Abstract
BackgroundHepatitis 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 FindingsWe 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 TNFα 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 IFNγ. Addition of IFNα prevented the effect of LVP on DC function. Restoration of IFNγ 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.ConclusionsLVP 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 IFNα, 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.
Highlights
Hepatitis C virus (HCV) infection is a major public health problem because of the high incidence of chronicity which often leads to liver cirrhosis and hepatocellular carcinoma [1]
LVP that are low density lipoproteins containing viral capsids. These particles are naturally coated with antibodies allowing their separation from normal lipoproteins by protein A-microbeads. These purified LVP were used throughout this paper. immature DC (iDC) were cultured with 4 HCV-RNA copies/cell for 24 and 48 h before harvesting of supernatants and cells
LVP entry is accompanied by protein synthesis as exemplified by positive NS5A nonstructural protein staining of most dendritic cell (DC)
Summary
HCV infection is a major public health problem because of the high incidence of chronicity which often leads to liver cirrhosis and hepatocellular carcinoma [1]. One form of HCV-RNA containing structures with low density has been purified from plasma of chronically-infected patients [5,6,7,8] These particles named Lipo-Viro-Particles (LVP) appeared as large lipoprotein-like structures enriched in triglycerides containing internal viral capsids and carrying viral envelope proteins at their surface [9]. Hepatitis C virus (HCV) can be purified from serum of chronically-infected patients in the form of Lipo-ViroParticles (LVP), which are triglycerid-rich lipoprotein-like particles containing viral RNA and proteins. 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 IFNc. Addition of IFNa prevented the effect of LVP on DC function. By acting on TLR4 pathway with LVP, HCV may 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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