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HIV-1 RNA structure effects on latency reversal

HIV-1 RNA 结构对潜伏期逆转的影响

基本信息

批准号：
9411353
负责人：
Silvia Rouskin
金额：
$ 30.97万
依托单位：
WHITEHEAD INSTITUTE FOR BIOMEDICAL RES
依托单位国家：
美国
项目类别：
财政年份：
2017
资助国家：
美国
起止时间：
2017-08-08 至 2019-07-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/9411353
关键词：
Antigens Binding Biological Biological Assay CD4 Positive T Lymphocytes Cause of Death Cell Death Cell Line Cell Nucleus Cell model Cells Chemicals Clinical Trials Complex Computer Simulation Defect Dimerization Epitopes Event Gene Expression Genetic Transcription Genome Goals Gold HIV HIV-1 Health Highly Active Antiretroviral Therapy Histones Human Immune Immune System Diseases Immune System and Related Disorders Immunization In Vitro Individual Infection Integration Host Factors Interphase Cell Knowledge Latent Virus Lead Life Life Cycle Stages Memory Messenger RNA Modeling Modification Mutation Nitrogen Participant Pathway interactions Pharmaceutical Preparations Phase Physiological Polymerase Procedures Process Production Proteins Proviruses RNA RNA Binding RNA Folding RNA Probes RNA Processing RNA Viruses RNA analysis RNA-Directed DNA Polymerase Reagent Research Rest Running Shock Signal Transduction Site Stress Structure Subcellular structure Surface System T-Cell Activation T-Lymphocyte Tail Techniques Testing Toxic effect Transcription Process Translations Variant Viral Viral Load result Viral Proteins Viral reservoir Virion Virus Virus Replication Work base clinically relevant design dimer dimethyl sulfate drug candidate experimental study genomic RNA helicase high reward high risk immune activation immune clearance innovation insight interest killings latent infection memory CD4 T lymphocyte methylisoamylnitrosamine novel particle protein expression purge small molecule three dimensional structure viral DNA viral RNA

项目摘要

7. PROJECT SUMMARY/ABSTRACT As part of its infection cycle, HIV-1 integrates into the genome of CD4+ T cells. After initial infection, a subset of these cells returns to a `resting memory' state. The viral DNA is still present in the genome of these memory cells but it is silent, a phase in the viral life cycle called the latent phase. These memory cells harbor the virus and can produce infectious particles upon stimulation as long as the infected cell is alive. Latent infection, therefore, requires lifelong treatment of infected individuals to suppress rebounds in viral load. The current strategy to cure HIV-1 is to reactivate latently infected cells, which will subsequently result in their clearance. Reactivation can lead to either cell death caused by the toxic effects of viral replication or immune clearance by the presentation of viral epitopes on the surface of the infected cell. Approaches to reactivate the latent virus reservoir have focused on increasing HIV-1 gene expression, as it is thought that latency is maintained by multiple blocks to global transcription. Drug candidates for reactivation, called latency reversing agents (LRA), target different steps in the transcription process (e.g. histone tail modification, polymerase elongation) but are designed to avoid causing general activation of T cells, which would result in massive immune dysfunction. To date, clinical trials with the most promising LRA drugs have failed to reduce the latent HIV-1 reservoir. Curiously, LRA treatment can robustly induce viral RNA expression in primary HIV-1 latency models, however a comparable increase in viral proteins and replication is not observed, which is required for successful clearance. These findings have led to the proposal of an additional post-transcriptional block to viral protein expression in resting T cells. The ~10kb HIV-1 RNA genome folds into a complex three dimensional structure and specific features of this structure are critically involved in regulating multiple post-transcriptional steps including transport of the viral RNA out of the nucleus, translation of viral protein, and packaging of the RNA genome into the viral particle. The proposed research will test the hypothesis that the post-transcriptional block, which is not bypassed by LRA stimulation, is due to specific aspects of HIV-1 RNA structure, which is an innovative idea for the HIV cure field. We will employ a novel technique (DMS-MaPseq) developed recently in the Rouskin lab, which allows for targeted RNA structure probing in living cells. Importantly, the simplicity of the DMS-MaPseq approach will enable RNA structure probing of the entire HIV-1 genome in several different cellular conditions. This work will be significant because it will provide critical information on the native HIV-1 RNA structure, which has never been examined in its physiological context within T-cells where host factors can dramatically influence RNA folding. In addition, this high-risk, high-reward project can directly benefit the prominent “shock and kill strategy” for latently infected T cell clearance by providing insight into the post- transcriptional block to LRA activity.

7. 项目总结/文摘