Impaired allostimulatory function of dendritic cells in chronic hepatitis C infection

Background & Aims: Dendritic cells (DC), which play an essential role in th e triggering of primary antiviral immune reactions, may also contribute, in some viral models, to the propagation of viral infection and the pathogene sis of viral disease. During natural infection with hepatitis C virus (HCV) , the interactions between the virus and DC may contribute to viral persist ence, a general feature of HCV infection. Methods: We compared the phenotyp ical and biological functions of monocyte-derived DC from patients with chr onic hepatitis C (HCVDC; n = 6), seronegative individuals (naive-DC; n = 8) , long-term responders to antiviral therapy (LTR-DC; n = 8), and a group of patients with non-HCV-hepatic disorders (n = 11). The presence and the nat ure of HCV sequences during the DC cultures was assessed by reverse transcr iption-polymerase chain reaction and the analysis of the viral quasispecies distribution. Results: Although HCV-DC displayed a normal morphology, phen otype, and capacity to capture antigen, their ability to stimulate the prol iferation of allogeneic T cells was dramatically impaired in comparison wit h naive-DC (P = 0.0013). Mixing experiments revealed that HCV-DC did not af fect the proliferation of T cells induced by naive-DC. Remarkably, the allo stimulatory function of LTR-DC or DC from patients with non-HCV-hepatic dis orders did not show any impairment. The presence of HCV genomic sequences c ould be documented for 5 of 6 HCV carriers either in the cells and/or the s upernatants of the DC cultures. The presence of HCV sequences was found in the DC cultures from one patient showing a dramatic allostimulation defect. For that patient, extensive analysis of the viral quasispecies distributio n revealed the presence, in the DC cultures, of genomic sequences of a uniq ue nature, distinct from those identified in the patient's mononuclear cell s, serum, or liver. Conclusions: Overall, these results indicate that chron ic infection by HCV is associated with an allostimulatory defect of monocyt e-derived DC, possibly because these cells constitute an extrahepatic reser voir for the virus. Although the exact mechanism responsible for such an al teration remains to be unraveled, our observations argue against an active immunosuppression-based mechanism.