Regulatuion of HIV-1 Gene Expression in Latency by YY1, RuvB2, and ZAP

YY1、RuvB2 和 ZAP 对潜伏期 HIV-1 基因表达的调节

基本信息

批准号：
8547375
负责人：
STEPHEN Paine GOFF
金额：
$ 20万
依托单位：
COLUMBIA UNIVERSITY HEALTH SCIENCES
依托单位国家：
美国
项目类别：
财政年份：
2013
资助国家：
美国
起止时间：
2013-08-14 至 2016-07-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8547375
关键词：
3&apos Untranslated Regions Acquired Immunodeficiency Syndrome Antiviral Agents Antiviral Therapy CD4 Positive T Lymphocytes Cell Therapy Cells DNA Detection Gagging Gene Expression Genetic Transcription HIV HIV-1 Highly Active Antiretroviral Therapy Immune system Interruption Maintenance Mediating Methods MicroRNAs Nonsense-Mediated Decay Patients Plasma Post-Transcriptional Regulation Proteins Proviruses RNA Decay Reporting Repression Rest Role Small Interfering RNA Source Surface System T memory cell T-Lymphocyte Technology Transcriptional Regulation Translational Repression Translations Viral Viral Genes Viral Proteins Virus Virus Latency Virus Replication Work Zinc Fingers inhibitor/antagonist latent infection memory CD4 T lymphocyte protein expression public health relevance research study viral RNA viral detection

项目摘要

DESCRIPTION (provided by applicant): With Highly Active AntiRetroviral Therapy (HAART), HIV-1 replication can be controlled to maintain a plasma level of viral RNA below detection by conventional means. However, the continued presence of silent HIV-1 proviral DNA in memory CD4+ T cells is a major barrier to the eradication of the virus in AIDS patients. Multiple mechanisms have been reported by which HIV-1 proviruses are maintained in a silent state in these cells. The major block to active viral replication is believed to be at the transcriptional level. However, viral RNAs can be detected in long-term HAART-treated patients by sensitive detection methods, suggesting that transcriptional control may not be the only mechanism underlying the maintenance of viral latency. This project now aims to understand the post-transcriptional control of HIV-1 gene expression mediated by three regulatory systems: the Nonsense Mediated Decay (NMD) system; a repressor of HIV translation (RVB2) which we have recently identified; and the Zinc- finger Antiviral Protein (ZAP) which silences and triggers degradation of many viral RNAs. We will specifically explore the possible role of each of these systems in the maintenance of HIV-1 latency. We will examine the levels of HIV-1 RNA and protein expression in CD4-positive memory T cells from HIV-1 infected patients after manipulating the functions of each of these regulatory systems using siRNA knockdown technology. Discovery of the major mechanisms controlling post-transcriptional regulation of HIV-1 gene expression is an essential first step toward the release of repression and the activation of viral replication. This activation will permit the detection of virus-infected cells y the immune system and facilitate the clearance of infected cells by therapies that target viral proteins expressed in and on the surface of memory T cells.

描述（由申请人提供）：通过高效抗逆转录病毒疗法（HAART），可以控制HIV-1复制以维持血浆病毒RNA水平低于常规手段的检测水平。然而，记忆 CD4+ T 细胞中持续存在的沉默 HIV-1 前病毒 DNA 是根除艾滋病患者中病毒的主要障碍。据报道，HIV-1原病毒通过多种机制在这些细胞中保持沉默状态。据信，病毒活跃复制的主要阻碍是在转录水平。然而，通过敏感的检测方法可以在长期接受HAART治疗的患者中检测到病毒RNA，这表明转录控制可能不是维持病毒潜伏期的唯一机制。该项目现在旨在了解三个调控系统介导的 HIV-1 基因表达的转录后控制：无义介导的衰变 (NMD) 系统；我们最近发现了一种 HIV 翻译抑制因子 (RVB2)；锌指抗病毒蛋白 (ZAP) 可沉默并触发许多病毒 RNA 的降解。我们将具体探讨这些系统在维持 HIV-1 潜伏期中的可能作用。在使用 siRNA 敲除技术操纵每个调节系统的功能后，我们将检查 HIV-1 感染患者的 CD4 阳性记忆 T 细胞中的 HIV-1 RNA 和蛋白质表达水平。发现控制 HIV-1 基因表达转录后调控的主要机制是解除抑制和激活病毒复制的重要第一步。这种激活将允许免疫系统检测到病毒感染的细胞，并通过针对记忆 T 细胞内和表面表达的病毒蛋白的疗法促进清除受感染的细胞。