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感染性疾病 细胞。 HIV潜在细​​胞不会通过免疫系统或组合抗病毒治疗（CART）发出 调节病毒RNA转录和随后的蛋白质翻译。长期寿命的中央记忆CD4+ T 细胞子集（TCM）被认为是主要的HIV储备。潜伏期逆转剂（LRAS）重新激活 通过免疫反应或CART清除HIV，休眠病毒基因表达。但是，电流 由于HIV的异质机制，LRA未能减少临床试验中的储层大小 潜伏期。另外，LRA对免疫功能产生负面影响。这项研究的长期目标是 鉴定替代药物目标以普遍影响反向潜伏期和免疫力 HIV功能治疗的响应。 Wnt/β-catenin途径限制了HIV复制，也通过促进艾滋病毒潜伏期参与 TCM的自我更新和增殖，而β-catenin并未探索HIV潜伏期逆转。 wnt 信号将β-catenin易位到形成与TCF/LEF的规范转录复合物的细胞核 转录因子诱导下游基因表达（规范β-catenin信号传导）。最近， 还报道了β-catenin与其他转录因子的相互作用，FOX家族蛋白也有报道 独立于规范的β-catenin信号（非传统β-catenin）来调节基因表达 信号）。 该提案的理由是基于先前的报告和我们的初步数据1） 用TCF/LEF复合物抑制β-catenin重新激活HIV潜伏T细胞和免疫刺激，2） 通过β-catenin衰减观察到HDAC抑制剂的协同潜伏期逆转效应。这 这项研究的目的是揭示β-catenin信号通路在潜在感染的T细胞中的作用。 中心假设是非经典β-catenin信号传导允许潜伏期重新激活并刺激 免疫细胞功能，这将有助于设计新的消除HIV策略。这个目的 项目将由三个特定目标与本科研究人员团队完成：1）评估 HIV潜伏期中非典型的β-catenin信号传导2）阐明LRA与LRA和 β-catenin信号传导和3）评估免疫激活中β-catenin非传统信号传导。 这项研究的意义不仅是找到让病毒从潜伏期释放的新途径 而且还与其他LRA产生协同作用，并成为随后的免疫刺激剂 重新激活的细胞清除率使得在成功的联合疗法中创新。