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

 描述（由申请人提供）： 虽然抗逆转录病毒疗法（ART）大大降低了HIV感染的死亡率和发病率，但如果停止ART，病毒反弹很快就会加剧。因此，治愈仍然是艾滋病毒/艾滋病研究的一个关键优先事项。 治愈HIV感染的主要障碍是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。最近的工作表明，CD 4 + T记忆干细胞（TSCM）-记忆CD 4 + T细胞的一个子集，表现出增强的自我更新以及分化成更成熟的记忆子集的能力-可能是潜伏感染的记忆CD 4 + T细胞的水库，持续在ART治疗的HIV感染的个人的关键组成部分。本提案的目的是测试一种新的治疗干预，旨在选择性阻断长寿命CD 4 + TSCM储库的自我更新，从而破坏记忆性CD 4 + T细胞中的总体病毒持久性。我们假设，调节“干性”（即，我们建议以Wnt/β-连环蛋白通路为靶点，干扰潜伏感染的CD 4 + 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）ART中断后病毒反弹的动力学的影响。值得注意的是，这种方法不依赖于诱导病毒再活化。这项工作将在SIV感染，ART抑制的恒河猴（RM）中进行，我们可以在其中测试新的干预措施，并进行比HIV感染者更严格和侵入性的采样。在目标1中，我们将在健康RM中测试选择性β-连环蛋白抑制剂PRI-724，以确定有效性和毒性的生物信号的最佳给药策略。在目标2中，我们将研究β-连环蛋白抑制在SIV感染的ART抑制的RM中减少记忆性CD 4 + T细胞库的大小的影响。在目标3中，我们将通过分析β-连环蛋白抑制对病毒储库的影响来进行功能分析。 治疗中断后病毒反弹的动力学。拟议的研究具有高度创新性，将为记忆性CD 4 + 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一个转化研究计划，重点是新的CD 4 + TSCM特定的艾滋病毒根除策略，有可能对艾滋病毒治疗和治愈产生变革性的影响。

 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.