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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

基本信息

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
项目类别：
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

项目摘要

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/文摘