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Molecular Mechanisms of HIV Latency

HIV潜伏期的分子机制

基本信息

批准号：
10409598
负责人：
Eric M. Verdin
金额：
$ 13.78万
依托单位：
BUCK INSTITUTE FOR RESEARCH ON AGING
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：
2016-04-15 至 2023-06-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10409598
关键词：
Binding Sites Biological Blood CD4 Positive T Lymphocytes CRISPR interference CRISPR/Cas technology Cell Line Cells Cessation of life Chimeric Proteins Clustered Regularly Interspaced Short Palindromic Repeats Cocaine Collaborations Data Drug user Epigenetic Process Exhibits Experimental Models FRAP1 gene Fluorescence Gene Expression Genes Genetic Epistasis Genetic Transcription Genomics Goals Guide RNA HIV HIV Genome HIV Infections HIV-1 Human In Vitro Individual Infection Label Lymphoid Cell Maintenance Maps Methamphetamine Modeling Molecular Mononuclear Paint Pathway interactions Patients Pharmaceutical Preparations Phenotype Process Proteins RNA Regulation Reporter Repression Resolution Rest Role Shock Systems Biology T-Cell Activation Techniques Testing United States Viral Viral Load result Viral reservoir Virus Virus Integration Virus Latency antiretroviral therapy base cell type crosslink differential expression drug abuser drug of abuse env Gene Products exhaustion experimental study follow-up genome wide screen genome-wide illicit drug use innovation mTOR Inhibitor memory CD4 T lymphocyte methamphetamine effect new technology novel novel therapeutics public health relevance reactivation from latency response small hairpin RNA small molecule small molecule inhibitor stimulant use synergism tool transcription factor transcriptome sequencing

项目摘要

DESCRIPTION: Post-integration viral latency is a major barrier to eradicating HIV-1 infection. The current theoretical paradigm for eliminating the viral reservoir is known as `Shock and Kill', reactivation of latent virus using non-targeted small molecules. Key hurdles to this approach have recently emerged such as inefficient and/or stochastic viral reactivation, avoidance of global T-cell activation, and limited cellular death upon re-activation. It is also becoming apparent that our understanding of the molecular mechanisms of HIV latency are fragmentary and in particular the relevance of drugs of abuse on the initiation and maintenance of HIV latency. Here, we propose to explore on a genomic scale the landscape of cellular factors that regulate HIV latency establishment and maintenance and their relationship to drugs of abuse. Our exploration will be based on validating a recently completed genome scale shRNA screen for genes that control latency maintenance and reactivation. We propose to expand this screen using the novel CRISPR-Cas9 technology based on targeting via a guide RNA fusion proteins that either activate (CRISRa) or inhibit (CRISPRi) gene expression. These screens will focus on the mTOR pathway and on methamphetamine as we have recently uncovered evidence that they may act independently or together to modulate the reactivation of latent HIV. We will validate and mechanistically explore both pathways and other top hits in primary CD4 T cells and in cells from HIV-infected patients. We also propose to further develop and exploit new dual-fluorescence reporter HIV-1 genomes to identify, quantify, and purify latently infected cells in their native state, without inducing viral reactivation. This new latency model will allow us to study the effect of drugs of abuse, particularly methamphetamine, on the establishment and maintenance of latency in primary human lymphoid cells and to study the very earliest mechanisms of HIV-1 latency establishment. By combining the power of our dual-labeled latency model with high-resolution single-cell systems-biology techniques, we are uniquely suited to map out the cellular regulatory networks that control HIV latency and the role of drugs of abuse in this process.

项目成果

期刊论文数量（2）

专著数量（0）

科研奖励数量（0）

会议论文数量（0）

专利数量（0）

Histone Deacetylase 7 mediates tissue-specific autoimmunity via control of innate effector function in invariant Natural Killer T Cells.

DOI：
10.7554/elife.32109
发表时间：
2018-04-17
期刊：
eLife
影响因子：
7.7
作者：
Kasler HG;Lee IS;Lim HW;Verdin E
通讯作者：
Verdin E

The mTOR Complex Controls HIV Latency.

DOI：
10.1016/j.chom.2016.11.001
发表时间：
2016-12-14
期刊：
Cell host & microbe
影响因子：
30.3
作者：
Besnard E;Hakre S;Kampmann M;Lim HW;Hosmane NN;Martin A;Bassik MC;Verschueren E;Battivelli E;Chan J;Svensson JP;Gramatica A;Conrad RJ;Ott M;Greene WC;Krogan NJ;Siliciano RF;Weissman JS;Verdin E
通讯作者：
Verdin E