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: 10336870
• 负责人: Rafick Pierre Sekaly
• 金额: $ 30.85万
• 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/10336870
• 关键词: Harnessing; IL; 10; cART; treated

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.

虽然目前的抗逆转录病毒疗法已经预防了艾滋病并降低了大多数人与艾滋病毒相关的发病率和死亡率 对于感染者来说，不存在能够根除或功能性治愈 HIV 感染的治疗方案。 HIV在一小部分潜伏感染细胞中的持续存在仍然是根除HIV的主要障碍 主要是因为病毒持续存在的机制仍然未知。我们组已经生成了 在 cART 治疗的 HIV 感染人类和 SIV 感染恒河猴中取得了显着且令人信服的结果 (RM) 表明白细胞介素 (IL)-10 在建立和维持 通过 (i) 阻碍早期抗病毒先天免疫反应和 HIV/SIV 特异性适应性免疫反应来消除 HIV 病毒库 (ii) 促进作为主要 HIV/SIV 储存库的 Tfh 和 Tr1 细胞的分化。的重要性 IL-10在HIV建立和维持中的作用促使默克公司成功开发出Rhesus 目前正在临床测试的抗人 IL-10 抗体形式；该抗体的管理证明 针对 SIV 感染 RM 的概念研究是安全且耐受性良好的；它还概括了一些生物 人类抗体的活动，因为它显示出对 Tfh 频率的负面影响，这可能会转化为更小的 水库。在本提案中，我们将检验系统性中和 IL-10 活性的假设 在淋巴组织中会导致细胞免疫反应恢复、Tfh 和 Tr1 降低 数量和艾滋病毒储存库的衰减。预测成功临床干预的生物标志物涉及 抗 IL-10 并导致 HIV 根除尚不存在。在目标 1 中，我们将执行公正的 OMIC 识别细胞亚群、可溶性效应分子、代谢物和分子途径的综合方法， 这是从 PBMC 和组织中分离的细胞亚群中 IL-10 对 HIV 储存库进行调节的基础 cART 治疗了 HIV 感染者。我们将鉴定与低水平 IL-10 相关的标记物 相反，可以降低 Tfh 和 Tr1 细胞中的 HIV 储存量，并实现有效的先天抗病毒和细胞介导的免疫。 这些标记物将用于监测旨在恢复先天性的抗 IL-10 干预措施的影响 根除艾滋病毒的抗病毒免疫和细胞介导的免疫。 IL-10调节的直接证明 将通过检查 IL-10 阻断对大范围病毒持久性的影响来提供 HIV 持久性 对接受 ART 治疗、感染 SIV 的 RM 进行的研究。 Aim 2 的临床前试验将使我们能够确定 通过早期 IL-10 阻断来实现先天免疫，因为这种干预应抑制 NLRX-1 的上调，NLRX-1 是一种 我们已经证明该分子在早期 HIV/SIV 传播中发挥着关键作用，反之亦然 HIV/SIV 储存库的播种。目标 3 的临床前试验应该能够恢复适应性免疫 通过阻止产生 IL-10 的 Tr1 细胞的发育来做出反应； IL-10封锁也会触发 Tfh 细胞中的 HIV/SIV 储存库衰退，其生存和分化依赖于 IL-10。成就 这些目标将导致制定一项急需的旨在根除艾滋病毒的战略。