Gamma delta T cells promote inflammation in aviremic HIV infection and normal aging

γ δ T 细胞促进无病毒血症 HIV 感染和正常衰老中的炎症

• 批准号: 10655453
• 负责人: Jennifer E Snyder-Cappione
• 金额: $ 73.27万
• 依托单位: BOSTON UNIVERSITY MEDICAL CAMPUS
• 依托单位国家: 美国
• 财政年份: 2020
• 资助国家: 美国
• 起止时间: 2020-08-15 至 2025-05-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10655453
• 关键词: Age; Aging; Algorithms; Architecture; Automobile Driving; Bioinformatics; Biological; Biopsy; Blood; Cardiovascular Diseases; Cell Culture Techniques; Cell Lineage; Cell Separation; Cell physiology; Cells; Cessation of life; Chronic; Circulation; Colon; Color; Cross-Sectional Studies; Cytometry; Data; Data Analyses; Data Set; Dementia; Development; Disease; Elderly; Ensure; Epithelial Cells; Epithelium; Exhibits; Exposure to; Flow Cytometry; Gastrointestinal tract structure; Geriatric Assessment; Glean; HIV; HIV Enteropathy; HIV Infections; Image; Immune; In Vitro; Individual; Inflammaging; Inflammation; Inflammatory; Intestinal permeability; Intestines; Introns; Link; Longitudinal Studies; Malignant Neoplasms; Marker Discovery; Measurement; Measures; Movement; Multivariate Analysis; Osteoporosis; Outcome; Outcome Measure; Pathologic Processes; Peripheral Blood Mononuclear Cell; Persons; Phenotype; Plasma; Population; Proteomics; RNA; Reporting; Role; Sampling; Site; Small Intestines; Sorting; Stroke; T-Cell Receptor; T-Lymphocyte; T-Lymphocyte Subsets; Testing; Tight Junctions; Tissues; Viral; Viral Load result; Visualization; aged; antagonist; bone loss; cohort; comorbidity; cytokine; cytotoxicity; detection assay; experimental study; frailty; gastrointestinal; human old age (65+); in vitro Assay; inflammatory marker; inhibitor; innovation; insight; intestinal barrier; intestinal epithelium; latent HIV reservoir; microbial products; monolayer; mortality; multiplex detection; normal aging; novel; novel therapeutic intervention; novel therapeutics; prevent; prospective; receptor; response; systemic inflammatory response; γδ T cells

ABSTRACT Even with successful viral control, HIV-infected individuals exhibit co-morbidities associated with older age, including osteoporosis, stroke, dementia, and cancer. In aviremic HIV+ individuals and the general geriatric population, age-associated diseases and mortality correlate with plasma markers of inflammation and intestinal permeability. The gut is a major reservoir of latently HIV-infected cells, and HIV enteropathy, defined as pathologic processes in the small intestine and colon, is a hallmark of HIV infection. Our preliminary data implicate gamma delta T cells as an inflammatory driver in ART-suppressed HIV infection and with normal aging. gamma delta T cells are a non-conventional T cell lineage that comprise ≤10% of circulating T cells yet are found in considerably higher proportions in the epithelium of the intestine. Also, there is evidence that this unique T cell population regulates intestinal barrier function during normal conditions, and that gamma delta T pro-inflammatory activity causes damage at epithelial sites and to epithelial barriers. Therefore, we hypothesize that with virally suppressed HIV infection and with normal aging, gastrointestinal gamma delta T cells are stimulated via directly harboring HIV and/or exposure to inflammatory factors and this aberrant activation leads to breakdown of tight junctions of the intestinal epithelial barrier, causing increased release of microbial products and inflammatory gamma delta T cells into the circulation. Further, we predict that aged gamma delta T cells exhibit functional profiles skewed towards inflammatory cytokines/cytotoxicity in response to either direct HIV infection and/or stimulatory factors. In this application, we propose to test these hypotheses using advanced and innovative approaches, including 25-color flow cytometry, 31-color imaging mass cytometry of recto-sigmoid biopsies, 19- and 33-plex analyses of plasma and cell culture supernatants, respectively, and multiple algorithms for multivariate analysis of collected datasets. Our bioinformatic data analysis plan will enable identifying novel gamma delta T cell subsets and parsing the differential impacts of age with and without HIV infection. In Aim 1 we will perform a cross-sectional study of our HIV and Aging cohort to determine the links between circulating gamma delta T cell subsets, plasma inflammatory and intestinal permeability markers, and intestinal architecture and cellular composition. In Aim 2 we will determine the temporal links between gamma delta T cell subsets, plasma markers, and the onset and/or progression of geriatric outcomes via a longitudinal study of older subjects with and without ART-suppressed HIV. In Aim 3, we will perform in vitro assays to determine how age and HIV infection impact gamma delta T cell functions, including the capacity to breakdown intestinal epithelial cell monolayers. We predict that our proposed experiments will identify the biological mechanisms that drive the increased systemic inflammation and age-associated comorbidities in both aviremic HIV+ individuals and the general geriatric population; such insight could lead to the development of novel therapeutics to reduce ‘inflamm-aging’-associated diseases and deaths.

摘要 即使成功地控制了病毒，艾滋病毒感染者也会出现与年龄较大有关的并发症， 包括骨质疏松症、中风、痴呆和癌症。在艾滋病毒血症的HIV+个体和一般老年人中， 人口、年龄相关疾病和死亡率与炎症和肠道炎症的血浆标志物相关。 磁导率肠道是潜伏性HIV感染细胞的主要储存库，HIV肠病定义为： 小肠和结肠的病理过程是HIV感染的标志。我们的初步数据 γ δ T细胞作为ART抑制HIV感染的炎症驱动因子， 衰老γ δ T细胞是一种非常规T细胞谱系，其占循环T细胞的≤10%，但在外周血中发现。 在肠上皮中的比例相当高。同时，有证据表明这种独特的T细胞 在正常情况下，群体调节肠屏障功能，并且γ δ T促炎活性 导致上皮部位和上皮屏障的损伤。因此，我们假设， 受抑制的HIV感染和正常衰老，胃肠道γ δ T细胞通过直接携带 HIV和/或暴露于炎症因子，这种异常激活导致细胞紧密连接的破坏， 肠上皮屏障，导致微生物产物和炎性γ δ T细胞释放增加， 流通。此外，我们预测老化的γ δ T细胞表现出倾向于炎症的功能特征， 细胞因子/细胞毒性响应于直接HIV感染和/或刺激因子。在本申请中，我们 建议使用先进和创新的方法来测试这些假设，包括25色流式细胞术， 31-直肠乙状结肠活检的彩色成像质谱细胞术，血浆和细胞培养的19和33重分析 上清液，以及用于收集的数据集的多变量分析的多种算法。我们 生物信息学数据分析计划将能够识别新的γ δ T细胞亚群，并分析不同的影响 有和没有艾滋病毒感染的年龄。在目标1中，我们将对我们的艾滋病毒和老龄化进行横断面研究 队列，以确定循环γ δ T细胞亚群、血浆炎症和肠 渗透性标志物和肠结构和细胞组成。在目标2中，我们将确定 γ δ T细胞亚群、血浆标志物与老年性脑梗死的发生和/或进展之间的时间联系 通过对有和没有ART抑制的HIV的老年受试者进行纵向研究，在目标3中，我们 进行体外试验，以确定年龄和艾滋病毒感染如何影响γ δ T细胞功能，包括能力 破坏肠上皮细胞单层。我们预测，我们提出的实验将确定 生物学机制，驱动增加全身炎症和年龄相关的合并症， 艾滋病毒血症的HIV+个体和一般老年人群;这种认识可能导致发展 减少“炎症性衰老”相关疾病和死亡的新型疗法。