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 对于受感染的人，不存在能够根除或从功能上治愈艾滋病毒感染的治疗方案。 艾滋病毒在一小群潜伏感染细胞中的持久性仍然是根除艾滋病毒的主要障碍 这在很大程度上是因为病毒持续存在的机制尚不清楚。我们的团队已经产生了 CART治疗HIV感染者和SIV感染猕猴的显著和令人信服的结果 (RMS)提示白介素10在血管紧张素转换酶的建立和维持中起重要作用 通过(I)阻止早期抗病毒先天免疫和HIV/SIV特异性获得性免疫反应的HIV储备库 以及(Ii)促进作为HIV/SIV主要储存库的Tfh和TR1细胞的分化。重要的是 IL-10在建立和维持艾滋病毒方面已促使默克公司成功研发出一种恒河猴 目前正在临床试验的抗人IL-10抗体的形式；该抗体的给药证明 SIV感染RMS的概念研究是安全和耐受性良好的；它还概括了几种生物学 人类抗体的活性，因为它对TFH频率有负面影响，可以翻译成较小的 水库。在这项提议中，我们将系统地检验中和IL-10活性的假设 而在淋巴组织中会导致细胞免疫反应的恢复，Tfh和TR1降低 数字，以及艾滋病毒储存库的腐烂。预测成功的临床干预的生物标记物 没有提供抗IL-10和导致根除艾滋病毒的药物。在目标1中，我们将执行公正的组学 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IL-10在从外周血单个核细胞和组织中分离的细胞亚群中对HIV储存库进行调节的基础 CART治疗艾滋病毒感染者。我们将确定与低水平IL-10和 反之，可降低HIV在Tfh和TR1细胞中的蓄积量和有效的先天抗病毒和细胞免疫。 这些标记物将用于监测旨在恢复先天缺陷的抗IL-10干预的影响 抗病毒免疫和细胞免疫根除艾滋病毒。IL-10调控的直接证据 将通过检查IL-10阻断对病毒持久性的影响来提供艾滋病毒持久性 ART治疗、SIV感染的RMS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阻断先天免疫，因为这种干预应该抑制NLRX-1，a 我们已经证明了分子在HIV/SIV的早期传播中发挥了关键作用，反过来在 艾滋病毒/SIV水库的播种。AIM 3的临床前试验应该允许恢复获得性免疫 通过阻止产生IL-10的TR1细胞的发展来做出反应；IL-10的阻断也将触发 HIV/SIV贮存库在依赖IL-10生存和分化的TFH细胞中腐烂。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.