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/艾滋病需要采取策略来清除潜伏的、转录沉默的原病毒的储存库，因为即使存在有效的高效抗逆转录病毒治疗，HIV 仍会持续存在于 CD4+ T 记忆细胞中。尽管进行了大量研究，我们对传播和维持艾滋病毒的分子机制的了解仍然有限。原代人类 CD4+ 记忆 T 细胞的储存库仍然不完整。我们的初步数据表明，白介素 15 (IL-15) 是急性期唯一上调的 γ 细胞因子。 HIV 感染，通过限制性失活增加人类 CD4+ T 记忆细胞对感染的敏感性因素 SAMHD1。此外，IL-15 特异性增加 CD4+ T 记忆细胞与干细胞样的数量 HIV 感染的 CD4+ T 细胞群的特性 (TSCM)。我们假设 HIV 感染了 CD4+ T 记忆具有干细胞样特性的细胞（CD4+ T 中枢记忆/干细胞样）启动并维持持久的病毒复制受控的患者体内的病毒库。我们将探讨控制的分子机制使用既定技术对原代人 CD4+ T 细胞的感染易感性和潜伏期维持，例如飞行时间质谱流式细胞仪 (CyTOF)、基因组编辑和下一代测序。我们将识别 CD4+ T 记忆细胞中的流产、沉默和生产性感染，定义特定的细胞程序 HIV持续存在并调节这些途径使CD4+ T记忆细胞难以感染。我们将研究 FDA 批准的 JAK1/2 和 mTOR 抑制剂如何调节 CD4+ T 的感染和增殖记忆细胞。我们将通过生成分层结构来定义负责 HIV 在体内持续存在的细胞谱系插入相同基因位置但从不同 CD4+ T 获得的患者来源原病毒图谱使用高分辨率的下一代测序方法进行记忆群体。拟议的研究不仅将描述建立和维持 HIV 的 CD4+ T 记忆细胞的特征储库，但也要检查 FDA 批准的治疗干预措施是否可用于预防潜在的 HIV 感染和/或消除人类 CD4+ T 记忆细胞区室中的 HIV 持续存在。