Multivariate Computational Analysis of Gamma Delta T Cell Inhibitory Receptor Signatures Reveals the Divergence of Healthy and ART-Suppressed HIV plus Aging
Multivariate Computational Analysis of Gamma Delta T Cell Inhibitory Receptor Signatures Reveals the Divergence of Healthy and ART-Suppressed HIV plus Aging
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DOI：
10.3389/fimmu.2018.02783
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发表时间：
2018-12-05
影响因子：
7.3
通讯作者：
Snyder-Cappione, Jennifer E.
中科院分区：
文献类型：
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作者：
Belkina, Anna C.;Starchenko, Alina;Snyder-Cappione, Jennifer E.
即使有有效的病毒控制，HIV感染者比一般人群更容易发生与年龄较大相关的疾病，这些严重的非艾滋病事件（SNAE）与血浆炎症和凝血标志物有关。在HIV感染的病毒血症中，驱动炎症的细胞亚群尚未阐明。此外，ART抑制的HIV感染是否导致未感染老年人中发现的炎症事件的过早诱导，或者当HIV和老年人共存时是否存在新的炎症网络尚不清楚。在这项研究中，我们测量了5个抑制性受体（IR）的组合表达的7个免疫细胞亚群和16个血浆标记物的外周血单核细胞（PBMC）和血浆样本，分别从艾滋病毒和老化队列包括ART抑制的艾滋病毒感染和未感染的控制分层的年龄（≥ 50岁）。对于数据分析，使用多种多变量计算算法[聚类识别、表征和回归（CITRUS）、偏最小二乘回归（PLSR）和偏最小二乘判别分析（PLS-DA）]来确定免疫参数差异是否可以区分受试者组，并研究是否存在病毒血症HIV和年龄对免疫特征的交叉影响。在CITRUS分析中，γ δ（γ δ）T细胞上的IR表达专门将HIV+受试者与对照分开，并且在HIV+受试者中用TIGIT表达追踪来自γ δ T细胞的炎性细胞因子和细胞毒性介质的分泌。此外，在PSLR模型中，血浆标志物预测了具有和不具有HIV的受试者中TIGIT+ γ δ Τ细胞的百分比，并且γ δ Τ细胞IR特征和血浆标志物的PLS-DA模型显著地将所有四个受试者组（未感染的年轻人、未感染的老年人、HIV+年轻人和HIV+老年人）分层。这些数据暗示γ δ T细胞作为ART抑制的HIV感染中的炎症驱动因子，并提供了有和没有ART抑制的HIV感染的不同“炎症-衰老”过程的证据。
Even with effective viral control, HIV-infected individuals are at a higher risk for morbidities associated with older age than the general population, and these serious non-AIDS events (SNAEs) track with plasma inflammatory and coagulation markers. The cell subsets driving inflammation in aviremic HIV infection are not yet elucidated. Also, whether ART-suppressed HIV infection causes premature induction of the inflammatory events found in uninfected elderly or if a novel inflammatory network ensues when HIV and older age co-exist is unclear. In this study we measured combinational expression of five inhibitory receptors (IRs) on seven immune cell subsets and 16 plasma markers from peripheral blood mononuclear cells (PBMC) and plasma samples, respectively, from a HIV and Aging cohort comprised of ART-suppressed HIV-infected and uninfected controls stratified by age (= 50 years old). For data analysis, multiple multivariate computational algorithms [cluster identification, characterization, and regression (CITRUS), partial least squares regression (PLSR), and partial least squares-discriminant analysis (PLS-DA)] were used to determine if immune parameter disparities can distinguish the subject groups and to investigate if there is a cross-impact of aviremic HIV and age on immune signatures. IR expression on gamma delta (gamma delta) T cells exclusively separated HIV+ subjects from controls in CITRUS analyses and secretion of inflammatory cytokines and cytotoxic mediators from gamma delta T cells tracked with TIGIT expression among HIV+ subjects. Also, plasma markers predicted the percentages of TIGIT+ gamma delta T cells in subjects with and without HIV in PSLR models, and a PLS-DA model of gamma delta T cell IR signatures and plasma markers significantly stratified all four of the subject groups (uninfected younger, uninfected older, HIV+ younger, and HIV+ older). These data implicate gamma delta T cells as an inflammatory driver in ART-suppressed HIV infection and provide evidence of distinct "inflamm-aging" processes with and without ART-suppressed HIV infection.