Targeting beta-catenin to disrupt the T memory stem cell reservoir

靶向 β-连环蛋白破坏 T 记忆干细胞库

• 批准号: 9075131
• 负责人: Ann M Chahroudi
• 金额: $ 89.25万
• 依托单位: EMORY UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2015
• 资助国家: 美国
• 起止时间: 2015-07-01 至 2017-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9075131
• 关键词: AIDS/HIV problem; Aftercare; Anatomy; Antineoplastic Agents; Biological; Biology; CD4 Positive T Lymphocytes; CREB-binding protein; Cells; Clinical; Clinical Data; Data; Development; Disease remission; Dose; Evolution; Exhibits; Fire - disasters; HIV; HIV Infections; Health; Hematopoietic stem cells; Human; Individual; Interruption; Intervention; Kinetics; Lead; Life; Macaca mulatta; Memory; Modeling; Molecular; Molecular Target; Morbidity - disease rate; Nature; Pathway interactions; Patients; Pharmaceutical Preparations; Pharmacologic Substance; Play; Population; Positioning Attribute; Property; Regimen; Research; Role; SIV; Safety; Sampling; Signal Pathway; Signal Transduction; Source; Specific qualifier value; Stem cells; Structure; T-Lymphocyte Subsets; Testing; Therapeutic; Toxic effect; Translating; Translational Research; Viral; Viremia; Virus; Virus Activation; Work; analog; antiretroviral therapy; base; beta catenin; cancer cell; cancer stem cell; design; human CREBBP protein; immunological intervention; inhibitor/antagonist; innovation; memory CD4 T lymphocyte; mortality; novel; novel therapeutic intervention; pre-clinical; programs; research study; self-renewal; small molecule; stemness

 DESCRIPTION (provided by applicant): ABSTRACT While antiretroviral therapy (ART) greatly reduces the mortality and morbidity of HIV infection, viral rebound quickly ensues if ART is stopped. As such, a cure remains a key priority in HIV/AIDS research. The main obstacle to curing HIV infection is the persistent reservoir of latently infected cells that causes rebound of viremia if ART is interrupted. Recent work demonstrates that CD4+ T memory stem cells (TSCM) - a subset of memory CD4+ T cells that exhibits enhanced self-renewal as well as the ability to differentiate into more mature memory subsets - may represent a key component of the reservoir of latently infected memory CD4+ T cells that persists in ART-treated HIV-infected individuals. The objective of this proposal is to test a novel therapeutic intervention aimed at selectively blocking the self- renewal of the long-lived CD4+ TSCM reservoir, thereby disrupting overall virus persistence in memory CD4+ T cells. We hypothesize that phylogenetically-conserved, stem cell-specific signaling pathways that regulate the "stemness" (i.e., multipotency, self-renewal, long-term persistence) of hematopoietic stem cells and are active in CD4+ TSCM are essential to promote long-term viral persistence under ART. We propose to pharmacologically target the Wnt/beta-catenin pathway to interfere with the self-renewal and drive the differentiation of latently infected CD4+ TSCM. We will determine the impact of this immunological intervention on (i) the size and anatomic distribution of the virus reservoir and (ii) the kinetics of viral rebound once ART is interrupted.Of note, this approach is not dependent on the induction of virus reactivation. This work will be carried out in SIV-infected, ART-suppressed rhesus macaques (RMs), in whom we can test novel interventions and perform more rigorous and invasive sampling than would be possible in HIV-infected humans. In Aim 1, we will test the selective beta-catenin inhibitor PRI-724 in healthy RMs to define an optimal dosing strategy for both biological signal of efficacy as well as toxicity. In Aim 2, we will investigate the impact of beta-catenin inhibition in reducing the size f memory CD4+ T cell reservoirs in SIV-infected ART-suppressed RMs. In Aim 3, we will perform a functional analysis of the impact of beta-catenin inhibition on virus reservoirs by analyzing the dynamics of viral rebound after treatment interruption. The proposed studies are highly innovative and will provide critical new information on the biology of viral persistence in memory CD4+ T cells. The results of this project may lead to a translational research program focusing on novel CD4+ TSCM specific strategies for HIV eradication that has the potential to have a transformative impact on HIV treatment and cure.

 描述（由申请人提供）： 摘要 虽然抗逆转录病毒治疗 (ART) 大大降低了 HIV 感染的死亡率和发病率，但如果停止 ART，病毒很快就会反弹，因此，治疗仍然是 HIV/艾滋病研究的一个关键优先事项。潜伏感染细胞的持续储存，如果 ART 中断，会导致病毒血症反弹。最近的研究表明，CD4+ T 记忆干细胞 (TSCM) - 记忆 CD4+ T 细胞的一个子集，表现出增强。自我更新以及分化成更成熟的记忆子集的能力 - 可能代表潜伏感染的记忆 CD4+ T 细胞库的关键组成部分，该细胞在接受 ART 治疗的 HIV 感染者中持续存在。该提案的目的是测试。一种新颖的治疗干预措施，旨在选择性地阻断长寿命 CD4+ TSCM 库的自我更新，从而破坏记忆 CD4+ T 细胞中的整体病毒持久性，我们捕获了系统发育上保守的干细胞特异性信号传导。调节造血干细胞“干性”（即多能性、自我更新、长期持续性）并在 CD4+ TSCM 中活跃的途径对于促进 ART 下的长期病毒持续性至关重要。 /β-连环蛋白途径干扰潜伏感染的 CD4+ TSCM 的自我更新并驱动其分化。我们将确定这种免疫干预对 (i) 大小和的影响。病毒库的解剖分布以及（ii）ART 中断后病毒反弹的动力学。值得注意的是，该方法不依赖于病毒重新激活的诱导。这项工作将在感染 SIV 且 ART 抑制的恒河猴中进行。我们可以在猕猴 (RM) 中测试新的干预措施，并进行比 HIV 感染者更严格和更具侵入性的采样。在目标 1 中，我们将测试选择性 β-连环蛋白抑制剂。在健康 RM 中使用 PRI-724，以确定功效和毒性生物信号的最佳剂量策略 在目标 2 中，我们将研究 β-连环蛋白抑制对减少 SIV- 中记忆 CD4+ T 细胞库大小的影响。在目标 3 中，我们将通过分析 β-连环蛋白抑制对病毒库的影响进行功能分析。 治疗中断后病毒反弹的动态变化。拟议的研究具有高度创新性，将为记忆 CD4+ T 细胞中病毒持久性的生物学提供重要的新信息。该项目的结果可能会导致专注于新型 CD4+ TSCM 特异性的转化研究计划。根除艾滋病毒的战略有可能对艾滋病毒的治疗和治愈产生变革性影响。