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.

项目总结/摘要 由于建立了一个潜伏感染宿主的子集，HIV仍然是一种不可治愈的传染病 细胞HIV潜伏细胞不能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。长寿的中央记忆CD 4 + T细胞 细胞亚群（TCM）被认为是主要的HIV储库。潜伏期逆转剂（LRA）重新激活 休眠病毒基因表达，随后通过免疫应答或cART清除HIV。但目前 由于HIV的异质性机制，LRA在临床试验中未能减少储库大小 延迟。此外，LRA对免疫功能有负面影响。这项研究的长期目标是 鉴定普遍影响逆转潜伏期和免疫的替代药物靶标 对HIV功能性治愈的反应。 Wnt/β-catenin通路限制HIV复制，并且还通过促进HIV的潜伏期而参与HIV的潜伏期。 TCM的自我更新和增殖，而β-连环蛋白尚未被探索用于HIV潜伏期逆转。所述Wnt 一个信号将β-连环蛋白转位到细胞核，与TCF/LEF形成典型的转录复合物 转录因子诱导下游基因表达（经典β-连环蛋白信号传导）。最近， β-连环蛋白与其他转录因子FOX家族蛋白的相互作用也有报道， 独立于经典β-catenin信号传导调节基因表达（非经典β-catenin 信令）。 这一建议的理由是基于以前的报告和我们的初步数据，1） 用TCF/LEF复合物抑制β-连环蛋白重新激活HIV潜伏T细胞和免疫刺激，和2） HDAC抑制剂通过β-连环蛋白衰减观察到协同潜伏期逆转效应。的 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。的 中心假设是非典型β-连环蛋白信号传导允许潜伏期再激活并刺激 免疫细胞功能，这将有助于设计新的艾滋病毒根除战略。的目的 该项目将由一个本科研究团队完成三个具体目标：1）评估 2）阐明LRA和LRA之间的协同相互作用， β-连环蛋白信号传导，和3）评估免疫活化中的β-连环蛋白非经典信号传导。 本研究的意义不仅在于找到了新的途径，让病毒从潜伏期释放出来， 而且还与其他LRA产生协同效应， 重新激活细胞清除，使LRA连续联合治疗的创新。