Exploring the role of the Wnt/B-catenin signaling pathway on HIV reservoir

摘要 治愈HIV感染的关键障碍是潜伏感染的记忆CD4+T细胞的储存库，尽管 长期的ART，并通过细胞增殖来维持。该潜伏油藏涉及一种非均质油气藏。 记忆中不同分化阶段的CD4+T细胞亚群。每个子集都显示不同的 增殖能力、艾滋病毒转录活性和病毒诱导性。呈现分化的细胞 表型是储集层中克隆扩张的主要原因。然而，这种扩展的克隆通常 HIV储备库的核心可能在于具有高存活率和高存活率的多潜能记忆CD4+T细胞 自我更新能力，如中枢(CM)和干细胞记忆(SCM)的CD4+T细胞。 Wnt/β-连环蛋白信号通路调节这些细胞的自我更新和分化之间的平衡 长寿记忆的CD4+T细胞。我们最近发现，抑制β-连环蛋白与 转录共激活因子CPB抑制SCM和CM CD4+T细胞的增殖并改变其功能 ART抑制的SIV感染猕猴中更具分化表型的转录组 (RMS)。Wnt/β-Catenin信号通路也与抑制艾滋病毒复制有关， Wnt配体分泌CD8+T细胞的潜在作用这个应用程序的目标是调查这种双重情况 Wnt/β-catenin信号通路在艾滋病毒持久性中的作用 靶向Wnt/β-Catenin途径的两个关键步骤可以通过以下方式改变艾滋病毒储存库的维持：(I)干扰 通过SCM和CM的CD4+T细胞的自我更新能力，以及(Ii)减轻HIV转录抑制。vbl.使用 高度相关的SIV感染ART治疗的RMS模型，我们将在三个具体的 目标。在目标1中，我们将表征β-连环蛋白介导的药理调节的影响 转录对记忆、CD4+T细胞动力学和SIV储存库组成的影响。在目标2中，我们将评估 短暂诱导长寿命记忆CD4+T细胞分化增强潜伏期逆转的活性 探员。在目标3中，我们将探讨Wnt配体分泌阻断对长寿命记忆CD4+T细胞的影响 自我更新和SIV延迟。 建议的实验建立在对CD4+T细胞储存库的免疫复杂性的认识基础上 动力学。这项概念上的创新工作将提供有关艾滋病毒生物学的重要新信息 存留在记忆中的CD4+T细胞。

ABSTRACT The key obstacle to cure HIV infection is a reservoir of latently-infected memory CD4+ T cells that persist despite long-term ART and is maintained though cellular proliferation. This latent reservoir involves a heterogeneous population of memory CD4+ T cell subsets at various differentiation stages. Each subset displays a distinct proliferative capacity, HIV transcriptional activity, and viral inducibility. Cells presenting a differentiated phenotype account for the majority of clonal expansions in the reservoir. However, such expended clones often wax and wane and the core of HIV reservoir likely lies in multipotent memory CD4+ T cells with high survival and self-renewal abilities such as central (CM) and stem cell memory (SCM) CD4+ T cells. The Wnt/β-catenin signaling pathway regulates the balance between self-renewal and differentiation of these long-lived memory CD4+ T cells. We recently showed that inhibition of the interaction of β-catenin with the transcriptional coactivator CPB decreased the proliferation of SCM and CM CD4+ T cells and modified their transcriptome towards a more differentiated phenotype in ART-suppressed SIV-infected rhesus macaques (RMs). The Wnt/β-catenin signaling pathway has also been implicated in HIV replication suppression with a potential role of CD8+ T cell secretion of Wnt ligands. The objective of this application is to investigate this dual role of the Wnt/β-catenin signaling pathway on HIV persistence with the central hypothesis that pharmacological targeting of two critical steps of the Wnt/β-catenin pathway can alter HIV reservoir maintenance by (i) interfering with the self-renewal ability of SCM and CM CD4+ T cells, and (ii) alleviating HIV transcriptional repression. Using the highly relevant model of SIV-infected ART-treated RMs, we will address this hypothesis in three Specific Aims. In Aim 1, we will characterize the impact of the pharmacological modulation of β-catenin-mediated transcription on memory CD4+ T cell dynamics and SIV reservoir composition. In Aim 2, we will assess if the transient induction of long-lived memory CD4+ T cell differentiation potentiate the activity of a latency reversing agent. In Aim 3, we will explore the effect of Wnt ligand secretion blockade on long-lived memory CD4+ T cell self-renewal and SIV latency. The proposed experiments build upon an appreciation of the immunologic complexity of CD4+ T cell reservoir dynamics. This conceptually innovative work will provide critical new information on the biology of HIV persistence in memory CD4+ T cells.