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CRISPR/Cas9 technology toward understanding HIV latency in primary cells

CRISPR/Cas9 技术有助于了解原代细胞中的 HIV 潜伏期

基本信息

批准号：
9303273
负责人：
VICENTE PLANELLES
金额：
$ 18.94万
依托单位：
UNIVERSITY OF UTAH
依托单位国家：
美国
项目类别：
财政年份：
2016
资助国家：
美国
起止时间：
2016-07-01 至 2018-06-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/9303273
关键词：
Adverse effects Attenuated Biochemical Biochemical Pathway Biological Biological Assay CRISPR/Cas technology Candidate Disease Gene Cell Survival Cell model Cells Clustered Regularly Interspaced Short Palindromic Repeats Development Drug resistance Exploratory/Developmental Grant for Diagnostic Cancer Imaging Foundations Gene Proteins Genes Genetic Genetic Screening Genetic Transcription Genetic screening method Genome engineering Goals HIV HIV Infections HIV-1 Immune system Immunologic Deficiency Syndromes In Vitro Individual Infection Interruption Laboratories Lymphocyte Maintenance Memory Modeling Outcome Pathway interactions Patients Proviruses Publishing Reagent Regulator Genes Seeds Small Interfering RNA T memory cell T-Lymphocyte Technology Testing Therapeutic Agents Toxic effect Transformed Cell Line Validation Viral Viremia Virion Virus Virus Latency antiretroviral therapy base cell transformation cost cytokine feeding genetic manipulation genome-wide analysis in vivo knock-down novel novel therapeutics programs protein complex reactivation from latency small hairpin RNA targeted treatment tat Protein therapeutic development tool vector viral rebound

项目摘要

The presence of latent HIV in individuals treated with highly active combination antiretroviral therapy (cART) has been well established. Without additional therapies, individuals must remain on ART indefinitely in order to avoid development of severe immunodeficiency and spread of the virus. Because of the existence of this reservoir, treatment interruption invariably leads to viral rebound. Thus, it is generally accepted that eradication of the virus will require elimination of the latent reservoir. The fundamental goal of this proposal is adapt our primary TCM-based assay for HIV-1 latency described above to be amenable for testing of latency regulator genes via CRISPR/Cas9 technology. Our initial targets will therefore be candidate genes that are widely accepted to be important for either the establishment/maintenance of latency or for reactivation from latency, and a number of previously untested genes that were identified through genetic screens in various laboratories. Successful validation of novel genes/proteins that control viral latency will lead to identification of relevant pathways and mechanistic studies that will have the potential to spawn major new initiatives to develop novel therapeutics.

在接受高效联合抗逆转录病毒治疗的个体中潜伏HIV的存在（cART）已经建立。如果没有额外的治疗，个人必须无限期地继续接受ART，以避免出现严重的免疫缺陷和病毒传播。由于存在治疗中断总是导致病毒反弹。因此，人们普遍认为，根除病毒需要消除潜伏的宿主。该提案的基本目标是调整我们的主要基于中医药的HIV-1潜伏期检测在一些实施方案中，上文所述的用于通过CRISPR/Cas9技术测试潜伏期调节基因的方法是可行的。我们因此，最初的靶点将是被广泛接受的候选基因，这些候选基因对以下两个方面都很重要：延迟的建立/维持或从延迟中重新激活，以及一些以前未测试的这些基因是通过不同实验室的基因筛选鉴定出来的。控制病毒潜伏期的新基因/蛋白质的成功验证将导致识别相关的途径和机制研究，将有可能产生重大的新举措，开发新的治疗方法。