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

虽然目前的抗逆转录病毒疗法预防了艾滋病，并降低了大多数人与艾滋病毒有关的发病率和死亡率， 在受感染的个体中，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 这主要是因为病毒持续存在的机制仍不清楚。我们的小组已经产生了 在cART治疗的HIV感染的人和SIV感染的恒河猴中获得了显著和令人信服的结果 (RMs)提示白细胞介素（IL）-10在建立和维持 通过（i）阻碍早期抗病毒先天性和HIV/SIV特异性适应性免疫应答， 和（ii）促进作为主要HIV/SIV储库的Tfh和Tr 1细胞的分化。的重要性 IL-10在建立和维持艾滋病毒促使默克公司成功地开发了一种恒河猴 目前正在临床上测试的抗人IL-10 Ab的形式; 对SIV感染RM的概念研究是安全的，耐受性良好;它还概括了几种生物学特性， 人Ab的活性，因为它显示出对Tfh频率的负面影响，这可以转化为较小的 水库在这个建议中，我们将测试假设，中和IL-10活性全身 在淋巴组织中，Tfh和Tr 1的降低会导致细胞免疫反应的恢复， 数量，以及艾滋病毒储存库的衰减。预测成功临床干预的生物标志物， 抗IL-10和导致艾滋病毒根除的方法不可用。在目标1中，我们将执行无偏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， 其是在从PBMC和组织分离的细胞亚群中通过IL-10调节HIV储库的基础， cART治疗的HIV感染受试者。我们将鉴定与低水平IL-10相关的标志物， 相反地，Tfh和Tr 1细胞中的HIV储库较低，并且具有有效的先天性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免疫缺陷的抗IL-10干预的影响。 抗病毒免疫和细胞介导的免疫用于HIV根除。直接证明IL-10调节 HIV持续性将通过检查IL-10阻断对病毒持续性的影响来提供， ART治疗的SIV感染RM的研究。Aim 2的临床前试验将使我们能够确定 先天免疫通过早期IL-10阻断，因为这种干预应该抑制NLRX-1的上调， 我们已经证明，这种分子在HIV/SIV的早期传播中起着关键作用，相反，在 接种HIV/SIV宿主。Aim 3的临床前试验应允许恢复适应性免疫 通过阻止产生IL-10的Tr 1细胞的发展来产生免疫应答; IL-10阻断也会触发免疫应答。 Tfh细胞中的HIV/SIV储库衰减，其依赖于IL-10用于其存活和分化。成就 这些目标的实现将导致制定一项旨在根除艾滋病毒的迫切需要的战略。

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.