Abstract
Although a signature of increased interferon (IFN-)alpha production is observed in HIV-1 infection, the response of circulating plasmacytoid dendritic cells (PDC) to Toll-like receptor ligand stimulation is substantially impaired. This functional PDC deficit, which we specifically observed in HIV-1 infected individuals with less than 500 CD4+ T cells/µl, is not well understood. We provide evidence that the peripheral IFN-alpha production in HIV-1 infection is actively suppressed by the enhanced interaction of CD40 ligand (CD40L), a member of the tumor necrosis factor family, and its receptor CD40, which are both upregulated upon immune activation. Plasma levels of soluble CD40L were significantly higher in untreated HIV-1 infected individuals (n = 52) than in subjects on long-term antiretroviral therapy (n = 62, p<0.03) and in uninfected control donors (n = 16, p<0.001). Concomitantly, cell-associated CD40L and the expression of the receptor CD40 on the PDC were significantly upregulated in HIV-1 infection (p<0.05). Soluble and cell-associated CD40L inhibited the PDC-derived IFN-alpha production by CpG oligodeoxynucleotides dose-dependently. This suppressive effect was observed at much lower, physiological CD40L concentrations in peripheral blood mononuclear cells (PBMC) of HIV-1 infected individuals compared to controls (p<0.05). The CpG-induced IFN-alpha production in PBMC of HIV-1 infected donors was directly correlated with PDC and CD4+ T cell counts, and inversely correlated with the viral loads (p<0.001). In HIV-1 infected donors with less than 500 CD4+ T cells/µl, the CpG-induced IFN-alpha production was significantly correlated with the percentage of CD40-expressing PDC and the level of CD40 expression on these cells (p<0.05), whereas CD40L plasma levels played a minor role. In addition, low-dose CD40L contributed to the enhanced production of interleukin 6 and 8 in PBMC of HIV-1 infected donors compared to controls. Our data support the conclusion that the chronic immune activation in HIV-1 infection impairs peripheral PDC innate immune responses at least in part via enhanced CD40:CD40L interactions.
Highlights
Evidence is accumulating from human and simian studies that chronic immune activation with enhanced T-cell turnover and apoptosis plays a crucial role in lentiviral pathogenesis [1]
For the first time, that the upregulation of CD40 ligand (CD40L) and in particular the receptor CD40 on the surface of plasmacytoid dendritic cells (PDC) contributes to reduction of the PDC-derived IFN-alpha production in HIV-1 infection
The soluble CD40 ligand (sCD40L) plasma levels, the expression of cell-associated CD40L (cCD40L) on several cell populations and the expression of CD40 on the PDC were concomitantly upregulated in HIV-1 infected subjects (Fig. 1), which corroborates data by other groups [20,21,22,23,24]
Summary
Evidence is accumulating from human and simian studies that chronic immune activation with enhanced T-cell turnover and apoptosis plays a crucial role in lentiviral pathogenesis [1]. An important trigger of immune activation are the type I interferons (IFN), mainly produced by plasmacytoid dendritic cells (PDC) [2,3]. PDC express Toll-like receptors (TLR) 7 and 9 for the recognition of single-stranded RNA and CpG-like DNA, respectively. High-titered HIV-1 and in particular HIV-1 infected cells induce major IFN-alpha production [4,5,6]. The antiviral activity, is counteracted by the apoptosis of uninfected CD4+ bystander cells via enhanced expression of the tumor necrosis factor (TNF)-related apoptosisinducing ligand and its death receptor 5 [7]
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