Functionally Defining HIV-Host Interactions During the Early HIV-1 Lifecycle
在 HIV-1 生命周期早期从功能上定义 HIV 与宿主的相互作用
基本信息
- 批准号:10037560
- 负责人:
- 金额:$ 145.19万
- 依托单位:
- 依托单位国家:美国
- 项目类别:
- 财政年份:2020
- 资助国家:美国
- 起止时间:2020-03-01 至 2025-02-28
- 项目状态:未结题
- 来源:
- 关键词:AIDS/HIV problemAddressAnti-Retroviral AgentsAreaBehaviorBiochemicalBiologicalBiological AssayBiological PhenomenaBiological ProcessBiologyCRISPR/Cas technologyCell CompartmentationCell Culture TechniquesCell LineCell NucleusCell modelCellsCellular biologyComplexConflict (Psychology)ConsensusCryoelectron MicroscopyCytoplasmDNADataDevelopmentElectron MicroscopyEquipmentEventFluorescence MicroscopyGenesGeneticGenome engineeringGoalsHIVHIV GenomeHIV therapyHIV-1HumanImageIndividualInfectionIntegraseIntegrase InhibitorsIntegration Host FactorsKineticsKnowledgeLabelLife Cycle StagesLinkLocationMapsMeasurementMeasuresMelissaMethodsMicroscopyModelingMolecularMutationNatureNuclearNuclear PoreNuclear Pore ComplexPaintPathway interactionsPhasePhenotypePlayPositioning AttributePreventionProcessProvirus IntegrationProvirusesRNA-Directed DNA PolymeraseResearchResearch PersonnelResolutionReverse TranscriptionRoleRouteSeriesSpecialistStructureSystems BiologyTechniquesTechnologyTherapeuticTranslatingTreatment ProtocolsViralVirionVirusbasecell immortalizationcell typecryogenicsdrug developmentexperienceimaging approachimprovedin vivoinnovationinsightlive cell imagingmedical specialtiesmembermolecular imagingmultidisciplinarynovelparticlepopulation basedpre-exposure prophylaxispreventsmall molecule inhibitortherapeutic targettooltraffickingtreatment optimizationuptakevirology
项目摘要
ABSTRACT: The early phase of the HIV lifecycle encompasses the steps from virus fusion to provirus integration
and represents a critical therapeutic target. Small molecule inhibitors of HIV encoded reverse transcriptase and
integrase are central components of many therapeutic treatment regimens and pre-exposure prophylaxis.
Despite the therapeutic importance of these steps, the field still lacks consensus on several outstanding
questions including how trafficking and uncoating are linked to reverse transcription, how and in what state the
provirus transits through the nuclear pore, what host factors are involved in these processes, and what
distinguishes between a virus that will establish successful infection and one that will fail. Due to the inefficient
and relatively stochastic nature of early phase replication, only a small percentage (~15%) of particles that enter
the cytoplasm after fusion will result in successful provirus integration. As a result, population-based assays that
measure what most viruses do may or may not actually capture what successful viruses do. Nevertheless,
technical limitations have historically mandated a reliance on population-based assays, immortalized cell line
models, and indirect measurements of biological processes whose underlying assumptions don’t necessarily
reflect the biological priors. Only recently have innovations in single-particle tracking, molecular imaging, gene
editing, and structural determination allowed for researchers to overcome these limitations, but these specialized
technologies have not yet been brought together to answer these critical questions in HIV biology. Here, we
assemble a team of HIV researchers with complementary expertise in these powerful approaches to dissect and
define the interactions, kinetics, and dynamics between fusion and integration that result in productive infection.
We propose to leverage a newly optimized toolbox of molecular labeling methods, a technique collectively
termed Infectious Virion Tracking (IVT), to image and track the behavior of individual viral components, ultimately
separating individual virions that result in successful infection from those that enter the cell non-productively.
Additional specialized technologies including primary cell CRISPR-Cas9 gene editing and cryogenic electron
microscopy will be leveraged to interrogate the structure and function of individual components along the route
to productive infection. Wielding this novel and innovative series of tools, approaches, and equipment, we aim
to: 1) Define the infectious pathway of HIV from fusion to integration in optimized cell culture models and primary
human target cells; 2) Determine the role of host permissivity factors and viral components in the processes of
the early phase of the HIV life-cycle; and 3) Visualize and define the structure of the viral based machines
associated with the HIV genome as it progresses through reverse transcription, traffics through the cytoplasm,
enters the nucleus, and ultimately integrates in the host chromosomal DNA. As a collaborative team with
complementary specialties that address critical limitations in the field, we are in a unique position to make
significant contributions to our current understanding of the early phases of HIV replication.
摘要:HIV 生命周期的早期阶段包括从病毒融合到原病毒整合的步骤
并代表了 HIV 编码逆转录酶的关键治疗靶点。
整合酶是许多治疗方案和暴露前预防的核心组成部分。
尽管这些步骤具有治疗重要性,但该领域仍然对几个突出的问题缺乏共识
问题包括贩运和脱壳如何与逆转录相关、如何以及在什么状态下
原病毒通过核孔转运,这些过程涉及哪些宿主因素,以及什么
区分会成功感染的病毒和由于效率低下而失败的病毒。
以及早期复制的相对随机性,只有一小部分(~15%)的粒子进入
融合后的细胞质将导致原病毒成功整合。
衡量大多数病毒的行为可能会也可能不会真正捕获成功病毒的行为,
技术限制历来要求依赖基于群体的测定、永生化细胞系
模型和生物过程的间接测量,其基本假设不一定
直到最近,单粒子追踪、分子成像、基因方面才出现了创新。
编辑和结构确定使研究人员能够克服这些限制,但这些专门的
技术尚未汇集在一起来回答艾滋病毒生物学中的这些关键问题。
组建一支艾滋病毒研究人员团队,他们在这些强大的方法上具有互补的专业知识来剖析和
定义导致生产性感染的融合和整合之间的相互作用、动力学和动态。
我们建议利用新优化的分子标记方法工具箱,该技术统称为
称为传染性病毒粒子追踪(IVT),最终对单个病毒成分的行为进行成像和追踪
将导致成功感染的单个病毒颗粒与那些非生产性进入细胞的病毒颗粒分开。
其他专业技术,包括原代细胞 CRISPR-Cas9 基因编辑和低温电子
将利用显微镜来询问沿途各个组件的结构和功能
我们的目标是利用这一系列新颖和创新的工具、方法和设备。
1) 定义 HIV 在优化的细胞培养模型和原代细胞中从融合到整合的感染途径
人类靶细胞;2)确定宿主许可因子和病毒成分在过程中的作用
HIV 生命周期的早期阶段;3) 可视化并定义基于病毒的机器的结构
与 HIV 基因组相关,因为它通过逆转录进行,通过细胞质运输,
进入细胞核,并最终整合到宿主染色体DNA中,作为一个协作团队。
解决该领域关键限制的互补专业,我们处于独特的地位
对我们目前对艾滋病毒复制早期阶段的理解做出了重大贡献。
项目成果
期刊论文数量(0)
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会议论文数量(0)
专利数量(0)
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Paul D. Bieniasz其他文献
Paul D. Bieniasz的其他文献
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{{ truncateString('Paul D. Bieniasz', 18)}}的其他基金
Broad neutralization of pandemic threat coronaviruses
广泛消除大流行威胁冠状病毒
- 批准号:
10327989 - 财政年份:2022
- 资助金额:
$ 145.19万 - 项目类别:
Broad neutralization of pandemic threat coronaviruses
广泛消除大流行威胁冠状病毒
- 批准号:
10841237 - 财政年份:2022
- 资助金额:
$ 145.19万 - 项目类别:
Effects of Interferon on primate lentiviruses
干扰素对灵长类慢病毒的影响
- 批准号:
10619797 - 财政年份:2022
- 资助金额:
$ 145.19万 - 项目类别:
Coronavirus neutralizing antibody epitopes and immunogens
冠状病毒中和抗体表位和免疫原
- 批准号:
10841241 - 财政年份:2022
- 资助金额:
$ 145.19万 - 项目类别:
Effects of Interferon on primate lentiviruses
干扰素对灵长类慢病毒的影响
- 批准号:
10708965 - 财政年份:2022
- 资助金额:
$ 145.19万 - 项目类别:
Coronavirus neutralizing antibody epitopes and immunogens
冠状病毒中和抗体表位和免疫原
- 批准号:
10327993 - 财政年份:2022
- 资助金额:
$ 145.19万 - 项目类别:
Functionally Defining HIV-Host Interactions During the Early HIV-1 Lifecycle
在 HIV-1 生命周期早期从功能上定义 HIV 与宿主的相互作用
- 批准号:
10594493 - 财政年份:2020
- 资助金额:
$ 145.19万 - 项目类别:
Host protein targets of HIV-1 Vpr in gene expression, cell cycle and innate immunity
HIV-1 Vpr 在基因表达、细胞周期和先天免疫中的宿主蛋白靶点
- 批准号:
10265576 - 财政年份:2020
- 资助金额:
$ 145.19万 - 项目类别:
Host protein targets of HIV-1 Vpr in gene expression, cell cycle and innate immunity
HIV-1 Vpr 在基因表达、细胞周期和先天免疫中的宿主蛋白靶标
- 批准号:
10681282 - 财政年份:2020
- 资助金额:
$ 145.19万 - 项目类别:
Host protein targets of HIV-1 Vpr in gene expression, cell cycle and innate immunity
HIV-1 Vpr 在基因表达、细胞周期和先天免疫中的宿主蛋白靶标
- 批准号:
10681282 - 财政年份:2020
- 资助金额:
$ 145.19万 - 项目类别:
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