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: 10463861
• 负责人: Rafick Pierre Sekaly
• 金额: $ 76.96万
• 依托单位: EMORY UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2018
• 资助国家: 美国
• 起止时间: 2018-07-01 至 2023-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10463861
• 关键词: Achievement; Acquired Immunodeficiency Syndrome; Anatomy; Antibodies; Attenuated; B-Lymphocytes; Berlin; Biological; Biological Markers; Blood; Bone Marrow Cell Transplantation; Cells; Cellular Immunity; Cellular Stress; Chronic Phase; Clinic; Clinical; Clinical Trials; Collaborations; DNA; Development; Disease remission; Exposure to; Frequencies; Goals; HIV; HIV Infections; Human; Human Activities; Humoral Immunities; Immune; Immune response; Immunity; Individual; Infection; Inflammation; Infusion procedures; Interleukin-10; Interruption; Intervention; Kinetics; Location; Lymphoid Cell; Lymphoid Tissue; Macaca; Macaca mulatta; Maintenance; Modeling; Molecular; Monitor; Morbidity - disease rate; Myeloid Cells; Natural Immunity; Pathway interactions; Patients; Pattern; Peripheral Blood Mononuclear Cell; Phenotype; Play; RNA; Reagent; Regimen; Regulatory T-Lymphocyte; Rhesus; Role; SIV; Signal Transduction; Structure; T cell response; T memory cell; T-Lymphocyte; T-Lymphocyte Subsets; Testing; Therapeutic; Therapeutic Intervention; Therapeutic antibodies; Tissues; Translating; Up-Regulation; Viral; Viral Load result; Viral reservoir; Virus; acute infection; adaptive immune response; adaptive immunity; antiviral immunity; cytokine; efficacy testing; functional restoration; human subject; imaging approach; in vivo; inhibitor; memory CD4 T lymphocyte; microbial; monocyte; mortality; nonhuman primate; novel strategies; pathogen; peripheral lymphoid organ; preclinical trial; predictive marker; prevent; restoration; spatiotemporal; success; Achievement; Acquired Immunodeficiency Syndrome; Anatomy; Antibodies; Attenuated; B-Lymphocytes; Berlin; Biological; Biological Markers; Blood; Bone Marrow Cell Transplantation; Cells; Cellular Immunity; Cellular Stress; Chronic Phase; Clinic; Clinical; Clinical Trials; Collaborations; DNA; Development; Disease remission; Exposure to; Frequencies; Goals; HIV; HIV Infections; Human; Human Activities; Humoral Immunities; Immune; Immune response; Immunity; Individual; Infection; Inflammation; Infusion procedures; Interleukin-10; Interruption; Intervention; Kinetics; Location; Lymphoid Cell; Lymphoid Tissue; Macaca; Macaca mulatta; Maintenance; Modeling; Molecular; Monitor; Morbidity - disease rate; Myeloid Cells; Natural Immunity; Pathway interactions; Patients; Pattern; Peripheral Blood Mononuclear Cell; Phenotype; Play; RNA; Reagent; Regimen; Regulatory T-Lymphocyte; Rhesus; Role; SIV; Signal Transduction; Structure; T cell response; T memory cell; T-Lymphocyte; T-Lymphocyte Subsets; Testing; Therapeutic; Therapeutic Intervention; Therapeutic antibodies; Tissues; Translating; Up-Regulation; Viral; Viral Load result; Viral reservoir; Virus; acute infection; adaptive immune response; adaptive immunity; antiviral immunity; cytokine; efficacy testing; functional restoration; human subject; imaging approach; in vivo; inhibitor; memory CD4 T lymphocyte; microbial; monocyte; mortality; nonhuman primate; novel strategies; pathogen; peripheral lymphoid organ; preclinical trial; predictive marker; prevent; restoration; spatiotemporal; success

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.

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 感染的个体，一种能够消除或在功能上治愈HIV感染的治疗方案。 艾滋病毒在一小群潜在感染细胞中的持久性仍然是消除艾滋病毒的主要障碍 很大程度上是因为基于病毒持久性的机制仍然未知。我们的小组已经产生了 在手推车治疗的艾滋病毒感染的人和SIV感染的猕猴中，重要而令人信服的结果 （RMS）建议白介素（IL）-10在建立和维护中起重要作用 （i）阻碍早期抗病毒先天和HIV/SIV特异性适应性免疫反应的HIV储藏 （ii）促进主要HIV/SIV储藏的TFH和TR1细胞的分化。重要性 IL-10在艾滋病毒的建立和维持中，促使默克成功发展了恒河 目前正在诊所测试的抗人IL-10 AB的形式；在证明 对SIV感染RMS的概念研究是安全且耐受性的。它还概括了几种生物学 人类AB的活动显示对TFH频率的负面影响，可能会翻译成较小的TFH频率 水库。在此提案中，我们将检验以下假设：IL-10的中和 在淋巴组织中，将导致细胞免疫反应的恢复，TFH和TR1降低 数字和艾滋病毒水库中的腐烂。预测成功临床干预措施的生物标志物 抗IL-10并导致根除HIV。在AIM 1中，我们将执行公正的OMIC 鉴定细胞子集，可溶性效应分子，代谢产物和分子途径的综合方法， 这是IL-10在从PBMC和组织中分离的细胞子集对HIV储量的调节的基础。 手推车治疗了艾滋病毒感染的受试者。我们将确定与低水平IL-10相关的标记和 相反，在TFH和TR1细胞中降低HIV储量以及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抗IL-10干预措施的影响，旨在恢复先天 抗病毒免疫和细胞介导的消除HIV的免疫力。直接证明IL-10调节 通过检查IL-10封锁对大型病毒持续性的影响，将提供HIV持久性 对ART处理的SIV感染RMS的研究。 AIM 2的临床前试验将使我们能够确定恢复 IL-10早期封锁的先天免疫力，因为这种干预应抑制NLRX-1的上调 分子我们已经证明在早期的HIV/SIV传播中起着至关重要的作用，相反 HIV/SIV储层的播种。 AIM 3的临床前试验应允许恢复自适应免疫 通过防止IL-10产生TR1细胞的发展来反应； IL-10封锁也将触发 TFH细胞中的HIV/SIV储层衰减依赖于IL-10的生存和分化。成就 在这些目标中，将导致制定旨在消除艾滋病毒的急需战略。