Table_1_Multivariate Computational Analysis of Gamma Delta T Cell Inhibitory Receptor Signatures Reveals the Divergence of Healthy and ART-Suppressed HIV+ Aging.pdf

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 (≤35 or ≥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 (γδ) T cells exclusively separated HIV+ subjects from controls in CITRUS analyses and secretion of inflammatory cytokines and cytotoxic mediators from γδ T cells tracked with TIGIT expression among HIV+ subjects. Also, plasma markers predicted the percentages of TIGIT+ γδ T cells in subjects with and without HIV in PSLR models, and a PLS-DA model of γδ 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 γδ 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.

即便实现了有效的病毒抑制，HIV感染者仍较普通人群面临更高的老年相关并发症风险，且这类严重非艾滋病事件（serious non-AIDS events, SNAEs）与血浆炎症及凝血标志物水平密切相关。目前，病毒抑制型HIV感染中驱动炎症反应的细胞亚群尚未阐明。此外，接受抗逆转录病毒治疗（Antiretroviral Therapy, ART）抑制的HIV感染，究竟是会提前诱导未感染老年人的炎症反应，还是在HIV与衰老共存时形成全新的炎症网络，目前仍不明确。本研究针对“HIV与衰老”队列展开，该队列纳入经ART抑制的HIV感染者与未感染对照人群，并按年龄分层为≤35岁组与≥50岁组；研究人员分别对外周血单个核细胞（peripheral blood mononuclear cells, PBMC）样本中的7种免疫细胞亚群上的5种抑制性受体（inhibitory receptors, IRs）组合表达水平，以及血浆样本中的16种血浆标志物进行了检测。数据分析阶段，本研究采用多种多变量计算算法，包括聚类识别、表征与回归算法（cluster identification, characterization, and regression, CITRUS）、偏最小二乘回归（partial least squares regression, PLSR）以及偏最小二乘判别分析（partial least squares-discriminant analysis, PLS-DA），旨在探究免疫参数差异能否区分受试者组别，并分析病毒抑制型HIV感染与衰老对免疫特征是否存在交叉影响。CITRUS分析显示，γδ T细胞（gamma delta T cells）上的抑制性受体表达可唯一区分HIV阳性受试者与未感染对照；在HIV阳性受试者中，γδ T细胞分泌的炎症细胞因子与细胞毒性介质水平与TIGIT表达水平显著相关。此外，在PLSR模型中，血浆标志物可预测无论是否感染HIV的受试者体内TIGIT阳性γδ T细胞的占比；而结合γδ T细胞抑制性受体特征与血浆标志物的PLS-DA模型，可显著区分全部4组受试者：未感染青年组、未感染老年组、HIV感染青年组及HIV感染老年组。本研究结果证实，γδ T细胞是经ART抑制的HIV感染中炎症反应的驱动因素之一，并为存在与不存在ART抑制HIV感染的两类人群存在截然不同的“炎症衰老（inflamm-aging）”进程提供了实验依据。