Type I interferon upregulates Bak and contributes to T cell loss during human immunodeficiency virus (HIV) infection.
Type I interferon upregulates Bak and contributes to T cell loss during human immunodeficiency virus (HIV) infection.
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DOI：
10.1371/journal.ppat.1003658
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发表时间：
2013
期刊：
影响因子：
6.7
通讯作者：
Katsikis PD
中科院分区：
文献类型：
--
作者：
Fraietta JA;Mueller YM;Yang G;Boesteanu AC;Gracias DT;Do DH;Hope JL;Kathuria N;McGettigan SE;Lewis MG;Giavedoni LD;Jacobson JM;Katsikis PD
I型干扰素（IFN）在致病性HIV和SIV感染中的作用尚不清楚，有相互矛盾的观察结果表明保护作用与免疫病理作用。因此，我们研究了IFNα/β对HIV感染中T细胞死亡和病毒血症的影响。对慢性HIV-1感染中8种促凋亡分子和抗凋亡分子的体外分析显示，促凋亡分子Bak在CD4+ T细胞中升高，与CD95/ fas介导的细胞凋亡敏感性直接相关，与CD4+ T细胞计数负相关。凋亡敏感性和Bak表达主要在效应记忆T细胞中增加。通过RNA干扰敲低Bak抑制CD95/ fas诱导的hiv -1感染个体的T细胞死亡。在hiv -1感染患者中，ifn α刺激的基因表达与体外T细胞Bak水平、CD95/ fas介导的细胞凋亡和病毒血症呈正相关，与CD4+ T细胞计数呈负相关。体外刺激IFNα/β可增强健康供体T细胞中Bak表达、CD95/Fas表达和CD95/Fas介导的细胞凋亡，诱导hiv -1感染患者的hiv特异性CD8+ T细胞死亡。HIV-1在体外使T细胞对CD95/ fas诱导的凋亡敏感，这是toll样受体（TLR）7/9和I型ifn依赖性的。HIV-1的这种致敏作用是由于对T细胞的间接影响，因为它发生在外周血单核细胞培养物中，而不是纯化的CD4+ T细胞。最后，在急性SIV感染期间，峰值ifn - α水平和病毒载量呈负相关，提示潜在的抗病毒作用，但在慢性SIV感染期间呈正相关，表明病毒驱动ifn - α产生或ifn - α可能促进病毒控制的丧失。上述发现表明I型ifn在HIV-1感染期间具有阶段特异性的相反作用，并提示这些细胞因子有助于T细胞耗竭、细胞免疫失调和疾病进展的新机制。I型干扰素（IFNα/β）是细胞在应答病毒感染时产生的先天免疫介质。尽管IFNα/β的保护作用已得到证实，但尚不清楚这些细胞因子在HIV-1感染期间是有益还是有害。我们报道HIV-1感染使T细胞更容易发生程序性死亡，这种增强的凋亡易感性与促凋亡和抗凋亡分子的异常表达有关。重要的是，IFNα/β增加了促凋亡蛋白Bak的表达水平，Bak是线粒体凋亡机制的主要看门人。暴露于IFNα/β的健康供体T细胞增加了Bak的表达，并诱导了与hiv -1感染患者T细胞相似的凋亡敏感性。此外，IFNα产生和Bak表达升高与患者T细胞凋亡增加、CD4+ T细胞数量降低和病毒载量升高相关。在HIV-1感染的灵长类动物模型中，我们观察到IFNα的增加与早期感染的低峰值病毒载量相关，但在慢性感染期间高病毒血症和CD4+ T细胞计数减少。这些研究确定了I型IFN可能诱导HIV-1感染免疫功能障碍的新机制。
The role of Type I interferon (IFN) during pathogenic HIV and SIV infections remains unclear, with conflicting observations suggesting protective versus immunopathological effects. We therefore examined the effect of IFNα/β on T cell death and viremia in HIV infection. Ex vivo analysis of eight pro- and anti-apoptotic molecules in chronic HIV-1 infection revealed that pro-apoptotic Bak was increased in CD4+ T cells and correlated directly with sensitivity to CD95/Fas-mediated apoptosis and inversely with CD4+ T cell counts. Apoptosis sensitivity and Bak expression were primarily increased in effector memory T cells. Knockdown of Bak by RNA interference inhibited CD95/Fas-induced death of T cells from HIV-1-infected individuals. In HIV-1-infected patients, IFNα-stimulated gene expression correlated positively with ex vivo T cell Bak levels, CD95/Fas-mediated apoptosis and viremia and negatively with CD4+ T cell counts. In vitro IFNα/β stimulation enhanced Bak expression, CD95/Fas expression and CD95/Fas-mediated apoptosis in healthy donor T cells and induced death of HIV-specific CD8+ T cells from HIV-1-infected patients. HIV-1 in vitro sensitized T cells to CD95/Fas-induced apoptosis and this was Toll-like receptor (TLR)7/9- and Type I IFN-dependent. This sensitization by HIV-1 was due to an indirect effect on T cells, as it occurred in peripheral blood mononuclear cell cultures but not purified CD4+ T cells. Finally, peak IFNα levels and viral loads correlated negatively during acute SIV infection suggesting a potential antiviral effect, but positively during chronic SIV infection indicating that either the virus drives IFNα production or IFNα may facilitate loss of viral control. The above findings indicate stage-specific opposing effects of Type I IFNs during HIV-1 infection and suggest a novel mechanism by which these cytokines contribute to T cell depletion, dysregulation of cellular immunity and disease progression. Type I interferons (IFNα/β) are innate immune mediators that are produced by cells in response to viral infections. Although the protective effects of IFNα/β are well-established, it is not clear whether these cytokines are beneficial or deleterious during HIV-1 infection. We report that HIV-1 infection renders T cells more prone to undergo programmed death and that this enhanced apoptosis susceptibility is associated with abnormal expression of pro- and anti-apoptotic molecules. Importantly, IFNα/β increases the expression level of the pro-apoptotic protein, Bak, a major gatekeeper of the mitochondrial apoptosis machinery. Exposure of healthy donor T cells to IFNα/β increased Bak expression and induced an apoptosis sensitivity that is similar to what is observed in HIV-1-infected patient T cells. Furthermore, elevated IFNα production and Bak expression correlated with heightened T cell apoptosis, low CD4+ T cell numbers and high viral loads in patients. In a primate model of HIV-1 infection, we observed that increased IFNα was associated with low peak viral loads in early infection, but high viremia and decreased CD4+ T cell counts during chronic infection. These studies identify a novel mechanism by which Type I IFN may induce immune dysfunction in HIV-1 infection.
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