Cell culture-produced hepatitis C virus impairs plasmacytoid dendritic cell function.
Previous studies suggested a functional impairment of dendritic cells (DCs) in patients with chronic hepatitis C. To investigate whether this effect was mediated by a direct interaction of hepatitis C virus (HCV) with DCs, we studied the effects of infectious cell culture-produced hepatitis C virus (HCVcc) on peripheral blood mononuclear cells (PBMCs), ex vivo isolated plasmacytoid, and myeloid DCs and in vitro generated monocyte-derived DCs of healthy blood donors. HCVcc inhibited toll-like receptor (TLR)-9 (CpG and herpes simples virus)-mediated interferon alpha (IFN-alpha) production by peripheral blood mononuclear cells (PBMC) and plasmacytoid DCs. This inhibitory effect was also observed in response to ultraviolet (UV)-inactivated, noninfectious HCVcc, and it was not abrogated by neutralizing antibodies, and thus did not appear to require DC infection. Influenza A virus restored maturation and TLR9-mediated IFN-alpha production. In contrast to its effect on plasmacytoid DCs, HCVcc did not inhibit TLR3-mediated and TLR4-mediated maturation and interleukin (IL)-12, IL-6, IL-10, interferon gamma (IFN-gamma), and tumor necrosis factor alpha (TNF-alpha) production by myeloid DCs and monocyte-derived DCs. Likewise, HCVcc did neither alter the capacity of myeloid DCs nor monocyte-derived DCs to induce CD4 T cell proliferation. Whereas phagocytosis of apoptotic hepatoma cells resulted in DC maturation, this effect was independent of whether the phagocytosed Huh7.5.1 cells were infected with HCVcc. In contrast to HCVcc, vaccinia virus inhibited maturation and TNF-alpha expression of myeloid DC as well as maturation and IL-6 and IL-10 production of monocyte-derived DC.


CONCLUSIONS
HCVcc inhibited plasmacytoid DCs but not myeloid-derived and monocytoid-derived DCs via a direct interaction that did not require infection. The response of plasmacytoid DCs to influenza A virus infection was not impaired.
Immunology Section, Liver Diseases Branch, National Institute of Diabetes and Digestive and Kidney Diseases, National Institutes of Health, Department of Health and Human Services, Bethesda, MD 20892, USA.
Masaaki
M
Shiina
Barbara
B
Rehermann
D018929:Cell Culture Techniques / Q000379:methods; D016207:Cytokines / Q000096:biosynthesis; D003713:Dendritic Cells / Q000276:immunology* / Q000821:virology*; D005434:Flow Cytometry / Q000379:methods; D016174:Hepacivirus / Q000472:pathogenicity*; D006801:Humans; D009980:Influenza A virus / Q000276:immunology; D016898:Interferon-alpha / Q000096:biosynthesis; D007378:Interleukins / Q000096:biosynthesis; D009000:Monocytes / Q000166:cytology; D010950:Plasma Cells / Q000821:virology*
D016207:Cytokines; D016898:Interferon-alpha; D007378:Interleukins