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Hepatitis C Lipo-Viro-Particle from Chronically Infected Patients Interferes with TLR4 Signaling in Dendritic Cell.

Abstract : BACKGROUND: Hepatitis C virus (HCV) can be purified from serum of chronically-infected patients in the form of Lipo-Viro-Particles (LVP), which are triglycerid-rich lipoprotein-like particles containing viral RNA and proteins. Since LVP is a constant feature of chronically infected patients, we asked whether purified LVP could interfere with the immune response by acting directly on dendritic cell (DC) function. METHODS AND FINDINGS: We have analyzed the impact of LVP on the maturation monocyte-derived DC induced by TLR3 or TLR4 ligands. Following incubation with LVP, immature DC supported weak transient HCV-RNA replication and type I IFN synthesis. This, however, did not lead to viral particle production nor to maturation of DC. LVP-treatment prior to TLR3 stimulation by polyI:C only enhanced the secretion of IL-12, IL-6 and TNFalpha yielding typical mature DC. In contrast, LVP-treated DC activated by the TLR4 ligand LPS yielded phenotypically mature DC with reduced capacity to secrete both pro- and anti-inflammatory cytokines. Their ability to stimulate allogeneic T lymphocytes was strongly affected since activated T cells produced IL-5 and IL-13 instead of IFNgamma. Addition of IFNalpha prevented the effect of LVP on DC function. Restoration of IFNgamma secretion by T cells was obtained by blocking ERK activation in DC, while induction of IL-5 and IL-13 secretion was inhibited by blocking the p38-MAPK pathway in DC. CONCLUSIONS: LVP can interfere with TLR4-triggered maturation of DC, inducing a shift in DC function that stimulates Th2 cells instead of Th1, by a mechanism that is ERK- and p38-MAPK-dependent. The effect of LVP on DC polarization was reversed by IFNalpha, providing an additional rationale for the interferon therapy of chronically-infected patients. By acting on TLR4 pathway with LVP, HCV may thus exploit a natural protective mechanism of the liver and the intestine normally used to control inflammation and immunity to commensal microorganisms.
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Contributor : Laure Perrin-Cocon <>
Submitted on : Wednesday, April 4, 2007 - 10:24:38 AM
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Sophie Agaugué, Laure Perrin-Cocon, Patrice André, Vincent Lotteau. Hepatitis C Lipo-Viro-Particle from Chronically Infected Patients Interferes with TLR4 Signaling in Dendritic Cell.. PLoS ONE, Public Library of Science, 2007, 2, pp.e330. ⟨10.1371/journal.pone.0000330⟩. ⟨inserm-00139931⟩



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