Regulation of HIV Latency by Host Cell Transcriptional and Epigenetic Networks

宿主细胞转录和表观遗传网络对 HIV 潜伏期的调节

基本信息

批准号：
10425316
负责人：
Edward P Browne
金额：
$ 38.88万
依托单位：
UNIV OF NORTH CAROLINA CHAPEL HILL
依托单位国家：
美国
项目类别：
财政年份：
2019
资助国家：
美国
起止时间：
2019-07-16 至 2024-06-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10425316
关键词：
ATAC-seq Address Antiviral Therapy Back Behavior Biological Assay CD4 Positive T Lymphocytes Candidate Disease Gene Cell Proliferation Cell model Cells ChIP-seq Characteristics Chromatin Structure Data Set Development Environment Epigenetic Process Gene Expression Gene Expression Profile Gene Silencing Genes Genetic Genetic Transcription Goals HIV HIV Infections HIV-1 In Vitro Individual Infection Knowledge Lead Maintenance Methodology Methods Microscopy Modeling Molecular Monitor Nature Pathway interactions Patients Pattern Pharmaceutical Preparations Pharmacology Play Population Process Proviruses Regulation Repression Resistance Role Techniques Technology Testing Time Translating Virus Work antiretroviral therapy chromatin modification epigenetic regulation epigenetic silencing epigenomics experimental study genetic signature histone modification improved in vivo Model inhibitor insight interest knock-down new therapeutic target novel programs response selective expression single cell analysis single-cell RNA sequencing therapeutic development transcription factor transcriptomics

项目摘要

Project summary: The existence of long-lived reservoirs of latently infected cells is recognized as a primary barrier to a cure for HIV-1 infection. Thus, the development of therapeutic strategies to eliminate these reservoirs is a critical scientific goal. A key problem in this field is that little is known about the nature of latently infected cells, and the molecular mechanisms that regulate latency. We have recently discovered that latency is associated with a distinct host cell transcriptional signature. Our hypothesis is that this signature represents a host cell transcriptional and epigenetic program that regulates establishment or maintenance of latency. In the set of experiments we propose here, we will test this hypothesis directly, and investigate the molecular mechanisms by which the host cell environment regulates silencing of HIV transcription. This will be achieved directly testing the roles of individual genes from the latency signature in HIV transcription. We will also undertake a detailed analysis of epigenetic pathways that operate in latently infected cells, and directly examine their impact on integrated proviruses. Finally, we will use cutting edge technology that combines time-lapse microscopy and scRNAseq to discover transcriptomic features of cells that correlate with latency reversal. Thus, this dataset will lead to new targets for therapeutic manipulation of latency and guide further experiment to test these hypotheses in in vitro and in vivo models of latency.

项目概要：潜伏感染细胞的长寿命储存库的存在被认为是主要的治愈 HIV-1 感染的障碍。因此，治疗策略的发展消除这些水库是一个关键的科学目标。该领域的一个关键问题是很少有了解潜伏感染细胞的性质以及其分子机制调节延迟。我们最近发现延迟与不同的主机相关细胞转录签名。我们的假设是这个签名代表宿主细胞调节建立或维持的转录和表观遗传程序延迟。在我们在这里提出的一组实验中，我们将直接检验这个假设，并且研究宿主细胞环境调节的分子机制 HIV转录沉默。这将通过直接测试个人的角色来实现 HIV转录中潜伏特征的基因。我们还将进行详细的分析潜伏感染细胞中运作的表观遗传途径，并直接检查它们对整合原病毒的影响。最后，我们将使用尖端技术结合延时显微镜和 scRNAseq 来发现细胞的转录组特征与潜伏期反转相关。因此，该数据集将导致新的目标潜伏期的治疗操作并指导进一步的实验来检验这些假设潜伏期的体外和体内模型。