Background:  Toll-like receptor (TLR) signaling is thought to play an important role in innate antiviral defense. Our previous data using viral-relevant TLR ligands reveal selective dendritic cell (DC) defects in hepatitis C virus (HCV) and HIV infection. Here we investigated freshly isolated DC for TLR ligand induced maturation and activation of naïve T cells.

Methods:  Peripheral myeloid DC (MDC) and peripheral DC (PDC) were prepared from subjects with chronic HCV infection (n = 16) and healthy controls (n = 14). MDC were also prepared from HIV-infected subjects (n = 10). TLR-3 ligand (poly I:C), with or without tumor necrosis factor-alpha (TNF-a), stimulated MDC, and TLR-7/8 ligand (R848), in the presence or absence of TLR-9 ligand (CpG 2216) and interleukin-3 (IL-3), stimulated PDC were analyzed for ability to mature (CD83, CD86, and HLA DR MFI). Additionally, HCV and healthy control subject DC were analyzed for activation of 3 separate allogeneic healthy control naïve CD4 cell populations to secrete IFN-g.

Results:  Baseline MDC CD86 and HLA-DR MFI were greater in HIV than healthy control subjects (p = 0.04; p = 0.03). No difference in TLR-stimulated MDC maturation or ability to activate naïve CD4 cells was observed comparing healthy controls and HCV-infected subjects. HLA DR MFI was lower on HCV than healthy control PDC after TLR stimulation (p = 0.01). Additionally, TLR-stimulated PDC ability to activate naïve CD4 cells was lower in HCV-infected than in healthy control subjects (p = 0.01). In healthy controls, associations between TLR-stimulated MDC CD86 MFI and activation of naïve CD4 cells (p = 0.001), and between TLR-stimulated PDC HLA-DR MFI and activation of naïve CD4 cells (p = 0.001) were observed. In HCV-infected subjects, associations were observed between:  serum ALT and media-stimulated MDC CD83 MFI (p = 0.04), ALT and media-stimulated PDC CD83 MFI (p = 0.0003), ALT and TLR-stimulated PDC CD83 MFI (p = 0.02), TLR-stimulated MDC CD86 MFI and TLR-stimulated MDC activation of naïve CD4 cells (p = 0.01), and TLR-stimulated PDC HLA DR MFI and PDC ability to activate naïve CD4 cells (p <0.001).

Conclusions:  Activation/maturation state of MDC appears to be increased in HIV infection. TLR ligand-induced DC maturation is associated with ability to activate naïve CD4 cells. In HCV infection activation/maturation state of MDC and PDC appears to be related to the level of liver inflammation. Additionally, in chronic HCV infection circulating PDC are defective in ability to activate naïve CD4 cells, while no defect was observed with MDC.