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

• 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
• 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

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.

Joseph C. Mudd HIV-1感染中的先天性淋巴细胞丢失 项目摘要 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化疗的患者人数的显著增加， 接受抗逆转录病毒治疗的HIV-1+受试者的寿命继续缩短，平均死亡风险约为6 比一般人群高出一倍。这些死亡中有很大一部分与非艾滋病有关 定义合并症，如心血管疾病、癌症和肝脏疾病。几项大型队列研究 将这些合并症部分归因于早期持续的胃肠道（GI）残留损伤 在HIV-1病程中。在正常情况下，肠粘膜功能部分地由 细胞因子IL-17和IL-22。CD4 + T细胞是这些的重要来源，但也有IL-4的先天来源。 17和IL-22在肠道中的作用较少探索。先天性淋巴样细胞（ILC）能够产生IL-17， IL-22和沿着Th17/Th22细胞在HIV-1和SIV感染期间在肠道中迅速丢失。因此在 为了开发更有效的治疗方法，旨在减少治疗HIV-1感染时的胃肠道损伤， 需要完全理解ILC在肠粘膜健康中的作用。在这里，我们建议审查 ILC在HIV-1+人类和SIV的非人灵长类进行性宿主中丢失的机制 感染 ILC不允许HIV-1/SIV感染，ILC缺失不是所有病毒感染的普遍特征。 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是重要的， HIV-1/SIV感染中ILC耗竭的决定因素。我们假设CD4 T细胞提供了必要的 ILC的存活因素，这两个群体的损失有助于GI屏障损伤。在aim i中，我们 将探索CD4-辅助ILC的确切机制。我们将评估这些机制， 使用ILC的测量，来自健康供体的纯化的CD4 T细胞和ILC的体外共培养实验 可行性和功能性作为读数。我们将扩展这些发现，然后看看这些机制， ART期间的免疫功能障碍，通常以次优CD4 T细胞应答为特征 接受治疗 在第二个目标中，我们将在目标I的基础上进行扩展，通过治疗性靶向ILC重建作为增强免疫力的一种方式。 接受抗逆转录病毒治疗的SIV感染灵长类动物的肠道粘膜健康。我们假设治疗的目的是 改善肠粘膜健康将与ILC存活和功能的增加相关。解决 因此，我们将利用用ARV和多效性抗逆转录病毒药物治疗的SIV+猪尾猕猴的肠粘膜样品， 细胞因子IL-21。IL-21补充剂先前已被证明可增强GI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 与仅接受抗逆转录病毒药物治疗的SIV+动物的这些参数相比。 总而言之，这些研究将深入评估ILC对肠道粘膜的贡献 在治疗HIV-1和SIV感染中发挥作用，并提供重要的机制基本见解 调节ILC存活。