89 Several studies have suggested that DC can be infected with HCV, but the role of HCV in DC development and function is still elusive.59,90,91 Virologically, HCV first attaches itself to the host cell surface by means of weak interactions with glycosylaminoglycans or the

low-density lipoprotein receptor. Once bound and concentrated on the cell surface, virions are able to interact with entry receptors such as CD81 and SR-BI with high affinity. The virus–receptor complex then translocates to the tight junctions where claudin and occludin act as cofactors and induce receptor-mediated endocytosis.92 Barth et al.35 used HCV-like particles (HCV-LPs) to study the interaction of HCV with human DC. The iDC exhibited an envelope-specific and saturable binding of HCV-LPs, indicating receptor-mediated DC–HCV-LP interaction. They GDC-0068 in vivo revealed that HCV-LPs were rapidly taken up by DC in a temperature-dependent manner, and C-type lectins such as mannose receptor or DC-SIGN (DC-specific intercellular adhesion molecule 3-grabbing non-integrin) were not sufficient for mediating HCV-LP binding. Lambotin et al.93 suggested that HCV cell entry factors, which are crucial for viral uptake in hepatocytes, do not support the cell culture-produced HCV (HCVcc) uptake in DC subsets.

HCVcc acquisition by DC subsets does not depend on the C-type lectin DC-SIGN, but is partially selleck kinase inhibitor mediated by HCVcc E2 protein interaction at the cell surface. To date, the mechanisms whereby HCV affects DC function remain largely elusive.55 It is possible that HCV proteins play a role in suppressing protective immunity through interactions with host immune cells, such as DC. Indeed, the HCV core protein has been reported to impair the function of DC. The HCV core protein was able to selectively inhibit TLR4-induced IL-12 production after interacting with the gC1q receptor on the surface of MDDC by activating the phosphatidyl

inositol 3-kinase pathway, leading to reduced T helper type 1 (Th1) cell development.94,95 Dolganiuc et al.96 demonstrate that HCV core and NS3 proteins, but not envelope 2 proteins (E2), activate monocytes and inhibit DC differentiation in the absence of the intact virus, and induced production of the anti-inflammatory Fenbendazole cytokine IL-10 associated with elevated IL-10 and decreased IL-2 levels during T-cell proliferation. They also found that treatment-naive patients with chronic HCV infection had a reduced frequency of circulating PDC as the result of increased apoptosis and showed diminished IFN-α production after stimulation with TLR9 ligands.97 The HCV core protein reduced TLR9-triggered IFN-α and increased TNF-α and IL-10 production in peripheral blood mononuclear cells (PBMCs) but not in isolated PDC, suggesting that HCV core induces PDC defects. The addition of rTNF-α and IL-10 induced apoptosis and inhibited IFN-α production in PDC.