Heat shock protein 90 and HIV persistence
热休克蛋白 90 和 HIV 持久性
基本信息
- 批准号:8663192
- 负责人:
- 金额:$ 29.64万
- 依托单位:
- 依托单位国家:美国
- 项目类别:
- 财政年份:2013
- 资助国家:美国
- 起止时间:2013-05-17 至 2016-04-30
- 项目状态:已结题
- 来源:
- 关键词:1-Phosphatidylinositol 3-KinaseAchievementAcquired Immunodeficiency SyndromeAddressAffinityAffinity ChromatographyAftercareC-terminalCD4 Positive T LymphocytesCell DeathCell LineCell NucleusCellsChromatinClientComplexDNA Polymerase IIDetectionDisease remissionEpigenetic ProcessFamilyFeverFrequenciesGenesGenetic TranscriptionGenomicsHIVHIV InfectionsHeat-Shock Proteins 90Heat-Shock ResponseHighly Active Antiretroviral TherapyHistone DeacetylationHumanHyperthermiaImmune systemIntegration Host FactorsInterleukin-1Interleukin-2Interleukin-6LeadLengthLife ExpectancyLymphocyteMass Spectrum AnalysisMediatingMemoryModelingMolecular ChaperonesMusPathway interactionsPatientsPharmaceutical PreparationsPhenotypePhysiologicalPlasmaPositive Transcriptional Elongation Factor BProductionProtein AnalysisProtein IsoformsProtein Kinase CProteinsPublic HealthRNARNA chemical synthesisReporterRestRoleSendai virusSignal TransductionStressTNF geneTemperatureTestingTherapeuticTranscriptTranscriptional RegulationViralViral Load resultViremiaVirusVorinostatbryostatinchaperone machinerychromatin immunoprecipitationchromatin remodelingcytokineexpectationinhibitor/antagonistinnovationmouse modelnovelnovel therapeuticspreventpromoterprotein expressionpublic health relevancepurgereactivation from latencyresearch studytranscription factortreatment strategyultraviolet irradiationvector
项目摘要
DESCRIPTION: Highly active antiretroviral therapy (HAART) successfully reduces the viral load to below the limit of detection, but HIV replication resumes soon after patients cease therapy. It is believed that a small subset of persistent HIV- infected resting CD4+ T cells are activated in the absence of HAART and contribute to the rebound in patient viral load. This has led to a new treatment strategy that proposes a combination of latency-purging drugs and HAART, with the expectation that activating HIV-infected resting CD4+ T cells will eliminate the persistent viral reservoir by virus-mediated cell death, by the immune system, and by HAART. Reactivation of HIV latency in resting CD4+ T cells can also be induced nonchemically by heat shock. In ongoing experiments, we have found that heat shock protein 90 (Hsp90) is essential for HIV replication and that heat shock (39.5oC) significantly increases HIV infectivity with a simultaneous increase in Hsp90 protein expression. Similar studies by others suggest that reactivation of HIV latency by heat shock is dependent on Hsp90 expression. HIV latency is maintained in resting CD4+ T cells by suppression of the level of virus- specific proteins. Cellular activation results in production of these host factors, but these proteins need to be activated in order to induce HIV reactivation. The active P-TEFb complex and the NF-?B family of transcription factors are essential for HIV reactivation, and these cellular proteins are activated by the Hsp90 chaperone machinery. Similarly, certain chromatin-remodeling proteins that control HIV latency are activated by Hsp90 and lead to HIV reactivation. The examples mentioned above are part of a larger body of work showing that heat shock, and specifically Hsp90, influence HIV replication. Given these observations, we hypothesize that Hsp90 has a functional role in reactivating HIV latency. This hypothesis will be addressed in the experiments of the following Specific Aims: (1) to study how Hsp90 reactivates HIV latency in resting CD4+ T cells, and (2) to identify Hsp90-interacting proteins that reactivate HIV latency. These studies include expressing Hsp90 in untransformed primary human lymphocytes and analyzing the specific Hsp90-interacting proteins that induce HIV reactivation in latently infected resting CD4+ T cells. This hypothesis will be validated in the humanized NSG-BLT mouse model of HIV latency. The objective of this proposal is to identify Hsp90-interacting proteins that reactivate HIV latency, and analysis of these proteins may reveal novel targets for elimination of the latent HIV reservoir.
产品说明:高效抗逆转录病毒疗法(HAART)成功地将病毒载量降低到检测限以下,但HIV复制在患者停止治疗后很快恢复。据信,一小部分持续HIV感染的静息CD 4 + T细胞在没有HAART的情况下被激活,并有助于患者病毒载量的反弹。这导致了一种新的治疗策略,提出了潜伏期清除药物和HAART的组合,期望激活HIV感染的静息CD 4 + T细胞将通过病毒介导的细胞死亡,免疫系统和HAART消除持久的病毒库。HIV潜伏期在静止的CD 4 + T细胞中的重新激活也可以通过热休克非化学诱导。在正在进行的实验中,我们发现热休克蛋白90(Hsp 90)是HIV复制所必需的,并且热休克(39.5 ℃)显著增加HIV感染性,同时增加Hsp 90蛋白表达。其他人的类似研究表明,热休克对HIV潜伏期的再激活依赖于Hsp 90的表达。HIV潜伏期通过抑制病毒特异性蛋白质的水平而维持在静息的CD 4 + T细胞中。细胞活化导致这些宿主因子的产生,但这些蛋白质需要被活化以诱导HIV再活化。活性P-TEFb复合物和NF-?B家族转录因子是HIV再激活所必需的,这些细胞蛋白由Hsp 90伴侣机制激活。类似地,某些控制HIV潜伏期的染色质重塑蛋白被Hsp 90激活并导致HIV再激活。上面提到的例子是一个更大的工作机构的一部分,表明热休克,特别是热休克90,影响艾滋病毒的复制。鉴于这些观察结果,我们假设Hsp 90在重新激活HIV潜伏期中具有功能性作用。这一假设将在以下特定目的的实验中得到解决:(1)研究Hsp 90如何重新激活静息CD 4 + T细胞中的HIV潜伏期,以及(2)鉴定重新激活HIV潜伏期的Hsp 90相互作用蛋白。这些研究包括在未转化的原代人淋巴细胞中表达Hsp 90和分析在潜伏感染的静息CD 4 + T细胞中诱导HIV再活化的特异性Hsp 90相互作用蛋白。该假设将在HIV潜伏期的人源化NSG-BLT小鼠模型中得到验证。该提案的目的是确定重新激活HIV潜伏期的Hsp 90相互作用蛋白,对这些蛋白的分析可能揭示消除潜伏HIV库的新靶点。
项目成果
期刊论文数量(1)
专著数量(0)
科研奖励数量(0)
会议论文数量(0)
专利数量(0)
Genetically edited CD34+ cells derived from human iPS cells in vivo but not in vitro engraft and differentiate into HIV-resistant cells.
来自人类 iPS 细胞的基因编辑 CD34 细胞在体内但不在体外移植并分化为 HIV 抗性细胞。
- DOI:10.1073/pnas.2102404118
- 发表时间:2021
- 期刊:
- 影响因子:11.1
- 作者:Morvan,MaeligG;Teque,Fernando;Ye,Lin;Moreno,MaryE;Wang,Jiaming;VandenBerg,Scott;Stoddart,CherylA;Kan,YuetWai;Levy,JayA
- 通讯作者:Levy,JayA
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Cheryl Stoddart其他文献
Cheryl Stoddart的其他文献
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{{ truncateString('Cheryl Stoddart', 18)}}的其他基金
Single-chain antibodies to block HIV transcription and prevent reactivation from latently infected resting CD4+ T cells
单链抗体可阻断 HIV 转录并防止潜伏感染的静息 CD4 T 细胞重新激活
- 批准号:
10308728 - 财政年份:2020
- 资助金额:
$ 29.64万 - 项目类别:
Inhibition of heat shock protein 90 for sustained remission of HIV from persistent tissue reservoirs
抑制热休克蛋白 90 使持久性组织储存库中的 HIV 持续缓解
- 批准号:
10184988 - 财政年份:2020
- 资助金额:
$ 29.64万 - 项目类别:
HUMANIZED MOUSE MODELS FOR HIV THERAPEUTICS DEVELOPMENT
用于艾滋病毒治疗开发的人源化小鼠模型
- 批准号:
9915757 - 财政年份:2019
- 资助金额:
$ 29.64万 - 项目类别:
IGF::OT::IGF "HUMANIZED MOUSE MODELS FOR HIV THERAPEUTICS DEVELOPMENT"
IGF::OT::IGF“用于艾滋病治疗开发的人性化小鼠模型”
- 批准号:
8936706 - 财政年份:2013
- 资助金额:
$ 29.64万 - 项目类别:
IGF::OT::IGF "HUMANIZED MOUSE MODELS FOR HIV THERAPEUTICS DEVELOPMENT"
IGF::OT::IGF“用于艾滋病治疗开发的人性化小鼠模型”
- 批准号:
9004371 - 财政年份:2013
- 资助金额:
$ 29.64万 - 项目类别:
Tissue Based Small Animal Model for HIV Drug Discovery
用于 HIV 药物发现的基于组织的小动物模型
- 批准号:
7789059 - 财政年份:2006
- 资助金额:
$ 29.64万 - 项目类别:
TISSUE BASED SMALL ANIMAL MODEL FOR HIV DRUG DISCOVERY
用于艾滋病毒药物发现的基于组织的小动物模型
- 批准号:
7543538 - 财政年份:2006
- 资助金额:
$ 29.64万 - 项目类别:
TISSUE-BASED SMALL ANIMAL MODEL FOR HIV DRUG DISCOVERY
用于艾滋病毒药物发现的基于组织的小动物模型
- 批准号:
6348654 - 财政年份:2000
- 资助金额:
$ 29.64万 - 项目类别:
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