Identification of drugs that induce terminal transcriptional silencing of latent HIV-1 infection
诱导潜伏 HIV-1 感染末端转录沉默的药物的鉴定
基本信息
- 批准号:10223169
- 负责人:
- 金额:$ 68.96万
- 依托单位:
- 依托单位国家:美国
- 项目类别:
- 财政年份:2017
- 资助国家:美国
- 起止时间:2017-08-01 至 2023-07-31
- 项目状态:已结题
- 来源:
- 关键词:ATAC-seqAddressAlgorithmsAntibodiesAntiviral AgentsAntiviral ResponseBinding SitesBiologicalBiological AssayCD4 Positive T LymphocytesCRISPR/Cas technologyCatalogsCell LineCell modelCellsChemicalsClinicalClone CellsComplementDNADataDatabasesDefense MechanismsDevelopmentDiversity LibraryDrug CombinationsDrug ScreeningDrug TargetingElementsEventFundingGene SilencingGenerationsGenomeGenomicsHIVHIV-1HIV-2HumanIndividualInfectionInterventionLaboratoriesLeadLibrariesMethodsMolecularOpen Reading FramesPathway interactionsPatientsPattern recognition receptorPharmaceutical PreparationsPharmacologyPhasePhenotypeProcessProteinsProvirusesPubChemRNAReporterResearchRetrotransposonRoboticsSevere Acute Respiratory SyndromeSignal TransductionSpecificityStructureT-LymphocyteTLR3 geneTestingTherapeuticToxic effectViralViral ProteinsViral reservoirVirusVirus Diseasesactive controlanalogantiretroviral therapybasechemical synthesisclinical translationclinically relevantcombinatorialcostdruggable targetepigenetic silencinggene therapygenetic manipulationgenome-widehigh throughput screeninginnate immune mechanismslatent infectionlead seriesmacrophageoverexpressionresponsescaffoldscreeningsmall hairpin RNAsmall moleculetranscription factortranscriptome sequencing
项目摘要
As it is becoming increasingly clear that currently pursued HIV-1 reactivating strategies may not result
in therapeutic HIV-1 eradication, alternative eradication strategies need to be explored. We here propose to
develop terminal transcriptional silencing (TTS) strategies specific for latent HIV-1 infection events. TTS
strategies would have their biological equivalent in retro/lentiviral silencing. However, TTS would not target de
novo infection events, but have to transcriptionally silence pre-existing, latent provirus in the absence of viral
proteins, mostly RNA or non-integrated DNA that usually trigger the antiviral cellular response. Evidence for
the existence of cellular innate immune mechanisms that specifically target lentiviral infection is provided by
the fact that lentiviral silencing is a major roadblock for lentiviral-based gene therapy. The existence of innate
cellular defense mechanisms that can control pre-existing virus-style genome expression is suggested by the
existence of defense mechanisms against a related, evolutionary ancient class of “genomic intruders” called
retrotransposons. These defense mechanisms individually evolved in response to each different
retrotransposon class. Unfortunately, because of this specificity, mechanisms that continuously actively control
retrotransposons to suppress their genomic spread, actually are inactive against HIV-1. Specificity of TTS
strategies against HIV-1 infection is essential as, beyond the general consideration of toxicity issues of any
drug intervention, TTS strategies cannot cause (i) any interference with innate control mechanisms that
suppress retrotransposon activity or cause (ii) any interference with mechanisms that control epigenetic
silencing of genes in human cells. For the R61 phase, we propose an iterative approach that combines high
content analysis methods (ATAC-seq, RNA-seq, kinome array analysis) with pharmacological perturbation
screens to identify drug targets that specifically control the cellular innate antiviral response to HIV-1 infection.
The proposed research will take advantage of (i) a preexisting, large selection of HIV-1 reporter cells, (ii) the
finding that certain clinical HIV-1 and in particular HIV-2 strains cause a much more potent innate TTS
response than the commonly used laboratory adapted HIV-1 clones, and (iii) the finding that macrophages are
much more efficient in executing TTS than T cells. The deliverable of the R61 phase will be (1) the
identification of druggable targets that if pharmacologically addressed, enable TTS in latently HIV-1 infected T
cells and (2) HTS-compatible drug screening assays for the identification of TTS-inducing drugs against these
targets. In the R33 phase, we will perform the actual drug screens to identify TTS-inducing compounds.
Identified candidate compounds would be tested in primary cell models of latent infection and cell material
derived from HIV-1 patients. By the end of the R33 phase we expect to have identified at least one clinically
relevant TTS strategy comprising of one or several drugs.
随着越来越清楚的是,目前推行的HIV-1重新激活策略可能不会产生结果
在治疗性根除艾滋病毒-1方面,需要探索替代根除战略。我们在此提议
制定针对潜伏的HIV-1感染事件的末端转录沉默(TTS)策略。TTS
在逆转/慢病毒沉默方面,这些策略将具有生物学上的等价性。然而,TTS不会以De为目标
Novo感染事件,但在没有病毒的情况下必须转录沉默预先存在的潜伏前病毒
蛋白质,主要是RNA或非整合的DNA,通常会触发抗病毒细胞反应。证据:
针对慢病毒感染的细胞先天免疫机制的存在是由
慢病毒沉默是慢病毒基因治疗的主要障碍。与生俱来的存在
可以控制预先存在的病毒风格的基因组表达的细胞防御机制由
对一种相关的、进化的古代“基因组入侵者”的防御机制的存在,称为
反转录转座子。这些防御机制分别进化为对每个不同的
反转录转座子类。不幸的是,由于这种特殊性,持续主动控制的机制
用来抑制基因组传播的反转录转座子实际上对HIV-1没有作用。TTS的特异性
预防艾滋病毒-1感染的战略是至关重要的,因为除了对任何
药物干预,TTS策略不能造成(I)对先天控制机制的任何干扰
抑制反转录转座子活性或引起(Ii)对控制表观遗传的机制的任何干扰
人类细胞中的基因沉默。对于R61阶段,我们提出了一种结合HIGH的迭代方法
具有药理扰动的含量分析方法(ATAC-SEQ、RNA-SEQ、基因芯片分析)
筛选特定控制细胞对HIV-1感染的固有抗病毒反应的药物靶点。
拟议的研究将利用(I)预先存在的大量HIV-1报告细胞,(Ii)
发现某些临床上的HIV-1,特别是HIV-2毒株会导致更强的先天TTS
反应比常用的实验室适应的HIV-1克隆更好,以及(Iii)发现巨噬细胞
在执行TTS方面比T细胞效率高得多。R61阶段的交付成果将是(1)
确定药物靶点,如果药理处理,使TTS在潜伏的HIV-1感染T细胞
细胞和(2)HTS相容药物筛选试验用于TTS诱导药物的鉴定
目标。在R33阶段,我们将进行实际的药物筛选,以确定TTS诱导的化合物。
确定的候选化合物将在潜伏感染的原代细胞模型和细胞材料中进行测试
来自HIV-1患者。到R33期结束时,我们预计已经确定了至少一个临床上
由一种或多种药物组成的相关TTS策略。
项目成果
期刊论文数量(0)
专著数量(0)
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会议论文数量(0)
专利数量(0)
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OLAF KUTSCH其他文献
OLAF KUTSCH的其他文献
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{{ truncateString('OLAF KUTSCH', 18)}}的其他基金
Loss of Y-chromosome as a driver of HIV-1 latency
Y 染色体丢失是 HIV-1 潜伏期的驱动因素
- 批准号:
10882257 - 财政年份:2023
- 资助金额:
$ 68.96万 - 项目类别:
Control of latent/persistent HIV-1 infection in macrophages/microglia: A key role for the phosphatase PPM1A
控制巨噬细胞/小胶质细胞中潜伏/持续的 HIV-1 感染:磷酸酶 PPM1A 的关键作用
- 批准号:
10447757 - 财政年份:2021
- 资助金额:
$ 68.96万 - 项目类别:
Control of latent/persistent HIV-1 infection in macrophages/microglia: A key role for the phosphatase PPM1A
控制巨噬细胞/小胶质细胞中潜伏/持续的 HIV-1 感染:磷酸酶 PPM1A 的关键作用
- 批准号:
10322277 - 财政年份:2021
- 资助金额:
$ 68.96万 - 项目类别:
Identification of drugs that induce terminal transcriptional silencing of latent HIV-1 infection
诱导潜伏 HIV-1 感染末端转录沉默的药物的鉴定
- 批准号:
10205411 - 财政年份:2017
- 资助金额:
$ 68.96万 - 项目类别:
Overcoming HIV-1 transcriptional latency in unresponsive CD4 T cells
克服无反应 CD4 T 细胞中的 HIV-1 转录潜伏期
- 批准号:
9980780 - 财政年份:2017
- 资助金额:
$ 68.96万 - 项目类别:
Identification of drugs that induce terminal transcriptional silencing of latent HIV-1 infection
诱导潜伏 HIV-1 感染末端转录沉默的药物的鉴定
- 批准号:
9393866 - 财政年份:2017
- 资助金额:
$ 68.96万 - 项目类别:
Overcoming HIV-1 transcriptional latency in unresponsive CD4 T cells
克服无反应 CD4 T 细胞中的 HIV-1 转录潜伏期
- 批准号:
9410387 - 财政年份:2017
- 资助金额:
$ 68.96万 - 项目类别:
Kinomic analysis of host cell factors controlling latent HIV-1 infection
控制潜伏 HIV-1 感染的宿主细胞因子的基因组分析
- 批准号:
9325418 - 财政年份:2016
- 资助金额:
$ 68.96万 - 项目类别:
Kinomic analysis of host cell factors controlling latent HIV-1 infection
控制潜伏 HIV-1 感染的宿主细胞因子的基因组分析
- 批准号:
9292521 - 财政年份:2016
- 资助金额:
$ 68.96万 - 项目类别:
Kinomic analysis of host cell factors controlling latent HIV-1 infection
控制潜伏 HIV-1 感染的宿主细胞因子的基因组分析
- 批准号:
8930058 - 财政年份:2014
- 资助金额:
$ 68.96万 - 项目类别:
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