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

 描述(由申请人提供)： 摘要虽然抗逆转录病毒疗法(ART)极大地降低了艾滋病毒感染的死亡率和发病率，但如果ART停止，病毒很快就会反弹。因此，治愈仍然是艾滋病毒/艾滋病研究的关键优先事项。治愈艾滋病毒感染的主要障碍是潜伏感染细胞的持续蓄水池，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)--表现出增强的自我更新能力以及分化为更成熟的记忆亚群的记忆CD4+T细胞的子集--可能是潜伏感染的记忆CD4+T细胞储存库的关键组成部分，该细胞在接受ART治疗的HIV感染者中持续存在。这项建议的目的是测试一种新的治疗干预措施，旨在选择性地阻止长期存活的CD4+TSCM储存库的自我更新，从而扰乱记忆CD4+T细胞中整体病毒的持久性。我们假设，在ART下，系统发育保守的干细胞特异性信号通路调节造血干细胞的“干性”(即多潜能、自我更新、长期持续)，并活跃在CD4+TSCM中，对于促进病毒的长期持续至关重要。我们建议以Wnt/β-catenin通路为靶点来干预潜伏感染的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)病毒库的大小和解剖分布以及(Ii)一旦ART被中断后病毒反弹的动力学的影响。这项工作将在感染SIV的、ART抑制的恒河猴(RMS)中进行，在这些猕猴中，我们可以测试新的干预措施，并进行比艾滋病毒感染人类更严格和侵入性的采样。在目标1中，我们将在健康的RMS中测试选择性β-连环蛋白抑制剂PRI-724，以确定既有疗效又有毒性的生物信号的最佳剂量策略。在目标2中，我们将研究β-连环蛋白抑制在减少SIV感染的ART抑制的RMS中记忆的CD4+T细胞库大小方面的影响。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来进行功能分析 治疗中断后病毒反弹的动态变化。这项拟议的研究具有很高的创新性，将为病毒在记忆CD4+T细胞中持续存在的生物学提供关键的新信息。该项目的结果可能导致一项转化性研究计划，重点是针对HIV根除的新的CD4+TSCM特定策略，该策略可能对HIV的治疗和治愈产生革命性影响。

 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.