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Published on: September 1, 2015
Differential effects of hepatitis C virus JFH1 on human myeloid and plasmacytoid dendritic cells
Hua Liang1, Rodney S Russell, Nicole L Yonkers
1Department of Medicine, Division of Infectious and Rheumatic Diseases, Case Western Reserve University, Center for AIDS Research and VA Medical Center, Cleveland Ohio 44106, USA.
Insights
Hepatitis C virus (HCV) impairs dendritic cell (DC) function, affecting both myeloid DCs (mDCs) and plasmacytoid DCs (pDCs). This study reveals HCV disrupts T cell activation by DCs, contributing to immune dysfunction in chronic HCV infection.
Area of Science:
- Immunology
- Virology
- Cell Biology
Background:
- Dendritic cells (DCs) are crucial for immune responses but exhibit functional deficiencies during chronic Hepatitis C Virus (HCV) infection.
- Previous studies show conflicting results regarding the direct impact of replicative HCV on DC function.
- Understanding these direct effects is vital for elucidating immune evasion mechanisms in chronic HCV.
Purpose of the Study:
- To investigate the direct effects of Hepatitis C Virus (HCV) JFH1 strain on human myeloid DCs (mDCs) and plasmacytoid DCs (pDCs) function.
- To identify mechanisms by which HCV influences DC maturation and T cell activation.
- To determine if HCV replication within DCs is necessary for observed functional alterations.
Main Methods:
- Purified human mDCs and pDCs were treated with infectious HCV JFH1.
- DC maturation markers (CD83, CD86, CD40) and responses to Toll-like receptor (TLR) ligands (poly(I:C) for TLR3, R848 for TLR7) were assessed.
- T cell activation assays, recombinant HCV protein treatments, UV-inactivated HCV, and strand-specific PCR were employed.
Main Results:
- HCV JFH1 upregulated maturation markers on mDCs and did not inhibit poly(I:C)-induced maturation, but impaired their ability to activate naive CD4 T cells.
- HCV JFH1 inhibited R848-induced CD40 expression on pDCs and their capacity to activate naive CD4 T cells.
- HCV core protein, CD81-E2 interaction, and TLR2 were implicated in these effects; virus replication was not required.
Conclusions:
- HCV directly impairs the function of both mDCs and pDCs, specifically their ability to activate naive CD4 T cells, independent of viral replication.
- HCV-induced DC maturation and impaired T cell activation contribute to the DC subset defects observed in chronic HCV infection.
- These findings elucidate key mechanisms of immune dysregulation driven by direct viral-immune cell interactions in HCV.
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.
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