Harnessing IL-10 in cART treated SIV infected macaques to restore immunity and to eradicate HIV

在 cART 治疗的感染 SIV 的猕猴中利用 IL-10 恢复免疫力并根除 HIV

• 批准号: 10588314
• 负责人: Rafick Pierre Sekaly
• 金额: $ 79.33万
• 依托单位: EMORY UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2023
• 资助国家: 美国
• 起止时间: 2023-07-01 至 2028-06-30
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10588314
• 关键词: Achievement; Acquired Immunodeficiency Syndrome; Berlin; Biological; Bone Marrow Cell Transplantation; Cells; Cellular Immunity; Clinic; Clinical; Development; Disease remission; Frequencies; Goals; HIV; HIV Infections; Human; Human Activities; Immune response; Immunity; Individual; Instruction; Interleukin-10; Intervention; Lymphoid Tissue; Macaca; Macaca mulatta; Maintenance; Molecular; Monitor; Morbidity - disease rate; Natural Immunity; Pathway interactions; Patients; Peripheral Blood Mononuclear Cell; Play; Regimen; Rhesus; Role; SIV; Testing; Therapeutic; Therapeutic Intervention; Tissues; Translating; Up-Regulation; Viral; Virus; adaptive immune response; antiviral immunity; biomarker identification; cytokine; mortality; novel strategies; preclinical trial; predictive marker; prevent; restoration

While current ART has prevented AIDS and reduced HIV-related morbidities and mortality for the majority of infected individuals, a therapeutic regimen able to eradicate or functionally cure HIV infection does not exist. Persistence of HIV in a small pool of latently infected cells remains the major obstacle for HIV eradication largely because the mechanisms that underlie viral persistence are still unknown. Our group has generated significant and convincing results in cART treated HIV infected humans and SIV infected rhesus macaques (RMs) suggesting that Interleukin(IL)-10 plays an important role in the establishment and maintenance of the HIV reservoir by (i) impeding the early antiviral innate and the HIV/SIV specific adaptive immune response and (ii) promoting the differentiation of Tfh and Tr1 cells that are major HIV/SIV reservoirs. The importance of IL-10 in the establishment and maintenance of HIV has prompted Merck to successfully develop a Rhesus form of an anti-human IL-10 Ab that is currently being tested in clinic; administration of this Ab in a proof of concept study to SIV infected RMs was safe and well tolerated; it also recapitulated several of the biological activities of the human Ab as it showed a negative impact on Tfh frequencies which could translate in a smaller reservoir. In this proposal, we will test the hypothesis that neutralization of IL-10 activity systemically and in lymphoid tissues will lead to restoration of cellular immune responses, decreased Tfh and Tr1 numbers, and a decay in HIV reservoir. Biomarkers that predict successful clinical interventions involving anti-IL-10 and leading to HIV eradication are not available. In Aim 1, we will perform an unbiased OMICs integrated approach to identify cell subsets, soluble effector molecules, metabolites and molecular pathways, which underlie the modulation of HIV reservoirs by IL-10 in cell subsets isolated from PBMCs and tissues from cART treated HIV infected subjects. We will identify markers that are associated to low levels of IL-10 and conversely to lower HIV reservoir in Tfh and Tr1 cells and efficient innate antiviral and cell mediated immunity. These markers will be used to monitor the impact of the anti-IL-10 intervention that aims at restoring innate antiviral immunity and cell mediated immunity for HIV eradication. Direct demonstration that IL-10 regulates HIV persistence will be provided by examining the impact of IL-10 blockade on virus persistence in a large study of ART-treated, SIV-infected RMs. Preclinical trial of Aim 2 will allow us to determine the restoration of innate immunity by early IL-10 blockade as this intervention should inhibit the upregulation of NLRX-1, a molecule we have shown to play a critical role in the early HIV/SIV dissemination and conversely in the seeding of the HIV/SIV reservoir. Pre-clinical trial of Aim 3 should allow the restoration of the adaptive immune response by preventing the development of IL-10 producing Tr1 cells; IL-10 blockade will also trigger the HIV/SIV reservoir decay in Tfh cells which depend on IL-10 for their survival and differentiation. Achievement of these goals will lead to the development of a much-needed strategy aimed at eradicating HIV. RELEVANCE (See instructions): HIV eradication have become a realistic possibility as was shown by the Berlin patient who was cured of HIV by bone marrow transplantation of cells that cannot be infected by HIV. Therapeutic interventions which are less invasive must be explored and tested. We present here a novel strategy that targets IL-10, a cytokine that enhances the number of cells that can become reservoirs for HIV and inhibits antiviral immune responses. We expect that our approach will restore immune responses and decrease the reservoir size, thus promoting HIV remission.

虽然目前的抗逆转录病毒疗法预防了艾滋病，降低了大多数人与艾滋病毒有关的发病率和死亡率， 对于受感染的个体，能够根除或功能性治愈HIV感染的治疗方案不 存在. HIV在一小部分潜伏感染细胞中的持续存在仍然是HIV的主要障碍 根除的主要原因是病毒持续存在的机制仍不清楚。我们集团 在cART治疗的HIV感染者和SIV感染者中产生了显著和令人信服的结果 提示白细胞介素（IL）-10在建立和调节细胞凋亡中起重要作用。 通过（i）阻碍早期抗病毒先天性和HIV/SIV特异性适应性免疫应答， 免疫应答和（ii）促进作为主要HIV/SIV的Tfh和Tr 1细胞的分化 水库IL-10在建立和维持HIV中的重要性促使默克公司 成功地开发了一种恒河猴形式的抗人IL-10抗体，目前正在临床上进行测试; 在对SIV感染RM的概念验证研究中，给予该Ab是安全的且耐受性良好; 概括了人Ab的几种生物活性，因为它对Tfh显示出负面影响 可以在更小的水库中转换的频率。在本提案中，我们将检验以下假设： 全身和淋巴组织中IL-10活性的中和将导致细胞免疫功能的恢复。 免疫反应，Tfh和Tr 1数量减少，HIV储存库衰减。生物标志物可以预测 涉及抗IL-10并导致HIV根除的成功临床干预尚不可用。在Aim中 1，我们将执行一个公正的OMIC整合方法，以确定细胞亚群，可溶性效应细胞， 分子、代谢物和分子途径，它们是IL-10调节HIV储库的基础 在从PBMC和来自cART治疗的HIV感染受试者的组织分离的细胞亚群中。我们将确定 与Tfh和Tr 1细胞中低水平IL-10相关的标志物，相反，与较低的HIV储库相关 以及有效的天然抗病毒和细胞介导的免疫。这些标记将用于监测影响 抗IL-10干预旨在恢复先天抗病毒免疫和细胞介导的免疫， 根除艾滋病毒。IL-10调节HIV持续性的直接证明将通过检查 在ART治疗的SIV感染RM的大型研究中，IL-10阻断对病毒持久性的影响。 Aim 2的临床前试验将使我们能够通过早期IL-10阻断来确定先天免疫的恢复 因为这种干预应该抑制NLRX-1的上调，我们已经证明NLRX-1是一种分子， 在早期HIV/SIV传播和相反在HIV/SIV库的播种中的作用。临床前 目标3的试验应该通过防止发展来恢复适应性免疫反应。 IL-10的阻断也会触发Tfh细胞中HIV/SIV储库的衰减， 依赖IL-10来维持其存活和分化。实现这些目标将导致 制定一项旨在根除艾滋病毒的急需战略。 相关性（参见说明）： 正如柏林的一位病人所证明的那样， 艾滋病病毒通过骨髓移植的细胞不能被艾滋病病毒感染。治疗干预 必须探索和测试侵入性较小的方法。我们在这里提出了一种新的策略，目标是IL-10， 一种细胞因子，可增加可成为HIV储存库的细胞数量，并抑制抗病毒 免疫反应。我们希望我们的方法能恢复免疫反应，减少免疫反应。 水库的大小，从而促进艾滋病毒缓解。