Innate Lymphoid Cell Loss in HIV-1 and SIV Infection

约瑟夫·C·穆德 HIV-1感染中的先天淋巴样细胞丢失 项目摘要 截至2016年，全球3600万艾滋病毒/艾滋病患者中，大约有一半人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著进步 接受抗逆转录病毒治疗的HIV-1+受试者继续表现出较短的寿命，平均死亡风险约为6 是普通人群的三倍。这些死亡中有很大一部分与非艾滋病有关 定义心血管疾病、癌症和肝病等并存疾病。几项大型队列研究已经 将这些合并症部分归因于早期持续的胃肠道(GI)的残余损害 在HIV-1病程中。在正常情况下，肠道粘膜功能的部分维持是由 细胞因子IL-17和IL-22。CD4+T细胞是这些疾病的重要来源，但也有天生的IL- 17和IL-22是肠道中较少被研究的物质。先天淋巴样细胞(ILCs)能够产生IL-17和 在HIV-1和SIV感染期间，IL-22和Th17/Th22细胞在肠道中迅速丢失。因此，在 为了开发更有效的治疗方法，旨在减少经治疗的HIV-1感染的胃肠道损害，更多 完全了解ILCs在肠道粘膜健康中的作用是必要的。在这里，我们建议研究 HIV-1阳性人类和非人类灵长类SIV渐进宿主中ILC丢失的机制 感染。 ILC对HIV-1/SIV感染是不允许的，ILC耗尽也不是所有病毒的普遍特征 感染。在初步研究中，我们发现CD4T细胞丢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CD4T细胞提供了必要的 生存因素对ILC和这两个群体的丧失都会导致胃肠道屏障的损害。在AIM I中，我们 将探索CD4-HELP对ILC的确切机制。我们将通过以下方式评估这些机制： 健康献血者纯化的CD4T细胞与ILC的体外共培养实验 作为读数的可行性和功能性。我们将扩展这些发现，然后在 抗逆转录病毒治疗期间的免疫功能障碍，其特点通常是CD4T细胞反应不佳 去接受治疗。 在第二个目标中，我们将通过以ILC重建为治疗目标来扩展目标I，以此作为促进 接受抗逆转录病毒药物的SIV感染灵长类动物的肠道粘膜健康状况。我们假设治疗的目的是为了 肠粘膜健康的改善将与ILC存活率和功能的增加相关。致信地址 为此，我们将利用用抗逆转录病毒药物和多效性药物治疗的SIV+猪尾猕猴的肠道粘膜样本。 细胞因子IL-21。补充IL-21之前已经被证明可以促进胃肠道屏障的修复，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的SIV+动物的这些参数相比。 综上所述，这些研究将深入评估ILCs对肠道粘膜的贡献。 在治疗HIV-1和SIV感染中的作用，并为机制提供重要的基础性见解 调节ILC生存。

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.