triggered by the HCV core protein to induce cytokines that in turn lead to PDC apoptosis and inhibit IFN-alpha production. These mechanisms are likely to contribute to HCV viral escape from immune responses.

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    • "For instance, monocytes secrete IL-10 in response to HCV core–mediated TLR2 stimulation in vitro (Dolganiuc et al., 2006). IL-10 producing HCV-specific CD8+ T cells inhibits IFN-α production (Duramad et al., 2003), but also promotes apoptosis of pDCs (Dolganiuc et al., 2006), and induces liver infiltration of chronically infected individuals, suggesting that they modulate liver immunopathology to favor HCV persistence (Accapezzato et al., 2004). In addition, intrahepatic HCV-specific IL- 10 producing CD8+ T cells prevent liver damage during chronic disease (Abel et al., 2006). "
    Viral Hepatitis - Selected Issues of Pathogenesis and Diagnostics, 11/2011; , ISBN: 978-953-307-760-4
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    • "Although the primary site of HCV infection is the liver, HCV RNA has been detected in peripheral blood DC (Bain et al., 2001; Goutagny et al., 2003; Navas et al., 2002; Tsubouchi et al., 2004) but the frequency of DC containing HCV RNA and the viral levels in DC are extremely low (Bain et al., 2001; Navas et al., 2002). Accumulating evidence suggests that HCV subverts DC function (Della Bella et al., 2007; Dolganiuc et al., 2006) because it was found that myeloid DC from patients with chronic HCV (Averill et al., 2007; Kanto et al., 2004), and both murine (Hiasa et al., 1998) and human (Dolganiuc et al., 2003; Sarobe et al., 2002) DC transduced to express HCV structural proteins exhibit impaired stimulation of allogeneic T cells. In addition, HCV core protein (HCVcore) was found to impair DC maturation and reduced their ability to prime antigen-specific CD4+ and CD8+ T cell responses (Sarobe et al., 2003) by downregulation of MHC and co-stimulatory molecules (Zimmermann et al., 2008). "
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    ABSTRACT: Hepatitis C virus core (HCVcore) protein was expressed in myeloid dendritic cells (DC) from C57/B6 mice (H-2K(b)) by electroporation of HCVcore mRNA to investigate its effect on the ability of DC to prime CD8+ T cells displaying a T cell receptor specific for OVA(257-264) peptide (SIINFEKL)/H-2K(b) complex. Expression of full length HCVcore(191), which is directed to the endoplasmic reticulum (ER) membrane by a C-terminal signal sequence, but not a truncated variant HCVcore(152), which has a wider subcellular localization including the nucleus, significantly reduced surface levels of the H-2K(b)/SIINFEKL complex and impaired the ability of DC to prime naïve CD8+ T cells when they had to process endogenous antigen but not when MHC class I molecules were loaded directly with SIINFEKL peptide. Exploitation of the MHC class I antigen-processing pathway by HCVcore(191) impairs the ability of DC to stimulate CD8+ T cells and may contribute to the persistence of HCV infection.
    Virology 05/2009; 389(1-2):1-7. DOI:10.1016/j.virol.2009.03.035 · 3.28 Impact Factor
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    • "Furthermore, some reports even indicated normal functioning of MDCs in patients with chronic HCV infection (Longman et al., 2005; Piccioli et al., 2005). Altered DC-trafficking behaviour with intrahepatic compartmentalization during chronic HCV infection has been suggested (Dolganiuc et al., 2006; Kunitani et al., 2002; Nattermann et al., 2006; Wertheimer et al., 2004). Two recent reports showed a further reduction in levels of circulating MDCs in patients with chronic hepatitis C who were receiving alpha interferon (IFN-a)based antiviral therapy (Itose et al., 2007; Shiina et al., 2006). "
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    ABSTRACT: Dendritic cell (DC) frequencies in the blood of patients with chronic hepatitis C virus (HCV) infection have been shown to be reduced significantly compared with those in healthy individuals. There is a further reduction of circulating myeloid DCs (MDCs) and plasmacytoid DCs (PDCs) in HCV patients receiving alpha interferon (IFN-alpha)-based antiviral therapy. Altered homing behaviour of DCs may be a possible mechanism for their 'loss' in peripheral blood in these clinical conditions. Systemic chemokine levels were measured by ELISA. Phenotypes and migratory properties of MDCs and PDCs from HCV patients were analysed by flow cytometry and chemotaxis assay. Compared with healthy controls, HCV patients had increased serum levels of inflammatory and constitutively expressed chemokines. Spontaneously generated MDCs from HCV patients were less mature, and both MDCs and PDCs showed intrinsic activation of receptors for inflammatory chemokines, thus suggesting an increased propensity to migrate towards inflammatory sites. IFN-alpha treatment in vitro induced MDC maturation and skewed the migratory response of both MDCs and PDCs towards chemokines expressed constitutively in secondary lymphoid organs. In conclusion, our results hint at altered homing behaviour of DCs during chronic HCV infection. IFN-alpha therapy may redirect DC migration from inflamed hepatic portal areas towards secondary lymphoid tissue.
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