Role of canonical and non-canonical beta-catenin signaling in HIV-1 latency

经典和非经典 β-连环蛋白信号传导在 HIV-1 潜伏期中的作用

• 批准号: 10871495
• 负责人: Taisuke Izumi
• 金额: $ 28.9万
• 依托单位: AMERICAN UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2022
• 资助国家: 美国
• 起止时间: 2022-08-23 至 2025-07-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10871495
• 关键词: Role; canonical; non; beta; catenin

PROJECT SUMMARY/ABSTRACT HIV remains an incurable infectious disease due to establishing a subset of latently infected reservoir cells. HIV latent cells are not eradicated by immune systems or combination antiviral therapy (cART) by regulating viral RNA transcription and subsequent protein translations. The long-lived central memory CD4+ T cell subset (TCM) is regarded as the predominant HIV reservoir. Latency reversal agents (LRAs) reactivate dormant viral gene expression, following HIV clearance by immune response or cART. However, the current LRAs have failed to reduce the reservoir size in the clinical trial due to the heterogeneous mechanisms in HIV latency. In addition, LRAs negatively affect immune function. The long-term goal for this research is the identification of alternative pharmaceutical targets to universally influence reverse latency and immune response for HIV functional cure. The Wnt/β-catenin pathway restricts HIV replication and is also involved in HIV latency by promoting self-renewal and proliferation of TCM, while β-catenin is not being explored for HIV latency reversal. The Wnt signal translocates β-catenin to the nucleus that forms a canonical transcriptional complex with the TCF/LEF transcription factors to induce downstream gene expressions (canonical β-catenin signaling). Recently, Interactions of β-catenin with other transcription factors, FOX family proteins, have also been reported, which regulates gene expression independently of canonical β-catenin signaling (non-canonical β-catenin signaling). The rationale of this proposal is based on the previous reports and our preliminary data that 1) inhibition of β-catenin with TCF/LEF complex reactivated HIV latent T cells and immune stimulations, and 2) synergistic latency reversal effect was observed with the HDAC inhibitor by β-catenin attenuation. The objective of this study is to reveal the role of β-catenin signaling pathways in latently infected T cells. The central hypothesis is that the non-canonical β-catenin signaling allows latency reactivation and stimulates immune cell function, which will aid in the design of new strategies for HIV eradication. The objective of this project will be accomplished by three specific aims with a team of undergraduate researchers: 1) Evaluation of non-canonical β-catenin signaling in HIV latency 2) Elucidation of synergistic interaction between LRAs and β-catenin signaling, and 3) Assessment of β-catenin non-canonical signaling in immune activation. The significance of this study is not only finding the novel pathway to let viruses released from latency but also creating a synergistic effect with other LRAs and being an immunostimulant for the subsequent reactivated cell clearance that makes innovation in the successive combination LRA therapy.

项目概要/摘要 由于潜伏感染病毒库的建立，艾滋病毒仍然是一种无法治愈的传染病 HIV 潜伏细胞不会被免疫系统或联合抗病毒治疗 (cART) 根除。 调节病毒 RNA 转录和随后的蛋白质翻译。 细胞亚群（TCM）被认为是主要的 HIV 病毒库。 通过免疫反应或 cART 清除 HIV 后，病毒基因处于休眠状态。 由于 HIV 的异质机制，LRA 在临床试验中未能减少储存库的大小 此外，LRA 对免疫功能产生负面影响。这项研究的长期目标是。 识别替代药物靶标以普遍影响反向潜伏期和免疫 HIV 功能性治愈的反应。 Wnt/β-连环蛋白途径限制 HIV 复制，并且还通过促进 HIV 潜伏期来参与 HIV 潜伏期。 中药的自我更新和增殖，而 β-连环蛋白尚未被探索用于逆转 HIV 潜伏期。 信号将 β-catenin 转位至细胞核，与 TCF/LEF 形成典型的转录复合物 最近，转录因子诱导下游基因表达（典型的β-连环蛋白信号传导）。 β-连环蛋白与其他转录因子（FOX 家族蛋白）的相互作用也已被报道， 独立于经典 β-catenin 信号传导（非经典 β-catenin 信号）。 该提案的基本原理基于之前的报告和我们的初步数据：1) 使用 TCF/LEF 复合物抑制 β-连环蛋白，重新激活 HIV 潜伏 T 细胞并进行免疫刺激，以及 2) 通过 β-连环蛋白减弱观察到 HDAC 抑制剂的协同潜伏期逆转效应。 本研究的目的是揭示 β-catenin 信号通路在潜伏感染 T 细胞中的作用。 中心假设是非典型 β-连环蛋白信号传导允许潜伏期重新激活和刺激 免疫细胞功能，这将有助于设计消灭艾滋病毒的新策略。 该项目将由本科研究人员团队通过三个具体目标来完成：1）评估 HIV 潜伏期中非经典 β-连环蛋白信号传导的研究 2) 阐明 LRA 和 β-连环蛋白信号传导，以及 3) 评估免疫激活中的 β-连环蛋白非规范信号传导。 这项研究的意义不仅在于找到让病毒从潜伏状态中释放出来的新途径 而且还可以与其他 LRA 产生协同效应，并作为后续的免疫刺激剂 重新激活的细胞清除，使连续的联合LRA疗法具有创新性。