Differential effects of hepatitis C virus JFH1 on human myeloid and plasmacytoid dendritic cells.
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.
Liang
Hua
H
Department of Medicine, Division of Infectious and Rheumatic Diseases, Case Western Reserve University, Center for AIDS Research and VA Medical Center, Cleveland Ohio 44106, USA.
Russell
Rodney S
RS
Yonkers
Nicole L
NL
McDonald
David
D
Rodriguez
Benigno
B
Harding
Clifford V
CV
Anthony
Donald D
DD
D015703:Antigens, CD / Q000276:immunology; D015496:CD4-Positive T-Lymphocytes / Q000276:immunology; D002454:Cell Differentiation / Q000276:immunology; D002478:Cells, Cultured; D003713:Dendritic Cells / Q000166:cytology / Q000276:immunology* / Q000378:metabolism; D016174:Hepacivirus / Q000502:physiology*; D006801:Humans; D007113:Immunity, Innate / Q000276:immunology; D008024:Ligands; D008213:Lymphocyte Activation / Q000276:immunology; D022423:Myeloid Cells / Q000166:cytology / Q000276:immunology* / Q000378:metabolism; D051193:Toll-Like Receptors / Q000276:immunology / Q000378:metabolism; D014779:Virus Replication
D015703:Antigens, CD; D008024:Ligands; D051193:Toll-Like Receptors