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: 4.92). 12/2006; 177(10):6758-68. DOI: 10.4049/jimmunol.177.10.6758
Source: PubMed


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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    • "In addition, NK cell activity can be directly inhibited by HCV envelope [35], [36] and indirectly by core proteins [37], [38], suggesting that HCV immune evasion strategies may specifically target this cell population. The presence of circulating core in HCV-infected patients [39] makes it a good candidate for suppression of immune cells, which may not be directly infected, an interaction known to inhibit T cell responses [40]. Indeed, HCV-core protein has been shown to hamper dendritic cell (DC) maturation [39], directly suppress T cell activation [41] and to inhibit NK cell cytotoxicity indirectly through up-regulation and stabilization of MHC Class I molecules [37], [38]. "
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    ABSTRACT: Background: Hepatitis C viral (HCV) proteins, including core, demonstrate immuno-modulatory properties; however, the effect of extracellular core on natural killer (NK) cells has not previously been investigated. Aims: To characterise NKs in acute HCV infection over time, and, to examine the effect of exogenous HCV-core protein on NK cell phenotype and function. Methods: Acute HCV patients (n = 22), including 10 subjects who spontaneously recovered, were prospectively studied. Flow-cytometry was used to measure natural cytotoxicity and to phenotype NKs directly ex vivo and after culture with HCV-core protein. Microarray analysis was used to identify pathways involved in the NK cell response to exogenous HCV-core. Results: Direct ex vivo analysis demonstrated an increased frequency of immature/regulatory CD56(bright) NKs early in acute HCV infection per se which normalized with viral clearance. Natural cytotoxicity was reduced and did not recover after viral clearance. There was a statistically significant correlation between the frequency of CD56(bright) NKs and circulating serum levels of HCV core protein. In vitro culture of purified CD56(bright) NK cells with HCV-core protein in the presence of IL-15 maintained a significant proportion of NKs in the CD56(bright) state. The in vitro effect of core closely correlates with NK characteristics measured directly ex vivo in acute HCV infection. Pathway analysis suggests that HCV-core protein attenuates NK interferon type I responses. Conclusions: Our data suggest that HCV-core protein alters NK cell maturation and may influence the outcome of acute infection.
    PLoS ONE 07/2014; 9(7):e103219. DOI:10.1371/journal.pone.0103219 · 3.23 Impact Factor
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    • "Core has been reported to modulate the immune response at multiple levels, including the innate hepatocyte response [6] and T cells through binding to gC1qR [7], the globular region of complement protein 1q receptor. The precise interaction between Core and host proteins has been studied by various groups [5], showing pathways mediated through interactions with TLR2, TLR4 and gC1qR [8], [9]. "
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    ABSTRACT: Plasmacytoid Dendritic Cells (pDCs) represent a key immune cell population in the defense against viruses. pDCs detect viral pathogen associated molecular patterns (PAMPs) through pattern recognition receptors (PRR). PRR/PAMP interactions trigger signaling events that induce interferon (IFN) production to initiate local and systemic responses. pDCs produce Type I and Type III (IFNL) IFNs in response to HCV RNA. Extracellular HCV core protein (Core) is found in the circulation in chronic infection. This study defined how Core modulates PRR signaling in pDCs. Type I and III IFN expression and production following exposure to recombinant Core or β-galactosiade was assessed in human GEN2.2 cells, a pDC cell line. Core suppressed type I and III IFN production in response to TLR agonists and the HCV PAMP agonist of RIG-I. Core suppression of IFN induction was linked with decreased IRF-7 protein levels and increased non-phosphorylated STAT1 protein. Circulating Core protein interferes with PRR signaling by pDCs to suppress IFN production. Strategies to define and target Core effects on pDCs may serve to enhance IFN production and antiviral actions against HCV.
    PLoS ONE 05/2014; 9(5):e95627. DOI:10.1371/journal.pone.0095627 · 3.23 Impact Factor
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    • "Monocytes are a major cell type in PBMCs and several previous reports have indicated that monocytes could negatively regulate pDCs functions during viral infection [19], therefore monocytes may participate in the inhibition of IFN-α production by pDCs. To confirm this hypothesis, monocytes were purified from PBMCs by magnetic bead isolation and were co-cultured with varying concentrations of pDCs. "
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    ABSTRACT: Type I Interferon (IFN) is one of the first lines of defense against viral infection. Plasmacytoid dendritic cells (pDCs) are professional IFN-α-producing cells that play an important role in the antiviral immune response. Previous studies have reported that IFN-α production is impaired in chronic hepatitis B (CHB) patients. However, the mechanisms underlying the impairment in IFN-α production are not fully understood. Here, we report that plasma-derived hepatitis B surface antigen (HBsAg) and HBsAg expressed in CHO cells can significantly inhibit toll like receptor (TLR) 9-mediated Interferon-α (IFN-α) production in peripheral blood mononuclear cells (PBMCs) from healthy donors. Further analysis indicated that monocytes participate in the inhibitory effect of HBsAg on pDCs through the secretion of TNF-α and IL-10. Furthermore, TLR9 expression on pDCs was down-regulated by TNF-α, IL-10 and HBsAg treatment. This down-regulation may partially explain the inhibition of IFN-α production in pDCs. In conclusion, we determined that HBsAg inhibited the production of IFN-α by pDCs through the induction of monocytes that secreted TNF-α and IL-10 and through the down-regulation of TLR9 expression on pDCs. These data may aid in the development of effective antiviral treatments and lead to the immune control of the viral infections.
    PLoS ONE 09/2012; 7(9):e44900. DOI:10.1371/journal.pone.0044900 · 3.23 Impact Factor
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