Differential Effects of Hepatitis C Virus JFH1 on Human Myeloid and Plasmacytoid Dendritic Cells

Abstract

Dendritic cells (DCs) are reported to be functionally deficient during chronic hepatitis C virus (HCV) infection.Differing results have been reported on direct effects of intact replicative-form HCV on DC function. To better understand the effect of HCV on DC function, we treated freshly purified human myeloid DCs (mDCs) and plasmacytoid DCs (pDCs) with HCV JFH1. We found that HCV upregulated mDC maturation marker (CD83, CD86, and CD40) expression and did not inhibit Toll-like receptor 3 (TLR3) ligand [poly(I:C)]-induced mDC maturation, a finding consistent with the phenotype of DCs from HCV-infected subjects. At the same time, HCV JFH1 inhibited the ability of poly(I:C)-treated mDCs to activate naive CD4 T cells. In contrast, although there was no direct effect of virus on pDC maturation, HCV JFH1 inhibited TLR7 ligand (R848)-induced pDC CD40 expression, and this was associated with impaired ability to activate naive CD4 T cells. Parallel experiments with recombinant HCV proteins indicated HCV core protein may be responsible for a portion of the activity. Furthermore, HCV-mediated mDC maturation was dependent upon CD81-E2 interaction and, in part, TLR2. Using UV-treated HCV, we show that HCV-mediated mDC and pDC maturation is virus replication independent and, using strand specific PCR, we found no evidence for HCV replication within DCs. Because these effects of HCV on DC subset maturation and function in part recapitulate direct ex vivo analysis of DCs in chronic HCV infection, the mechanisms described here likely account for a portion of the DC subset defects observed in vivo.

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

“…In contrast, contact with HCVinfected cells triggers a robust IFN response in PDCs by a mechanism that requires active viral replication, direct cell-cell contact, TLR7 signaling, and an intact IFN receptor-dependent autocrine activation loop [67]. Importantly, the same events are triggered by HCV subgenomic replicon cells, but not by free virus particles, suggesting the existence of a novel cell-cell RNA transfer process whereby HCV-infected cells can activate PDCs to produce IFNs without directly infecting them [66][67][68].…”

Host–virus interactions in hepatitis B and hepatitis C infection

“…Two plausible explanations for DC dysfunction in chronic HCV infection are: (1) direct infection of HCV with DCs and (2) the influence of circulating HCV proteins on the function and number of DCs. Studies involving the inoculation of cell-cultured HCV (HCVcc) into various blood cells, including DCs, have been performed in order to reveal HCV tropism [86]. However, to date no direct evidence has been obtained for the replication and reproduction of HCVcc in these cells [87][88][89], although HCVcc does have a negative impact on IFN-a production by pDCs, independently of direct infection of HCV [90].…”

Role of Dendritic Cells in Chronic HCV Infection and its Correlation with Interferon and Ribavirin Treatment Outcomes

“…pDcs produce more interferon-α (IFN-α) per cell than any other cell type in the body, proinflammatory cytokines, and antigen presentation during viral infection making them aparticularly important component of the antiviral immune response. mDCs are derived from amyloid bone marrow precursor, produce large ammounts of interleukin-12 (IL-12) after bacterial or viral infection and prime Th1 T-cell responses (Liang et aL., 2009). All DCs express high levels of Toll-like receptors (TLRs), which are an important family of pathogen recognition receptors.…”