Molecular Mechanisms of HIV Latency
HIV潜伏期的分子机制
基本信息
- 批准号:10200723
- 负责人:
- 金额:$ 126.08万
- 依托单位:
- 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 2024-06-30
- 项目状态:已结题
- 来源:
- 关键词:Binding SitesBiologicalBloodCD4 Positive T LymphocytesCRISPR interferenceCRISPR/Cas technologyCell LineCellsCessation of lifeChimeric ProteinsClustered Regularly Interspaced Short Palindromic RepeatsCocaineCollaborationsDataDrug userEpigenetic ProcessExhibitsExperimental ModelsFRAP1 geneFluorescenceGene ExpressionGenesGenetic EpistasisGenetic TranscriptionGenomicsGoalsGuide RNAHIVHIV GenomeHIV InfectionsHIV-1HumanIn VitroIndividualInfectionLabelLymphoid CellMaintenanceMapsMethamphetamineModelingMolecularMononuclearPaintPathway interactionsPatientsPharmaceutical PreparationsPhenotypeProcessProteinsRNARegulationReporterRepressionResolutionRestRoleShockSystems BiologyT-Cell ActivationTechniquesTestingUnited StatesViralViral Load resultViral reservoirVirusVirus IntegrationVirus Latencyantiretroviral therapybasecell typecrosslinkdifferential expressiondrug abuserdrug of abuseenv Gene Productsexhaustionexperimental studyfollow-upgenome wide screengenome-wideillicit drug useinnovationmTOR Inhibitormemory CD4 T lymphocytemethamphetamine effectnew technologynovelnovel therapeuticspublic health relevancereactivation from latencyresponsesmall hairpin RNAsmall moleculesmall molecule inhibitorstimulant usesynergismtooltranscription factortranscriptome 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.
描述:整合后病毒潜伏期是根除HIV-1感染的主要障碍。目前消除病毒储存库的理论范例被称为“休克和杀死”,即使用非靶向小分子重新激活潜伏病毒。最近出现了这种方法的关键障碍,例如低效和/或随机的病毒再活化,避免整体T细胞活化,以及再活化后有限的细胞死亡。同样明显的是,我们对艾滋病毒潜伏期的分子机制的理解是零碎的,特别是滥用药物对艾滋病毒潜伏期的启动和维持的相关性。 在这里,我们建议在基因组规模上探索的景观,调节艾滋病毒潜伏期的建立和维护,以及它们的关系,滥用药物的细胞因子。我们的探索将基于验证最近完成的基因组规模的shRNA筛选控制潜伏期维持和再激活的基因。我们建议使用新的CRISPR-Cas9技术来扩展这种筛选,该技术基于通过引导RNA融合蛋白进行靶向,该融合蛋白可以激活(CRISRa)或抑制(CRISPRi)基因表达。这些筛选将集中在mTOR通路和甲基苯丙胺上,因为我们最近发现的证据表明,它们可能独立或共同作用,以调节潜伏的HIV的再激活。我们将验证和机械地探索这两种途径和其他顶级命中在原代CD 4 T细胞和艾滋病毒感染患者的细胞。我们还建议进一步开发和利用新的双荧光报告HIV-1基因组,以识别、量化和纯化天然状态的潜伏感染细胞,而不会诱导病毒重新激活。这个新的延迟模型将允许我们
研究滥用药物,特别是甲基安非他明对人类初级淋巴细胞潜伏期的建立和维持的影响,并研究HIV-1潜伏期建立的最早机制。通过将我们的双标记潜伏期模型与高分辨率单细胞系统生物学技术相结合,我们非常适合绘制控制HIV潜伏期的细胞调控网络以及滥用药物在此过程中的作用。
项目成果
期刊论文数量(0)
专著数量(0)
科研奖励数量(0)
会议论文数量(0)
专利数量(0)
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Eric M. Verdin其他文献
Eric M. Verdin的其他文献
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{{ truncateString('Eric M. Verdin', 18)}}的其他基金
Senescence, NAD+ decrease and Alzheimer's disease and related dementias Alzheimer's disease and related dementias
衰老、NAD 减少与阿尔茨海默病和相关痴呆症 阿尔茨海默病和相关痴呆症
- 批准号:
10187413 - 财政年份:2021
- 资助金额:
$ 126.08万 - 项目类别:
Senescence, NAD+ decrease and Alzheimer's disease and related dementias Alzheimer's disease and related dementias
衰老、NAD 减少与阿尔茨海默病和相关痴呆症 阿尔茨海默病和相关痴呆症
- 批准号:
10491086 - 财政年份:2021
- 资助金额:
$ 126.08万 - 项目类别:
Senescence, NAD+ decrease and Alzheimer's disease and related dementias Alzheimer's disease and related dementias
衰老、NAD 减少与阿尔茨海默病和相关痴呆症 阿尔茨海默病和相关痴呆症
- 批准号:
10647780 - 财政年份:2021
- 资助金额:
$ 126.08万 - 项目类别:
Lysine Malonylation and SIRT5 in Epigenetic Regulation
表观遗传调控中的赖氨酸丙二酰化和 SIRT5
- 批准号:
9198466 - 财政年份:2016
- 资助金额:
$ 126.08万 - 项目类别:
Identification of HIV latency biomarkers with a dual fluorescence reporter HIV
使用双荧光报告基因 HIV 鉴定 HIV 潜伏生物标志物
- 批准号:
9231361 - 财政年份:2015
- 资助金额:
$ 126.08万 - 项目类别:
Identification of HIV latency biomarkers with a dual fluorescence reporter HIV
使用双荧光报告基因 HIV 鉴定 HIV 潜伏生物标志物
- 批准号:
8892911 - 财政年份:2015
- 资助金额:
$ 126.08万 - 项目类别:
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