Plasma factors during chronic HIV-1 infection impair IL-12 secretion by myeloid dendritic cells via a virus-independent pathway.
Plasma factors during chronic HIV-1 infection impair IL-12 secretion by myeloid dendritic cells via a virus-independent pathway.
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慢性 HIV-1 感染期间的血浆因子通过不依赖于病毒的途径损害骨髓树突状细胞分泌 IL-12。
DOI：
10.1097/qai.0b013e31826afbce
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发表时间：
2012
期刊：
影响因子：
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通讯作者：
Bhardwaj,Nina
中科院分区：
文献类型：
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作者：
Miller,ElizabethA;Spadaccia,MeredithR;OʼBrien,MeaganP;Rolnitzky,Linda;Sabado,Rachel;Manches,Olivier;Frleta,Davor;Bhardwaj,Nina
目的：人类免疫缺陷病毒(HIV)感染时髓系树突状细胞(MDC)功能障碍可能阻碍先天免疫反应和获得性免疫反应的形成，并参与其发病机制。我们的目的是确定慢性HIV感染过程中的循环因素是否会损害MDC的功能，即分泌IL-12，一种支持Th1的细胞因子，以及T细胞刺激能力。重点研究了联合抗逆转录病毒疗法(CART)和HIV本身对MDC功能的影响。方法：在Toll样受体(TLR)刺激之前，将未感染的供者的单核细胞来源的DC(MoDC)与HIV感染者的血浆接触。通过细胞因子珠阵列检测细胞因子的分泌，并与初始γ+T细胞共培养后检测T细胞的增殖和干扰素的分泌。通过定量逆转录聚合酶链式反应(qRT-PCR)阵列和Western blotting分析TLR介导的信号转导中心基因的表达。结果：未经治疗的HIV感染者供者的单核细胞来源的DC暴露于血浆中，抑制了IL-12的分泌，并损害了CD4+T细胞的Th1偏斜。血浆献血者接受CART的抑制作用较小。去除血浆中的病毒并不能解除抑制，也不能减少IL-12的分泌。在转录水平上，TLR/NF-kappaB信号通路的关键调节因子IKKβ的表达减少对应于细胞因子分泌的抑制。结论：慢性艾滋病毒感染过程中的血浆因子损害了MDC的功能，可能影响对艾滋病毒、机会性病原体和疫苗的免疫反应的形成。尽管CART部分缓解了这种抑制，但这种抑制并不是由艾滋病毒直接介导的。
Objective:Myeloid dendritic cell (mDC) dysfunction during HIV infection may hinder the formation of both innate and adaptive immune responses and contribute to pathogenesis. Our objective was to determine whether circulating factors during chronic HIV infection impair mDC function with respect to secretion of IL-12, a pro-Th1 cytokine, and T-cell stimulatory capacity. Particular focus was placed on the effect of combination antiretroviral therapy (cART) and the role of HIV itself on mDC function.Methods:Monocyte-derived DC (moDC) from uninfected donors were exposed to plasma from HIV-infected individuals before Toll-like receptor (TLR) stimulation. Cytokine secretion was measured via cytokine bead arrays, and T-cell proliferation and IFNγ secretion was evaluated after coculture with naive CD4+ T cells. Expression of genes central to TLR-mediated signal transduction was analyzed via quantitative reverse transcriptase—polymerase chain reaction (qRT-PCR) arrays and western blot.Results:Exposure of monocyte-derived DC to plasma from untreated HIV-infected donors suppressed secretion of IL-12, and impaired Th1-skewing of CD4+ T cells. The suppressive effect was less by plasma donors receiving cART. Removal of virus from plasma did not relieve suppression nor was IL-12 secretion decreased on addition of HIV to control plasma. On a transcriptional level, decreased expression of IKKβ, a key regulator in the TLR/NF-kappaB signaling pathway, corresponded to suppressed cytokine secretion.Conclusions:Plasma factors during chronic HIV infection impair mDC function in a manner that likely impacts the formation of immune responses to HIV, opportunistic pathogens, and vaccines. Despite partial alleviation by cART, this suppression was not directly mediated by HIV.