Preventing CD4+ T memory cells from becoming HIV reservoirs

防止 CD4 T 记忆细胞成为 HIV 储存库

基本信息

批准号：
9914204
负责人：
Viviana A Simon
金额：
$ 59.33万
依托单位：
ICAHN SCHOOL OF MEDICINE AT MOUNT SINAI
依托单位国家：
美国
项目类别：
财政年份：
2018
资助国家：
美国
起止时间：
2018-05-18 至 2022-04-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/9914204
关键词：
AIDS/HIV problem Acute Antiviral Agents CD4 Positive T Lymphocytes CRISPR/Cas technology Cell Compartmentation Cell Cycle Progression Cell Lineage Cells Clonal Expansion Cytometry DNA Data Engineering FDA approved FRAP1 gene Frequencies Genetic Genetic Transcription Genome Genomics HIV HIV Infections Highly Active Antiretroviral Therapy Human Human immunodeficiency virus test Immune Infection Interleukin 2 Receptor Gamma Interleukin-15 Intervention JAK1 gene JAK2 gene Janus kinase Knowledge Location Maintenance Maps Memory Molecular Molecular Probes Pathway interactions Patients Persons Phenotype Phosphorylation Physiological Play Population Positioning Attribute Predisposition Proliferating Property Proviruses RNA Refractory Replication Origin Reporter Research Resolution Role SIV Seeds Site T-Lymphocyte Techniques Testing Therapeutic Therapeutic Intervention Time Viral reservoir Virus Virus Diseases Virus Replication antiretroviral therapy base clinically relevant cytokine experimental study genome editing in vivo inhibitor/antagonist innovation insight mTOR Inhibitor memory CD4 T lymphocyte next generation sequencing novel prevent programs purge self-renewal stem stem-like cell stemness therapeutic development vpr Gene Products

项目摘要

ABSTRACT Curing HIV/AIDS requires strategies to purge reservoirs harboring latent, transcriptionally silent proviruses, as HIV persists in CD4+ T memory cells even in the presence of effective highly active antiretroviral therapy. Despite intensive research, our understanding of the molecular mechanisms that seed and maintain the HIV reservoir in primary human CD4+ memory T cells remains incomplete. Our preliminary data indicate that interleukin-15 (IL-15), the only gamma cytokine up-regulated during acute HIV infection, increases human CD4+ T memory cell susceptibility to infection by inactivation of the restriction factor SAMHD1. Further, IL-15 specifically increases the number of CD4+ T memory cells with stem cell like properties (TSCM) in HIV-infected CD4+ T cell populations. We hypothesize that HIV infected CD4+ T memory cells with stem cell-like properties (CD4+ T central memory/stem cell-like) initiate and maintain the persistent viral reservoir in patients with controlled viral replication. We will probe the molecular mechanisms controlling infection susceptibility and latency maintenance in primary human CD4+ T cells using established techniques, such as mass-cytometry by time of Flight (CyTOF), genome editing and next generation sequencing. We will identify abortive, silent and productive infections in CD4+ T memory cells, define the cellular programs specific for HIV persistence and modulate these pathways to render CD4+ T memory cells refractory to infection. We will examine how FDA approved JAK1/2 and mTOR inhibitors modulate infection and proliferation of CD4+ T memory cells. We will define cell lineages responsible for HIV persistence in vivo by generating hierarchical maps of patient-derived proviruses inserted at the same genetic location but obtained from distinct CD4+ T memory populations using high-resolution, next generation sequencing approaches. The proposed studies will not only characterize the CD4+ T memory cells that establish and maintain the HIV reservoir, but also examine whether FDA approved therapeutic interventions may be used to prevent latent HIV infection and/or eliminate HIV persistence in the human CD4+ T memory cell compartment.

抽象的治愈艾滋病毒/艾滋病需要清除带有潜在的，抄写无声的病毒的水库，例如即使存在有效的高度活性抗逆转录病毒疗法，HIV仍然存在于CD4+ T记忆细胞中。尽管进行了深入的研究，但我们对播种和维持HIV的分子机制的理解原代人CD4+记忆T细胞中的储层仍然不完整。我们的初步数据表明，白介素-15（IL-15），这是急性期间唯一上调的伽玛细胞因子 HIV感染，增加了人类CD4+ T记忆细胞对感染的敏感性，通过灭绝限制因子SAMHD1。此外，IL-15特异性地增加了用干细胞喜欢的CD4+ T记忆细胞的数量 HIV感染的CD4+ T细胞种群中的性质（TSCM）。我们假设感染了HIV感染的CD4+ T记忆具有干细胞样性质（CD4+ T中心记忆/干细胞）的细胞启动并保持持久性病毒复制患者的病毒储存库。我们将探测控制的分子机制使用已建立的技术，原代人CD4+ T细胞中的感染敏感性和潜伏期维持，例如按飞行时间（CytoF），基因组编辑和下一代测序进行的质量仪。我们将识别CD4+ T记忆细胞中流产，无声和生产性感染，定义特定的蜂窝程序为了HIV持久性并调节这些途径以使CD4+ T记忆细胞难以感染感染。我们将检查FDA批准JAK1/2和MTOR抑制剂如何调节CD4+ T的增殖记忆单元。我们将通过生成层次结构来定义负责体内HIV持久性的细胞谱系插入相同遗传位置的患者衍生病毒的地图，但从不同的CD4+ T获得使用高分辨率的下一代测序方法的记忆群。拟议的研究不仅将表征建立和维持HIV的CD4+ T记忆细胞水库，还可以检查FDA是否可以使用FDA批准的治疗干预措施来防止潜在 HIV感染和/或消除人CD4+ T记忆细胞室中的HIV持久性。