Targeting the IL-10 pathway for an HIV Cure

针对 HIV 治愈的 IL-10 途径

• 批准号: 9326138
• 负责人: Rafick Pierre Sekaly
• 金额: $ 28.5万
• 依托单位: CASE WESTERN RESERVE UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2016
• 资助国家: 美国
• 起止时间: 2016-08-04 至 2018-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9326138
• 关键词: Acquired Immunodeficiency Syndrome; Animal Model; Animals; Anti-Retroviral Agents; Antibodies; Antiviral Agents; Antiviral Response; B-Lymphocytes; Biological; Blocking Antibodies; Blood; CD4 Positive T Lymphocytes; Cell physiology; Cells; Chronic; Clinical; Clinical Management; Clinical Trials; DNA; Dose; Down-Regulation; Excision; Flow Cytometry; Frequencies; Gene Expression Profile; Genes; Goals; HIV; HIV Infections; Homeostasis; Immune; Immune response; Individual; Infection; Inflammation; Interleukin-10; Interruption; Intervention; Lymph Node Tissue; Lymphocyte; Lymphoid Tissue; Macaca mulatta; Modeling; Molecular; Monitor; Monoclonal Antibodies; Morbidity - disease rate; Pathway interactions; Phase; Plasma; Production; Regimen; Research; Residual state; SIV; Safety; Seeds; Signal Transduction; Structure of germinal center of lymph node; T-Lymphocyte; Testing; Therapeutic; Tissues; Translating; Viral; Viral reservoir; Virus; Virus Latency; Virus Replication; Work; base; cost; exhaustion; immune checkpoint; immunosenescence; improved; in vivo; insight; mortality; nonhuman primate; novel; novel strategies; novel therapeutics; prevent; public health relevance; reconstitution; viral rebound

 DESCRIPTION (provided by applicant): While the recent optimization of ART has prevented AIDS and reduced AIDS-related morbidities and mortality for the majority of HIV-infected individuals, a scalable treatment that can cure HIV infection is still not available. Thus, lifelon administration of ART is necessary, posing significant challenges in terms of costs and clinical safety. Major obstacles to curing HIV infection include (1) persistent immune abnormalities, including inflammation, limited CD4 T cell reconstitution, and functional exhaustion of antiviral T cells; (ii) low levels of viral replication, particularly in tissues, and (iii) the presence of a sall pool of long-lived latently infected cells that are not affected by ART. Importantly, these contributors may be triggering and sustaining each other, thus creating a vicious cycle that maintains HIV persistence during ART. As such, novel approaches aimed at limiting residual inflammation, improving antiviral responses and reducing the survival of infected cells are needed for curing HIV. In this proposal, using the well-established nonhuman primate model of SIV infection, we will explore the effects of Interleukin (IL)-10 blockade on virus persistence in ART-treated, SIV- infected rhesus macaques (RMs). In preliminary work we have shown that IL-10 is a key contributor to HIV persistence by augmenting the survival of infected cells and of activated cells thereby favoring viral dissemination, increasing the expression of immune check point blockers (ICB), known to trigger T cell quiescence and viral latency, and having IL-10 producing B cells at the proximity of Tfh cells, major HIV reservoir. Based on these preliminary results, we propose that administration of an anti-IL-10 blocking antibody (αIL-10) will reduce HIV persistence by: (i) decreasing the survival of infected cells that can seed the HIV reservoir, and (ii) decreasing the expression of molecules known to be upstream regulators of T cell quiescence and HIV latency. In the R21 phase of this project we will administer αIL-10 to SIV infected cART treated RMs and define a dose that is safe and efficacious as monitored by the impact of the treatment on Tfh survival, germinal center organization, and the expression of ICB. In the R33 phase, once safety and optimal dose of this intervention are established, we will provide mechanistic insights into the positive impact of IL-10 neutralization on germinal center organization, Tfh survival and magnitude of the HIV reservoir. If our hypothesis is correct, we expect that by administration of αIL-10 in ART-treated, SIV-infected RMs, survival of infected and activated cells will be reduced, and more specifically for Tfh cells. Concomitantly, the persistent SIV reservoir will be progressively reduced. In summary, the proposed work will translate an improved understanding of HIV latency through rigorously controlled in vivo studies of a novel intervention in the most relevant animal model. If successful in inducing progressive reduction of the SIV reservoir, the proposed treatment would ultimately be tested in clinical trial aimed at curing HIV infection.

 描述(申请人提供)：虽然最近的抗逆转录病毒疗法的优化已经预防了艾滋病，并减少了大多数艾滋病毒感染者与艾滋病相关的发病率和死亡率，但仍然没有能够治愈艾滋病毒感染的可推广的治疗方法。因此，ART的终生给药是必要的，这在成本和临床安全性方面构成了重大挑战。治愈艾滋病毒感染的主要障碍包括：(1)持续性免疫异常，包括炎症、有限的CD4T细胞重建和抗病毒T细胞的功能衰竭 (2)低水平的病毒复制，特别是在组织中；(3)存在不受抗逆转录病毒治疗影响的长期潜伏感染细胞池。重要的是，这些贡献者可能相互触发和维持，从而造成恶性循环，在抗逆转录病毒治疗期间保持艾滋病毒的持久性。因此，需要旨在限制残余炎症、改善抗病毒反应和降低感染细胞存活率的新方法来治愈艾滋病毒。在这项建议中，我们将利用已建立的SIV感染的非人类灵长类动物模型，探讨白介素10(IL-10)阻断对经ART治疗的SIV感染恒河猴(RMS)病毒持久性的影响。在初步工作中，我们已经证明IL-10是HIV持续存在的关键因素，它通过增加感染细胞和激活细胞的存活从而有利于病毒传播，增加免疫检查点阻滞剂(ICB)的表达，已知触发T细胞静止和病毒潜伏，并使IL-10在HIV主要储存库Tfh细胞附近产生B细胞。基于这些初步结果，我们认为，给予抗IL-10阻断抗体(αIL-10)将通过以下方式减少艾滋病毒的持久性：(I)减少可为艾滋病毒储存库提供种子的感染细胞的存活；(Ii)减少已知为T细胞静止和艾滋病毒潜伏期上游调节的分子的表达。在这个项目的R21阶段，我们将给感染SIV的CART治疗的RMS注射αIL-10，并根据治疗对TFH存活率、生发中心组织和ICB表达的影响来确定安全有效的剂量。在R33阶段，一旦确定了这种干预的安全性和最佳剂量，我们将提供关于IL-10中和对生发中心组织、TFH存活和HIV储存库大小的积极影响的机械性见解。如果我们的假设是正确的，我们预计通过在ART治疗的SIV感染的RMS中注射αIL-10，感染和激活的细胞的存活率将会降低，更具体地说，对于TFH细胞。随之而来的是，持久性SIV储集层将逐步减少。总之，这项拟议的工作将通过在最相关的动物模型中进行一种新的干预措施的体内严格控制研究，来改善对艾滋病毒潜伏期的理解。如果成功地促使SIV蓄水池逐渐减少，拟议的治疗最终将在旨在治愈艾滋病毒感染的临床试验中进行测试。