雖然干擾素α(IFN-α)增量生成現(xiàn)象被發(fā)現(xiàn)于HIV-1感染個(gè)體，循環(huán)漿細(xì)胞樣樹(shù)突狀細(xì)胞(PDC)對(duì)Toll樣受體配體激活反應(yīng)的實(shí)質(zhì)上是受損的,。研究人員發(fā)現(xiàn),，HIV-1感染個(gè)體的CD4+T細(xì)胞少于500/μl，可是這種功能性PDC不足的原因還未可知,。近日,，德國(guó)國(guó)家逆轉(zhuǎn)錄病毒中心的Barbara Schmidt及其同事研究發(fā)現(xiàn)：慢性免疫活化在HIC-1感染中至少部分通過(guò)增強(qiáng)的CD40與CD40L相互作用，來(lái)削弱外周PDC的先天性免疫反應(yīng),。相關(guān)研究發(fā)表在3月21日美國(guó)《公共科學(xué)圖書(shū)館·綜合》（公共科學(xué)圖書(shū)館·綜合）上,。
干擾素（IFN）是一種廣譜抗病毒劑，并不直接殺傷或抑制病毒,，而主要是通過(guò)細(xì)胞表面受體作用使細(xì)胞產(chǎn)生抗病毒蛋白,，從而抑制乙肝病毒的復(fù)制；同時(shí)還可增強(qiáng)自然殺傷細(xì)胞（NK細(xì)胞）,、巨噬細(xì)胞和T淋巴細(xì)胞的活力,，從而起到免疫調(diào)節(jié)作用，并增強(qiáng)抗病毒能力干擾素是一組具有多種功能的活性蛋白質(zhì)（主要是糖蛋白）,，是一種由單核細(xì)胞和淋巴細(xì)胞產(chǎn)生的細(xì)胞因子,。它們?cè)谕N細(xì)胞上具有廣譜的抗病毒、影響細(xì)胞生長(zhǎng),，以及分化,、調(diào)節(jié)免疫功能等多種生物活性。
研究人員提供了證據(jù)證明,，在HIV-1感染者周邊IFN-α的產(chǎn)生會(huì)通過(guò)CD40配體(CD40L)增強(qiáng)的相互作用而被積極的抑制,，而且CD40L的受體CD40都通過(guò)免疫激活被上調(diào)。未接收任何處理的HIV-1感染個(gè)體的可溶性CD40L血漿水平明顯高于長(zhǎng)期接收抗逆轉(zhuǎn)錄病毒療法的個(gè)體(n = 62, p<0.03),，而在未感染的控制組中的水平則是(n = 16, p<0.001),。同時(shí)，在HIV-1感染者中,，細(xì)胞關(guān)聯(lián)的CD40L以及在PDC上表達(dá)的受體CD40都發(fā)生明顯的上調(diào)(p<0.05),。可溶性以及細(xì)胞關(guān)聯(lián)的CD40L通過(guò)CpG多聚核苷酸劑量依賴作用抑制了IFN-α的產(chǎn)生,。在HIV-1感染個(gè)體外周血單核細(xì)胞(PBMC)中,，對(duì)比于控制組CD40L的濃度(p<0.05),，這種抑制作用被發(fā)現(xiàn)更低。CpG誘導(dǎo)的IFN-α產(chǎn)生于HIV-1感染者的PBMC,，直接與PDC及CD4+ T細(xì)胞計(jì)數(shù)相關(guān),，并反相關(guān)于病毒量(p<0.001）。在HIV-1感染者CD4+ T細(xì)胞少于500/μl的患者中,，CpG誘導(dǎo)的IFN-α的表達(dá)水平明顯與表達(dá)CD40的PDC的百分比,，以及CD40在這些細(xì)胞中的表達(dá)水平(p<0.05)一一對(duì)應(yīng)。然而,，CD40L的血漿水平在這個(gè)過(guò)程中無(wú)足輕重,。
除此之外，對(duì)比于控制組,，低劑量的CD40L會(huì)促進(jìn)IL-6和IL-8在HIV-1感染的PBMC中增強(qiáng)性表達(dá),。研究數(shù)據(jù)支持了這個(gè)結(jié)論：慢性免疫活化在HIC-1感染中至少部分通過(guò)增強(qiáng)的CD40與CD40L相互作用，來(lái)削弱外周PDC的先天性免疫反應(yīng),。(生物谷Deepblue編譯)
doi: 10.1371/journal.pone.0033925
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PMID:
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.
