Innate Lymphoid Cell Loss in HIV-1 and SIV Infection

HIV-1 和 SIV 感染中的先天淋巴细胞损失

基本信息

批准号：
9618331
负责人：
Joseph Christopher Mudd
金额：
$ 15.84万
依托单位：
TULANE UNIVERSITY OF LOUISIANA
依托单位国家：
美国
项目类别：
财政年份：
2020
资助国家：
美国
起止时间：
2020-03-11 至 2022-02-28
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/9618331
关键词：
AIDS/HIV problem Acute Address Animals Blood CASP3 gene CD4 Positive T Lymphocytes CXCL10 gene Cardiovascular system Cell Count Cell Survival Cell physiology Cells Cessation of life Chronic Phase of Disease Coculture Techniques Cohort Studies Disease Event Exhibits Expression Profiling Frequencies Gastrointestinal tract structure Gene Expression General Population Genes Gut Mucosa HIV HIV-1 HLA-DR Antigens Health Homeostasis Human IL2RA gene Immune Immune System Diseases In Vitro Infection Inflammation Inflammation Mediators Inflammatory Inflammatory Response Interferon Type I Interferon Type II Interleukin-1 Interleukin-13 Interleukin-17 Interleukin-2 Interleukin-4 Interleukin-6 Liver diseases Longevity Lymphoid Cell Lymphopenia Macaca mulatta Macaca nemestrina Malignant Neoplasms Measurement Mediating Mediator of activation protein Molecular Morbidity - disease rate Mucosal Immunity Mucous Membrane Pathway interactions Patients Phenotype Plasma Population Primates Recovery Residual state Role SIV Sampling Signal Transduction Source Supplementation Syndrome T cell response T-Lymphocyte TNFRSF5 gene TNFSF5 gene Therapeutic Time Tissues Virus Diseases Work antiretroviral therapy comorbidity cytokine effective therapy experimental study gastrointestinal genetic signature immune function immune reconstitution improved in vivo inflammatory marker insight interest interleukin-22 mesenteric lymph node mortality risk natural killer cell protein 44-kDa negative affect nonhuman primate reconstitution repaired restoration therapeutic target transcriptome sequencing transcriptomics

项目摘要

Joseph C. Mudd Innate lymphoid cell loss in HIV-1 infection Project Summary As of 2016, roughly half of the 36 million people living with HIV/AIDS worldwide are accessing antiretroviral therapy (ART). While these numbers represent significant advances in the number of patients receiving treatment, HIV-1+ subjects on ART continue to exhibit shorter lifespans, averaging a risk of death roughly six times higher than that of the general population. A significant proportion of these deaths relate to non-AIDS defining co-morbidities such as cardiovascular, cancer, and liver diseases. Several large cohort studies have attributed these co-morbidities in part to residual damage to the gastrointestinal (GI) tract that is sustained early in HIV-1 disease course. Under normal circumstances, gut mucosal function is maintained in part by the cytokines IL-17 and IL-22. CD4+ T cells are important sources of these, yet there are also innate sources of IL- 17 and IL-22 in the gut that are less explored. Innate lymphoid cells (ILCs) are capable of producing IL-17 and IL-22 and along with Th17/Th22 cells, are rapidly lost in the gut during HIV-1 and SIV infection. Thus, in order to develop more effective therapies aimed at curtailing GI damage in treated HIV-1 infection, a more complete understanding of the role of ILCs in gut mucosal health is needed. Here, we propose to examine the mechanisms by which ILCs are lost in both HIV-1+ humans and nonhuman primate progressive hosts of SIV infection. ILCs are not permissive to HIV-1/SIV infection, and ILC depletion is not a generalized feature of all viral infections. In preliminary studies, we have identified CD4 T cell loss and inflammatory mediators as important determinant of ILC depletion in HIV-1/SIV infection. We hypothesize that CD4 T cells provide essential survival factors to ILCs and that loss of both of these populations contributes to GI barrier damage. In aim I, we will explore the precise mechanisms underlying CD4-help to ILCs. We will assess these mechanisms by in vitro co-culture experiments of purified CD4 T cells and ILCs from healthy donors, using measurements of ILC viability and functionality as readouts. We will extend these findings to then look at these mechanisms in settings of immune dysfunction during ART, which are often characterized by suboptimal CD4 T cell responses to therapy. In the second aim, we will expand upon aim I by therapeutically targeting ILC reconstitution as a way to boost gut mucosal health in SIV-infected primates receiving ARVs. We hypothesize that therapies aimed at improving gut mucosal health will be associated with increases in ILC survival and functionality. To address this, we will utilize gut mucosal samples of SIV+ pigtail macaques treated with ARVs and the pleiotropic cytokine IL-21. Il-21 supplementation has previously been shown to enhance GI barrier repair, and we will evaluate the effect of IL-21 therapy on ILC gene expression profiles, as well as ILC survival and functionality when compared to these parameters in SIV+ animals receiving ARVs alone. Taken together, these studies will provide an in-depth assessment into the contribution of ILCs to gut mucosal function in treated HIV-1 and SIV infection, and provide important fundamental insights into mechanisms regulating ILC survival.

约瑟夫·穆德 HIV-1 感染中先天性淋巴细胞损失项目概要截至 2016 年，全球 3600 万艾滋病毒/艾滋病感染者中约有一半正在接受抗逆转录病毒治疗治疗（ART）。虽然这些数字代表了接受治疗的患者数量的显着进步治疗后，接受 ART 的 HIV-1+ 受试者的寿命继续缩短，平均死亡风险约为 6 比一般人群高出数倍。这些死亡中很大一部分与非艾滋病有关定义心血管、癌症和肝脏疾病等合并症。多项大型队列研究已将这些合并症部分归因于早期持续的胃肠道残余损伤在 HIV-1 疾病过程中。正常情况下，肠粘膜功能部分由细胞因子 IL-17 和 IL-22。 CD4+ T 细胞是这些细胞的重要来源，但也有 IL- 的先天来源。肠道中的 17 和 IL-22 的研究较少。先天淋巴细胞 (ILC) 能够产生 IL-17 和在 HIV-1 和 SIV 感染期间，IL-22 以及 Th17/Th22 细胞在肠道中迅速丢失。因此，在为了开发更有效的疗法，旨在减少治疗 HIV-1 感染时胃肠道损伤，更需要完全了解 ILC 在肠道粘膜健康中的作用。在此，我们建议检查 HIV-1+人类和非人类灵长类SIV进展宿主中ILC丢失的机制感染。 ILC 不允许 HIV-1/SIV 感染，并且 ILC 耗竭并不是所有病毒的普遍特征感染。在初步研究中，我们已经确定 CD4 T 细胞损失和炎症介质很重要 HIV-1/SIV 感染中 ILC 耗竭的决定因素。我们假设 CD4 T 细胞提供必需的 ILC 的生存因素以及这两个群体的丧失都会导致胃肠道屏障受损。在目标一中，我们将探索 CD4 帮助 ILC 的精确机制。我们将通过以下方式评估这些机制：使用 ILC 测量，对来自健康供体的纯化 CD4 T 细胞和 ILC 进行体外共培养实验作为读数的可行性和功能。我们将扩展这些发现，然后研究这些机制 ART 期间免疫功能障碍的情况，通常以 CD4 T 细胞反应欠佳为特征来治疗。在第二个目标中，我们将通过治疗性靶向 ILC 重建来扩展目标 I，以此作为促进接受 ARV 治疗的感染 SIV 的灵长类动物的肠道粘膜健康状况。我们假设治疗的目的是改善肠道粘膜健康与 ILC 存活率和功能的增加有关。致地址为此，我们将利用经过 ARV 和多效性治疗的 SIV+ 猪尾猕猴的肠道粘膜样本细胞因子IL-21。先前已证明补充 IL-21 可以增强胃肠道屏障修复，我们将评估 IL-21 治疗对 ILC 基因表达谱以及 ILC 存活和功能的影响与单独接受抗逆转录病毒药物的 SIV+ 动物的这些参数进行比较。总而言之，这些研究将为 ILC 对肠粘膜的贡献提供深入的评估。在治疗 HIV-1 和 SIV 感染中发挥作用，并为机制提供重要的基本见解调节 ILC 存活。