80 Various approaches have been used to clarify the discrepancies and possible underlying mechanisms, including generation of MDDC or the analysis of peripheral blood DCs in patients with chronic HCV, by studying the effectiveness of recombinant HCV proteins or cell-culture-adapted strains of HCV on DC in vitro. Some researchers also reported that HCV-infected cells trigger a robust IFN response in PDC by a mechanism that requires active viral replication, direct cell–cell contact, and Toll-like receptor 7 (TLR7) signalling, and showed that the activated PDC supernatant inhibits HCV infection in an IFN receptor-dependent manner.81 As there is clearly controversy regarding MDC’s ability to activate

T cells, it is unclear whether on a per cell basis MDCs from HCV-infected individuals are able

to prime naive T cells. Additionally, reduced numbers of peripheral blood MDC have been observed in HCV-infected individuals and may play buy Ixazomib a role in the defective response to vaccine. Canaday et al.82 specifically focused on analysis of peptide–MHC complex formation and presentation, the culmination of uptake, degradation and trafficking of antigen. They Obeticholic Acid found that this specific antigen-presenting cell function is preserved in the setting of chronic HCV infection. As the liver is the primary site for HCV replication, DC changes in peripheral blood may or may not reflect what is happening locally at the site of infection. Several studies demonstrated enrichment Lepirudin of DC in the liver compartment compared with peripheral blood.80 Galle et al.83 employed electron microscopy, immunohistochemistry and immunofluorescence to show that DC are indeed enriched in the livers of HCV-infected individuals. Wertheimer et al.84 also showed a clear enrichment of DC in the intrahepatic compartment

compared with the peripheral circulation. To investigate the contribution of intrahepatic PDC and MDC to local immune responses during HCV infection, Lai et al.85,86 developed methods to isolate and characterize MDC and PDC from human liver. The MDC from HCV-infected liver demonstrated greater expression of MHC class II, CD86 and CD123, that were more efficient stimulators of allogeneic T cells and secreted less IL-10. In contrast, PDC were present at lower frequencies in HCV-infected liver and expressed higher levels of the regulatory receptor BDCA-2. In HCV-infected liver, the combination of enhanced MDC function and a reduced number of PDC might contribute to viral persistence in the face of persistent inflammation. Nattermann et al.87 demonstrated that chronic HCV infection, associated with intrahepatic DC enrichment, migration of DC is markedly affected by interaction of HCV E2 with CD81. A two-photon confocal microscopic analysis revealed that DC and T lymphocytes were rapidly recruited within human liver slices undergoing an ex vivo HCV infection.