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PLoS One. 2007 Mar 28;2(3):e330.

Hepatitis C lipo-Viro-particle from chronically infected patients interferes with TLR4 signaling in dendritic cell.

Author information

  • 1Institut National de la Santé et de la Recherche Médicale (INSERM), U851, Lyon, France.

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.

PMID:
17389921
[PubMed - indexed for MEDLINE]
PMCID:
PMC1828622
Free PMC Article

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