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.

尽管目前的艺术阻止了大多数艾滋病并降低了与HIV相关的病因和死亡率 在感染的个体中，能够根除或在功能上治愈HIV感染的治疗方案没有 存在。艾滋病毒在一小群潜在感染细胞中的持久性仍然是艾滋病毒的主要障碍 根除的主要是因为病毒持久性基础的机制仍然未知。我们的小组 在接受过的艾滋病毒感染的人中和感染的SIV中产生了重要而令人信服的结果 Rhesus Macaques（RMS）表明，白介素（IL）-10在机构和 （i）阻碍早期抗病毒药物和艾滋病毒/艾滋病毒特定自适应的艾滋病毒水库维护 免疫反应和（ii）促进主要HIV/SIV的TFH和TR1细胞的分化 水库。 IL-10在艾滋病毒的建立和维持中的重要性促使默克 成功地开发了目前正在诊所进行测试的抗人IL-10 AB的恒河猴形式。 在对SIV感染的RMS的概念研究证明中，对此AB进行了安全且耐受性良好。也是如此 概括了人类AB的几种生物学活性，因为它显示出对TFH的负面影响 可以在较小的储层中翻译的频率。在此提案中，我们将检验以下假设 IL-10活性的中和系统和淋巴组织中的中和将导致细胞恢复 免疫反应，TFH和TR1数量降低，以及HIV储层中的腐烂。预测的生物标志物 涉及抗IL-10并导致消除HIV的成功临床干预措施不可用。目标 1，我们将执行一种公正的OMIC集成方法来识别细胞子集，可溶性效应器 分子，代谢物和分子途径，这是IL-10对HIV储量调节的基础 在从PBMC和组织中分离出的细胞子集中，被CART处理的HIV感染受试者分离出来。我们将确定 与低水平IL-10相关的标记，相反，与TFH和TR1细胞中的HIV储量降低有关 有效的先天抗病毒和细胞介导的免疫力。这些标记将用于监视影响 旨在恢复先天抗病毒免疫和细胞介导的免疫力的抗IL-10干预措施 消除艾滋病毒。直接证明IL-10通过检查将提供艾滋病毒持久性 IL-10阻断对病毒持续性的影响在一项针对ART处理的SIV感染的RMS的研究中。 AIM 2的临床前试验将使我们能够通过IL-10早期封锁来确定先天免疫的恢复 由于这种干预应抑制NLRX-1的上调，因此我们已经证明可以发挥关键的分子 在早期艾滋病毒/SIV传播中的作用，相反在艾滋病毒/SIV储层的播种中作用。临床前 AIM 3的试验应允许通过防止发展来恢复自适应免疫反应 产生TR1细胞的IL-10； IL-10封锁还将触发TFH细胞中的HIV/SIV储层衰减 依赖IL-10的生存和分化。实现这些目标将导致 制定旨在消除艾滋病毒的急需战略。 相关性（请参阅说明）： 消除艾滋病毒已成为现实的可能性，如柏林患者所表明的那样 HIV通过无法感染HIV的细胞的骨髓移植。治疗干预措施 必须探索和测试较小的侵入性。我们在这里提出了针对IL-10的新型策略，一个 细胞因子可以增强可能成为HIV储层并抑制抗病毒的细胞数量 免疫反应。我们预计我们的方法将恢复免疫反应并减少 储层大小，从而促进HIV缓解。