Metabolic pathway activation distinguishes transcriptional signatures of CD8+ T cells from HIV-1 elite controllers.
Metabolic pathway activation distinguishes transcriptional signatures of CD8+ T cells from HIV-1 elite controllers.
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DOI：
10.1097/qad.0000000000002007
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发表时间：
2018-11-28
期刊：
影响因子：
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通讯作者：
Yu XG
中科院分区：
文献类型：
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作者：
Chowdhury FZ;Ouyang Z;Buzon M;Walker BD;Lichterfeld M;Yu XG
精英控制者（EC）被定义为在没有抗逆转录病毒治疗的情况下维持无法检测到的 HIV-1 复制水平的人，代表了持续、自然地控制 HIV-1 是可能的活生生的证据，至少在相对罕见的情况下是这样。了解这些特定患者复杂的免疫学和病毒学特征有望在更广泛的 HIV-1 感染患者群体中实现对 HIV-1 的无药物控制。我们使用无偏见的转录分析方法来表征 CD8+ T 细胞，这是迄今为止在一大群 EC (n=51) 中发现的与 HIV-1 免疫控制最强相关的细胞； HAART 治疗的患者 (n=32) 和 HIV-1 阴性患者 (n=10) 作为参考队列。我们从每个受试者的 PBMC 中分离出的总 CD8+ T 细胞中分离出 mRNA，然后对转录特征进行微阵列分析。我们观察到 EC 和 HAART 治疗患者之间存在显着的转录差异（590 个转录本，FDR 调整后的 p<0.05）。有趣的是，由 mTOR 和 eIF2 控制的代谢和信号通路以其在调节细胞生长、增殖和代谢中的关键作用而闻名，是差异表达基因中丰富的首要功能之一，这表明治疗上可行的靶点是自发 HIV-1 免疫控制的一个显着特征。随后的引导方法区分了 EC 的五个不同亚组，每个亚组都具有不同的转录特征。然而，尽管存在明显的异质性，mTOR 和 eIF2 信号传导的差异调节仍然是其中三个 EC 亚组的主要功能途径。这些研究表明，mTOR 和 eIF2 信号传导可能在调节 EC 的 CD8+ T 细胞功能方面发挥着非常普遍的作用。
Elite controllers (EC), defined as persons maintaining undetectable levels of HIV-1 replication in the absence of antiretroviral therapy, represent living evidence that sustained, natural control of HIV-1 is possible, at least in relatively rare instances. Understanding the complex immunologic and virologic characteristics of these specific patients holds promise for inducing drug-free control of HIV-1 in broader populations of HIV-1 infected patients. We used an unbiased transcriptional profiling approach to characterize CD8+ T cells, the strongest correlate of HIV-1 immune control identified thus far, in a large cohort of EC (n=51); HAART-treated patients (n=32) and HIV-1 negative (n=10) served as reference cohorts. We isolated mRNA from total CD8+ T cells isolated from PBMC of each subject followed by microarray analysis of the transcriptional signatures. We observed profound transcriptional differences (590 transcripts, FDR-adjusted p<0.05) between EC and HAART-treated patients. Interestingly, metabolic and signaling pathways governed by mTOR and eIF2, known for their key roles in regulating cellular growth, proliferation, and metabolism, were among the top functions enriched in the differentially expressed genes, suggesting a therapeutically actionable target as a distinguishing feature of spontaneous HIV-1 immune control. A subsequent bootstrapping approach distinguished five different subgroups of EC, each characterized by distinct transcriptional signatures. However, despite this marked heterogeneity, differential regulation of mTOR and eIF2 signaling remained the dominant functional pathway in three of these EC subgroups. These studies suggest that mTOR and eIF2 signaling may play a remarkably universal role for regulating CD8+ T cell function from EC.