Impairment of TLR7-dependent signaling in dendritic cells from chronic hepatitis C virus (HCV)-infected non-responders to interferon/ribavirin therapy.
OBJECTIVE
Dendritic cell (DC) dysfunction has been suggested to play a role in the weak antiviral T-cell responsiveness observed during the course of chronic hepatitis C virus (HCV) infection. This study was undertaken to evaluate whether changes in DC functions might be related to a different therapeutic outcome in HCV-infected patients.


METHODS
Peripheral blood DCs (PBDCs) or monocyte-derived DCs (MoDCs) were obtained from chronic HCV-infected patients, sustained virologic responders (SVR) or non-responders (NR) to interferon/ribavirin therapy, and from healthy controls (HC). The frequency of BDCA-1+, BDCA-3+ or CD16+ myeloid DCs (mDCs) and BDCA-2+ plasmacytoid DCs (pDCs), as well as the expression of the costimulatory molecule CD86 in each PBDC subset, were evaluated by flow cytometry. MoDCs from single individuals were stimulated with TLR2, TLR3, TLR4, and TLR7 ligands and analyzed for CD86, CD83, CD40, CD80, and CD209 expression. Finally, mitogen-activated protein kinase (MAPK) phosphorylation of TLR7-triggered MoDCs was assessed by Western blotting.


RESULTS
NR exhibited a reduced percentage of BDCA-1+ mDCs, as well as lower levels of CD86+ cells, in both BDCA-1+ mDCs and pDCs as compared to SVR and HC. Furthermore, MoDCs from NR displayed a defective CD86 and CD83 increase and ERK1/2 or p38-MAPK phosphorylation upon TLR7-cell triggering.


CONCLUSIONS
Our data suggest that a TLR7-dependent impairment of costimulatory molecule expression caused by HCV persistence may affect DC activity in NR patients.
Simone
Olivia
O
Department of Internal Medicine, Immunology and Infectious Diseases, Section of Internal Medicine, University of Bari Medical School, Bari, Italy.
Tortorella
Cosimo
C
Zaccaro
Bruna
B
Napoli
Nicola
N
Antonaci
Salvatore
S
D000998:Antiviral Agents / Q000494:pharmacology* / Q000627:therapeutic use; D002478:Cells, Cultured; D003713:Dendritic Cells / Q000276:immunology*; D024882:Drug Resistance, Viral / Q000276:immunology*; D019698:Hepatitis C, Chronic / Q000188:drug therapy / Q000209:etiology / Q000276:immunology*; D006801:Humans; D007369:Interferon Inducers; D007372:Interferons / Q000494:pharmacology / Q000627:therapeutic use; D012254:Ribavirin / Q000494:pharmacology / Q000627:therapeutic use; D015398:Signal Transduction / Q000276:immunology*; D051199:Toll-Like Receptor 7; D017211:Treatment Failure
D000998:Antiviral Agents; D007369:Interferon Inducers; C495348:TLR7 protein, human; D051199:Toll-Like Receptor 7; D012254:Ribavirin; D007372:Interferons
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