Dendritic cells in hepatitis C infection: can they (help) win the battle?

Abstract

Infection with hepatitis C virus (HCV) is a public health problem; it establishes a chronic course in ~85% of infected patients and increases their risk for developing liver cirrhosis, hepatocellular carcinoma, and significant extrahepatic manifestations. The mechanisms of HCV persistence remain elusive and are largely related to inefficient clearance of the virus by the host immune system. Dendritic cells (DCs) are the most efficient inducers of immune responses; they are capable of triggering productive immunity and maintaining the state of tolerance to self- and non-self antigens. During the past decade, multiple research groups have focused on DCs, in hopes of unraveling an HCV-specific DC signature or DC-dependent mechanisms of antiviral immunity which would lead to a successful HCV elimination strategy. This review incorporates the latest update in the current status of knowledge on the role of DCs in anti-HCV immunity as it relates to several challenging questions: (a) the phenotype and function of diverse DC subsets in HCV-infected patients; (b) the characteristics of non-human HCV infection models from the DCs' point of view; (c) how can in vitro systems, ranging from HCV protein- or peptide-exposed DC to HCV protein-expressing DCs, and in vivo systems, ranging from HCV protein-expressing transgenic mice to HCV-infected non-human primates, be employed to dissect the role of DCs in triggering/maintaining a robust antiviral response; and (d) the prospect of DC-based strategy for managing and finding a cure for HCV infection.

Hepatitis C Virus Fails To Activate NF-κB Signaling in Plasmacytoid Dendritic Cells

“…Exposure of pDCs from healthy donors to cell-free HCV particles (4,7,11,13,31) or cell-associated virus did not induce cell differentiation and production of proinflammatory cytokines. The major difference between both viral systems lies in the production of type I IFN, induced in pDCs exclusively by the cellassociated virus (35), and the blockade of TLR9-mediated production of IFN-␣, induced only by HCV particles (4,7,11,13,31).…”

“…The major difference between both viral systems lies in the production of type I IFN, induced in pDCs exclusively by the cellassociated virus (35), and the blockade of TLR9-mediated production of IFN-␣, induced only by HCV particles (4,7,11,13,31). We hypothesize that the sensing of the cell-associated virus via TLR7 (35), in contrast to the sensing of the HCV particles by regulatory receptors of pDCs, is responsible for this difference (13).…”

“…Even under these experimental conditions, cell- associated HCV did not block production of proinflammatory cytokines TNF-␣ or IL-6. In a control experiment, we showed that in contrast to HCV particles (4,7,11,13,31), HCV-infected Huh7.5 cells did not inhibit production of IFN-␣ by pDCs stimulated simultaneously (Fig. 4 B) or 2 h later with CpG-A (Fig.…”

“…Several reports have shown that exposure of pDCs from healthy donors to HCV particles results in no or only weak production of type I IFN and cell differentiation (4,7,11,13,31). A recent report has shown that pDCs exposed in direct cell-to-cell contact with HCV-infected hepatoma cells, unlike those exposed to cell-free HCV virions, produce large amounts of type I IFN via TLR7 signaling (35).…”

“…4B). We have previously shown that inhibition of TLR9-mediated production of IFN-␣ in pDCs by HCV particles is more efficient if the priming with the cell-free virus precedes stimulation with TLR9 agonist, in comparison with the simultaneous treatment (4,7,11,13,31). Therefore, we investigated the effect of priming of pDCs with HCV-infected Huh7.5 cells followed 2 h later by stimulation with CpG-A or CpG-B on production of TNF-␣ or IL-6 (Fig.…”