PLoS One：HIV-1感染者IFN-α的表达被抑制

虽然干扰素α(IFN-α)增量生成现象被发现于HIV-1感染个体，循环浆细胞样树突状细胞(PDC)对Toll样受体配体激活反应的实质上是受损的。研究人员发现，HIV-1感染个体的CD4+T细胞少于500/μl，可是这种功能性PDC不足的原因还未可知。近日，德国国家逆转录病毒中心的Barbara Schmidt及其同事研究发现：慢性免疫活化在HIC-1感染中至少部分通过增强的CD40与CD40L相互作用，来削弱外周PDC的先天性免疫反应。相关研究发表在3月21日美国《公共科学图书馆·综合》（公共科学图书馆·综合）上。

干扰素（IFN）是一种广谱抗病毒剂，并不直接杀伤或抑制病毒，而主要是通过细胞表面受体作用使细胞产生抗病毒蛋白，从而抑制乙肝病毒的复制；同时还可增强自然杀伤细胞（NK细胞）、巨噬细胞和T淋巴细胞的活力，从而起到免疫调节作用，并增强抗病毒能力干扰素是一组具有多种功能的活性蛋白质（主要是糖蛋白），是一种由单核细胞和淋巴细胞产生的细胞因子。它们在同种细胞上具有广谱的抗病毒、影响细胞生长，以及分化、调节免疫功能等多种生物活性。

研究人员提供了证据证明，在HIV-1感染者周边IFN-α的产生会通过CD40配体(CD40L)增强的相互作用而被积极的抑制，而且CD40L的受体CD40都通过免疫激活被上调。未接收任何处理的HIV-1感染个体的可溶性CD40L血浆水平明显高于长期接收抗逆转录病毒疗法的个体(n = 62, p<0.03)，而在未感染的控制组中的水平则是(n = 16, p<0.001)。同时，在HIV-1感染者中，细胞关联的CD40L以及在PDC上表达的受体CD40都发生明显的上调(p<0.05)。可溶性以及细胞关联的CD40L通过CpG多聚核苷酸剂量依赖作用抑制了IFN-α的产生。在HIV-1感染个体外周血单核细胞(PBMC)中，对比于控制组CD40L的浓度(p<0.05)，这种抑制作用被发现更低。CpG诱导的IFN-α产生于HIV-1感染者的PBMC，直接与PDC及CD4+ T细胞计数相关，并反相关于病毒量(p<0.001）。在HIV-1感染者CD4+ T细胞少于500/μl的患者中，CpG诱导的IFN-α的表达水平明显与表达CD40的PDC的百分比，以及CD40在这些细胞中的表达水平(p<0.05)一一对应。然而，CD40L的血浆水平在这个过程中无足轻重。

除此之外，对比于控制组，低剂量的CD40L会促进IL-6和IL-8在HIV-1感染的PBMC中增强性表达。研究数据支持了这个结论：慢性免疫活化在HIC-1感染中至少部分通过增强的CD40与CD40L相互作用，来削弱外周PDC的先天性免疫反应。(生物谷Deepblue编译)

doi: 10.1371/journal.pone.0033925
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Chronic Immune Activation in HIV-1 Infection Contributes to Reduced Interferon Alpha Production via Enhanced CD40:CD40 Ligand Interaction

Norbert Donhauser, Kathrin Pritschet, Martin Helm, Thomas Harrer, Philipp Schuster, Moritz Ries, Georg Bischof1 Jrg Vollmer, Sigrun Smola, Barbara Schmidt.

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.