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性CD 4 + T细胞的储存库， 长期ART，并通过细胞增殖维持。这种潜在的储层涉及非均质的 在不同分化阶段的记忆性CD 4 + T细胞亚群。每个子集显示一个不同的 增殖能力、HIV转录活性和病毒诱导。细胞呈现分化的 表型占库中克隆扩增的大多数。然而，这样的克隆体通常 艾滋病病毒库的核心可能在于具有高存活率的多能记忆CD 4 + T细胞， 自我更新能力，如中枢（CM）和干细胞记忆（SCM）CD 4 + T细胞。 Wnt/β-catenin信号通路调节这些细胞的自我更新和分化之间的平衡。 长寿命记忆性CD 4 + 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可降低SCM和CM CD 4 + T细胞的增殖，并改变其 ART抑制SIV感染的恒河猴中转录组向更分化的表型转变 （RM）。Wnt/β-连环蛋白信号通路也与HIV复制抑制有关， CD 8 + T细胞分泌Wnt配体的潜在作用。本申请的目的是研究这种双重 Wnt/β-catenin信号通路在HIV持续性中的作用，其中心假设是药理学 靶向Wnt/β-连环蛋白途径的两个关键步骤可以通过以下方式改变HIV储库维持：（i）干扰 与SCM和CM CD 4 + T细胞的自我更新能力，和（ii）减轻HIV转录抑制。使用 SIV感染ART治疗RM的高度相关模型，我们将在三个具体的研究中解决这一假设。 目标。在目标1中，我们将描述β-连环蛋白介导的药理学调节的影响。 转录对记忆CD 4 + 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性CD 4 + T细胞分化增强了潜伏期逆转的活性， 剂目的3：探讨Wnt配体分泌阻断对长寿命记忆性CD 4 + T细胞的影响 自我更新和SIV潜伏期。 所提出的实验建立在对CD 4 + T细胞库的免疫学复杂性的认识基础上 动力学这一概念上的创新工作将为艾滋病毒的生物学提供重要的新信息 记忆性CD 4 + T细胞的持久性。

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.