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: 10548588
• 负责人: Taisuke Izumi
• 金额: $ 8.16万
• 依托单位: SAINT JOSEPH'S 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 2023-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10548588
• 关键词: Acquired Immunodeficiency Syndrome; Acute; Address; Agonist; Antiviral Therapy; Attenuated; Automobile Driving; CD4 Positive T Lymphocytes; CD8-Positive T-Lymphocytes; Cell Line; Cell Nucleus; Cell physiology; Cells; Cellular Immunity; Chromatin; Clinical Trials; Communicable Diseases; Complex; Data; Epidemic; Evaluation; Flow Cytometry; Fluorescence Microscopy; Gene Expression; Genetic Transcription; Goals; HIV; HIV Infections; HIV-1; Heterogeneity; Histone Deacetylase Inhibitor; Immune; Immune response; Immune system; Immunization; Immunologic Adjuvants; Impairment; Knock-out; Lead; Mediating; Memory; Outcome; Pathway interactions; Pharmacologic Substance; Phenotype; Physical condensation; Protein Family; Proteins; Reporting; Research; Research Personnel; Role; Signal Pathway; Signal Transduction; T cell differentiation; T cell factor 4; T-Cell Proliferation; T-Lymphocyte; T-Lymphocyte Subsets; TCF Transcription Factor; Translations; Viral; Viral Genes; Viral reservoir; Virus; Virus Latency; WNT Signaling Pathway; antiretroviral therapy; attenuation; base; beta catenin; design; detection limit; immune activation; immune clearance; immune function; in vivo; inhibitor; innovation; latent HIV reservoir; memory CD4 T lymphocyte; negative affect; novel; novel strategies; pandemic disease; reactivation from latency; self-renewal; side effect; single cell analysis; transcription factor; undergraduate student; viral RNA

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.

项目摘要/摘要 艾滋病毒仍然是一种无法治愈的传染病，这是因为建立了一组潜伏感染的宿主 细胞。免疫系统或联合抗病毒疗法(CART)不会根除艾滋病毒潜伏细胞 调节病毒RNA转录和随后的蛋白质翻译。长寿的中枢记忆CD4+T细胞 细胞亚群被认为是HIV的主要储备库。潜伏期逆转代理(LRA)重新激活 通过免疫反应或CART清除HIV后的休眠病毒基因表达。然而，目前 在临床试验中，由于艾滋病毒的不同机制，LRA未能减少储存库的大小 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 确定可普遍影响逆转潜伏期和免疫的替代药物靶点 对HIV功能性治愈的反应。 Wnt/β-Catenin途径限制艾滋病毒复制，并通过促进 中医的自我更新和增殖，而β-连环蛋白尚未被探索用于逆转艾滋病毒潜伏期。WNT Signal将β-连环蛋白转移到细胞核，与Tcf/Lef形成规范的转录复合体 转录因子诱导下游基因表达(典型的β-连环蛋白信号)。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已有报道。 独立于典型的β-连环蛋白信号调节基因表达(非典型的β-连环蛋白 信令)。 这项建议的理由是基于之前的报告和我们的初步数据，即1) TcF/LEF复合体抑制β-连环蛋白激活的潜伏T细胞和免疫刺激 通过β-连环蛋白衰减观察到HDAC抑制剂的协同潜伏期逆转作用。这个 本研究的目的是揭示β-连环蛋白信号通路在潜伏感染T细胞中的作用。这个 中心假说是，非规范的β-连环蛋白信号允许潜伏期重新激活和刺激 免疫细胞功能，这将有助于设计根除艾滋病毒的新战略。这样做的目的是 项目将通过三个具体目标与本科研究人员团队一起完成：1)评估 非规范β-连环蛋白信号在艾滋病毒潜伏期中的作用2)阐明LRA和LRA之间的协同作用 β-连环蛋白信号，以及3)β-连环蛋白非规范信号在免疫激活中的评估。 这项研究的意义不仅在于找到了让病毒从潜伏期释放出来的新途径 而且还与其他LRA产生协同效应，并作为后续的免疫刺激剂 重新激活细胞清除，在连续的联合LRA治疗中进行创新。