Host factors regulating HIV latency and reactivation
调节HIV潜伏期和再激活的宿主因素
基本信息
- 批准号:10516096
- 负责人:
- 金额:$ 48.3万
- 依托单位:
- 依托单位国家:美国
- 项目类别:
- 财政年份:2021
- 资助国家:美国
- 起止时间:2021-11-01 至 2026-10-31
- 项目状态:未结题
- 来源:
- 关键词:AccelerationAffectAffinity ChromatographyAutomobile DrivingBindingBinding ProteinsBiologicalCD4 Positive T LymphocytesCell modelCellsCellular Metabolic ProcessChIP-seqChromatinChromatin Remodeling FactorChromatin StructureClustered Regularly Interspaced Short Palindromic RepeatsComplexDependenceERCC3 geneElementsEnvironmentEpigenetic ProcessGeneric DrugsGenesGenetic TranscriptionGoalsHIVHIV GenomeHIV-1HeterochromatinImpairmentIn VitroIndividualIntegration Host FactorsInterruptionKnock-outKnowledgeLinkMass Spectrum AnalysisMediatingMessenger RNAModificationMolecularMolecular ConformationNucleosomesPathway interactionsPharmaceutical PreparationsPositioning AttributePost-Translational Protein ProcessingProductivityProliferatingProteinsProvirusesRNA Polymerase IIRNA SplicingReportingReproducibilityResidual stateRoleSpironolactoneTestingTransactivationTranscription CoactivatorTranslational Protein ModificationViralViral ProteinsViremiaacrosome stabilizing factorantiretroviral therapycortistatindetection limitepigenetic silencingfollow-upin vivoin vivo Modelinhibitorinsightknock-downnoveloverexpressionprohibitinpromoterprotein complexreactivation from latencyrecruitsmall hairpin RNAsmall moleculetargeted agenttranscription factortranscription factor TFIIHtranscriptomicsviral rebound
项目摘要
Abstract
Our central premise is that HIV transcriptional inhibitors can be used as latency promoting agents (LPAs) in
block-and-lock functional cure approaches, aimed at reducing residual viremia during antiretroviral therapy (ART)
and limiting viral rebound upon treatment interruption (TI). This hypothesis came about with the discovery of the
Tat inhibitor, didehydro-Cortistatin A (dCA). In in vitro and in vivo models of HIV latency combining ART with
dCA accelerated HIV-1 suppression to below the limit of detection and blocked viral rebound upon TI or
stimulation with latency reversing agents (LRAs). The transcriptional shutdown by dCA resulted in the
heterochromatinization and loss of RNAPII at the HIV promoter. We recently reported on another LPA, the
generic drug Spironolactone (SP). Interestingly this drug degrades the host XPB subunit of the general
transcription factor TFIIH inhibiting HIV transcription in primary cells from infected individuals and blocking viral
reactivation from latency without affecting cellular transcriptomics7. This study is important because it highlights
that a host factor can be targeted to silence HIV without affecting cellular viability. In sum, the more knowledge
we gain on the interconnectivity between Tat, transcription factors regulatory mechanisms and how these affect
nucleosomes positioning around the HIV promoter, the more we can leverage transcriptional regulators as
antiviral targets.
To identify novel host factors regulating HIV transcription we used a chromatin affinity purification approach
together with mass spectrometry (ChAP-MS). We identified p32 (ASF/SF2 splicing factor-associated protein)
and FUBP3 (Far upstream element binding protein 3) in productively infected ART treated promoters but not in
dCA-treated where HIV was silenced; and PHB2 (prohibitin-2) was enriched in dCA treated promoters but
reduced in ART only treated ones. These results suggest that p32 and FUBP3 are HIV transcriptional
activators while PHB2 is a HIV silencing factor. Preliminary studies confirmed their transcriptional activity on
HIV. Here we propose a detailed molecular mechanistic study on how p32 and FUBP3 enhance and how PHB2
inhibits HIV transcription. Understanding their role in pre-initiation complex (PIC) formation, initiation, elongation
and nucleosome organization at the latent HIV promoter will be key for developing successful strategies for
durable HIV silencing. Strong effects of one or more of these factors will prompt the search for small-molecule
modulators. Our overarching goal is to durably silence latent HIV proviruses by driving each into stable
heterochromatin where they will remain “locked.” We propose the following aims:
Aim 1: Define the roles of p32, FUBP3 and PHB2 in HIV transcription and chromatin structure.
Aim 2: Identify protein complexes associated with p32, FUBP3 and PHB2 and study interaction with Tat.
Aim 3: Investigate the “block-and-lock” approach using single or combinations of factors and their dependence
on Tat/TAR circuitry.
摘要
我们的中心前提是HIV转录抑制物可以用作潜伏期促进剂(LPA)
阻断和锁定功能治疗方法,旨在减少抗逆转录病毒治疗期间的残余病毒血症(ART)
以及限制治疗中断时的病毒反弹(TI)。这一假说是在发现
TAT抑制剂,二氢皮质酮A(DCA)。联合应用抗逆转录病毒治疗的HIV潜伏期的体内外模型
DCA将HIV-1抑制速度加快至检测下限以下,并阻止病毒在感染或感染后反弹
潜伏期反转剂(LRA)刺激。DCA的转录关闭导致了
HIV启动子上RNAPII的异染色质和丢失。我们最近报道了另一种LPA,即
仿制药螺内酯(SP)。有趣的是,这种药物降解了通用的宿主XPB亚单位
转录因子TFIIH抑制感染者原代细胞中HIV的转录并阻断病毒
在不影响细胞转录的情况下从潜伏期重新激活。这项研究之所以重要,是因为它突出了
宿主因子可以在不影响细胞存活的情况下靶向沉默艾滋病毒。总而言之,知识越多
我们获得了tat、转录因子调控机制之间的相互联系以及它们是如何影响的。
核小体定位在HIV启动子周围,我们就越能利用转录调控因子作为
抗病毒靶标。
为了确定调节HIV转录的新宿主因子,我们使用了染色质亲和纯化方法
与质谱仪(CHAP-MS)联用。我们鉴定了p32(ASF/SF2剪接因子相关蛋白)
和FUBP3(远上游元件结合蛋白3),在经ART处理的高效感染启动子中,而在
在HIV被沉默的地方用DCA处理;PHB2(禁止蛋白-2)富含DCA处理的启动子,但是
只接受治疗的患者的抗逆转录病毒能力降低。这些结果表明p32和FUBP3是HIV的转录因子
而PHB2是一种艾滋病毒沉默因子。初步研究证实了它们的转录活性
爱滋病毒。在这里,我们提出了关于p32和FUBP3如何增强以及PHB2如何增强的详细的分子机制研究
抑制艾滋病毒转录。了解它们在预引发复合体(PIC)形成、引发、延伸中的作用
潜伏的HIV启动子上的核小体组织将是制定成功的策略的关键
持久的艾滋病毒沉默。这些因素中的一个或多个的强烈作用将促使人们寻找小分子
调制器。我们的首要目标是通过将每个潜伏的艾滋病毒前病毒驱赶到稳定状态来持久地压制潜伏的艾滋病毒前病毒
异染色质,它们将保持“锁定”状态。我们提出以下目标:
目的1:明确p32、FUBP3和PHB2在HIV转录和染色质结构中的作用。
目的2:鉴定与P32、FUBP3和PHB2相关的蛋白质复合体,并研究其与TAT的相互作用。
目标3:研究使用单一因素或因素组合及其相关性的“封锁锁定”方法
在TAT/TAR电路上。
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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Susana T Valente其他文献
Potent suppression of HIV viral replication by a novel inhibitor of Tat
- DOI:
10.1186/1742-4690-9-s1-o11 - 发表时间:
2012-05-25 - 期刊:
- 影响因子:3.900
- 作者:
Guillaume Mousseau;Mark A Clementz;Wendy N Bakeman;Nisha Nagarsheth;Michael Cameron;Jun Shi;Phil Baran;Rémi Fromentin;Nicolas Chomont;Susana T Valente - 通讯作者:
Susana T Valente
Susana T Valente的其他文献
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{{ truncateString('Susana T Valente', 18)}}的其他基金
Development and characterization of HIV-1 Tat degraders
HIV-1 Tat 降解剂的开发和表征
- 批准号:
10483950 - 财政年份:2022
- 资助金额:
$ 48.3万 - 项目类别:
Validation and characterization of Tat inhibitors identified through HTS
通过 HTS 鉴定的 Tat 抑制剂的验证和表征
- 批准号:
10258019 - 财政年份:2021
- 资助金额:
$ 48.3万 - 项目类别:
Host factors regulating HIV latency and reactivation
调节HIV潜伏期和再激活的宿主因素
- 批准号:
10427641 - 财政年份:2021
- 资助金额:
$ 48.3万 - 项目类别:
Validation and characterization of Tat inhibitors identified through HTS
通过 HTS 鉴定的 Tat 抑制剂的验证和表征
- 批准号:
10468812 - 财政年份:2021
- 资助金额:
$ 48.3万 - 项目类别:
Host factors regulating HIV latency and reactivation
调节HIV潜伏期和再激活的宿主因素
- 批准号:
10403317 - 财政年份:2021
- 资助金额:
$ 48.3万 - 项目类别:
Host factors regulating HIV latency and reactivation
调节HIV潜伏期和再激活的宿主因素
- 批准号:
10591707 - 财政年份:2021
- 资助金额:
$ 48.3万 - 项目类别:
Validation and characterization of Tat inhibitors identified through HTS
通过 HTS 鉴定的 Tat 抑制剂的验证和表征
- 批准号:
10591875 - 财政年份:2021
- 资助金额:
$ 48.3万 - 项目类别:
Identification and characterization of chromatin regulators of HIV-1 latency
HIV-1 潜伏期染色质调节因子的鉴定和表征
- 批准号:
9975693 - 财政年份:2018
- 资助金额:
$ 48.3万 - 项目类别:
Identification and characterization of chromatin regulators of HIV-1 latency
HIV-1 潜伏期染色质调节因子的鉴定和表征
- 批准号:
10591851 - 财政年份:2018
- 资助金额:
$ 48.3万 - 项目类别:
Identification and characterization of chromatin regulators of HIV-1 latency
HIV-1 潜伏期染色质调节因子的鉴定和表征
- 批准号:
10423663 - 财政年份:2018
- 资助金额:
$ 48.3万 - 项目类别:
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