雖然干擾素α(IFN-α)增量生成現(xiàn)象被發(fā)現(xiàn)于HIV-1感染個體,，循環(huán)漿細胞樣樹突狀細胞(PDC)對Toll樣受體配體激活反應的實質上是受損的,。研究人員發(fā)現(xiàn),，HIV-1感染個體的CD4+T細胞少于500/μl,，可是這種功能性PDC不足的原因還未可知,。近日,，德國國家逆轉錄病毒中心的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增強的CD40與CD40L相互作用,，來削弱外周PDC的先天性免疫反應。相關研究發(fā)表在3月21日美國《公共科學圖書館·綜合》（公共科學圖書館·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，而主要是通過細胞表面受體作用使細胞產生抗病毒蛋白,，從而抑制乙肝病毒的復制,；同時還可增強自然殺傷細胞（NK細胞）、巨噬細胞和T淋巴細胞的活力,，從而起到免疫調節(jié)作用,，并增強抗病毒能力干擾素是一組具有多種功能的活性蛋白質（主要是糖蛋白），是一種由單核細胞和淋巴細胞產生的細胞因子,。它們在同種細胞上具有廣譜的抗病毒,、影響細胞生長，以及分化,、調節(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的產生會通過CD40配體(CD40L)增強的相互作用而被積極的抑制,，而且CD40L的受體CD40都通過免疫激活被上調,。未接收任何處理的HIV-1感染個體的可溶性CD40L血漿水平明顯高于長期接收抗逆轉錄病毒療法的個體(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,，在HIV-1感染者中，細胞關聯(lián)的CD40L以及在PDC上表達的受體CD40都發(fā)生明顯的上調(p<0.05),?？扇苄砸约凹毎P聯(lián)的CD40L通過CpG多聚核苷酸劑量依賴作用抑制了IFN-α的產生,。在HIV-1感染個體外周血單核細胞(PBMC)中，對比于控制組CD40L的濃度(p<0.05),，這種抑制作用被發(fā)現(xiàn)更低,。CpG誘導的IFN-α產生于HIV-1感染者的PBMC，直接與PDC及CD4+ T細胞計數(shù)相關,，并反相關于病毒量(p<0.001）,。在HIV-1感染者CD4+ T細胞少于500/μl的患者中，CpG誘導的IFN-α的表達水平明顯與表達CD40的PDC的百分比,，以及CD40在這些細胞中的表達水平(p<0.05)一一對應,。然而，CD40L的血漿水平在這個過程中無足輕重,。
除此之外,，對比于控制組，低劑量的CD40L會促進IL-6和IL-8在HIV-1感染的PBMC中增強性表達,。研究數(shù)據(jù)支持了這個結論：慢性免疫活化在HIC-1感染中至少部分通過增強的CD40與CD40L相互作用,，來削弱外周PDC的先天性免疫反應。(生物谷Deepblue編譯)
doi: 10.1371/journal.pone.0033925
PMC:
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.
