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
基本信息
- 批准号:10882257
- 负责人:
- 金额:$ 42.43万
- 依托单位:
- 依托单位国家:美国
- 项目类别:
- 财政年份:2023
- 资助国家:美国
- 起止时间:2023-08-16 至 2024-07-31
- 项目状态:已结题
- 来源:
- 关键词:AddressAgingBinding SitesCD28 geneCD3 AntigensCD4 Positive T LymphocytesCell LineCellsChromatinChromosome abnormalityComplexDataDevelopmentDrug TargetingEnvironmentEventExhibitsFemaleGenesHIVHIV InfectionsHIV resistanceHIV-1HeterogeneityHistonesIL8 geneImmunologicsImpairmentIn VitroIndividualInfectionInterleukin GeneInterleukin-2LaboratoriesLong Terminal RepeatsMediatingMemoryModelingModificationMonoclonal AntibodiesNumerical Chromosomal AbnormalityPatientsPersonsPhasePhenotypePlayPopulationPositioning AttributePremature aging syndromeProteomicsProvirusesRNA Polymerase IIReportingResistanceRestRoleSeriesSex ChromosomesSignal TransductionSplenocyteStressSurrogate MarkersT-LymphocyteTherapeutic InterventionViralViral reservoirVirus LatencyY Chromosomeage effectantiretroviral therapychromosome X losschromosome Y losscurative treatmentsearly onsetexhaustionin vitro Modelinsightintegration sitelatent HIV reservoirlatent infectionmalemembernovel therapeutic interventionphenotypic biomarkerphosphoproteomicspromoterproteomic signatureresponseresponse biomarkersingle cell analysissingle-cell RNA sequencingtargeted treatmenttherapeutic developmenttherapeutic evaluationtranscription factortranscriptomics
项目摘要
ABSTRACT
The presence of extensive heterogeneity between individual latently HIV-1 infected T cells suggests that
latent HIV-1 infection can persist under greatly differing host cell conditions. While we and others have described
the biomolecular phenotype of latently infected T cells, the biomolecular driver(s) of these stable phenotypic
changes remain unknown. For primary T cells, the transition to a resting memory state or T cell exhaustion
effects may play a role, but latent infection is also found in naïve T cells or TfH cells suggesting additional
contributing mechanisms. Leading to this application, we addressed the question whether HIV infection can
trigger an irreversible modification of host cells that can explain the stability of latent infection events, and could
occur independent of memory status or CD4+ T cell subtype. We show that latently infected T cell lines and a
large percentage of in vitro generated latently infected primary T cells, when derived from male donors, exhibited
a Loss of Y-chromosome (LOY) phenotype. Numerical chromosomal aberrations, including the loss of sex
chromosomes, cause nonlinear transcriptomic changes, which would explain the observed extensive
transcriptomic heterogeneity between individual latently HIV-1 infected T cells. Extensive transcriptomic changes
can also result in impaired cellular signaling, and explain the widely differing reactivation response spectrum
between individual cells. For primary T cells, we demonstrate that latent HIV-1 infection events in LOY cells are
largely resistant to TCR/CD3-complex activation mediated reactivation, while latently infected T cells in
possession of their Y-chromosome promoted HIV-1 reactivation following TCR/CD3 activation. Loss of Y-
chromosome phenomena could thus explain the presence of a reactivation-resistant reservoir that has been first
described by the Siliciano group. As LOY is irreversible, this is the first report of a biomolecular alteration that
can mechanistically explain HIV-1 latency stability and reactivation inertness, which we consider the major hurdle
to viral eradication. In this application we will extend our studies on the correlation of LOY and reactivation
resistant HIV-1 latency. Our discovery provides us with the unique opportunity to separate the two phenotypic
parts of the latent reservoir based on a causative mechanism (LOY) that has functional consequences
(reactivation resistance), which will allow for the exploration and development of therapeutic strategies to
individually target these reservoir components using single cell analysis approaches (Aim 1). In parallel we will
investigate whether similar latency phenotypes can be found in T cells from female donors and whether loss of
X-chromosome (LOX), the most frequent numerical chromosomal aberration in females, plays a similar role for
HIV-1 latency control than LOY (Aim 2). The insights generated from this proposal should provide fundamental
new insights into HIV-1 latency control and guide the development of new therapeutic strategies to target the
latent HIV-1 reservoir, specifically the reactivation-resistant part of the HIV-1 reservoir.
摘要
潜伏性HIV-1感染的T细胞之间存在广泛的异质性表明,
潜伏HIV-1感染可在非常不同的宿主细胞条件下持续存在。虽然我们和其他人已经描述了
潜伏感染的T细胞的生物分子表型,这些稳定表型的生物分子驱动因子,
变化仍然未知。对于原代T细胞,向静息记忆状态或T细胞耗竭的转变
作用可能起作用,但在幼稚T细胞或TfH细胞中也发现了潜伏感染,这表明额外的
贡献机制。导致这一应用,我们解决了这个问题,艾滋病毒感染是否可以
引发宿主细胞的不可逆修饰,这可以解释潜伏感染事件的稳定性,
发生独立于记忆状态或CD 4 + T细胞亚型。我们发现,潜伏感染的T细胞系和
当来自男性供体时,大百分比的体外产生的潜伏感染的原代T细胞表现出
a Y染色体缺失(LOY)表型。染色体数目畸变,包括失去性别
染色体,导致非线性转录组学的变化,这将解释观察到的广泛的
HIV-1潜伏感染的T细胞之间的转录组异质性。广泛的转录组变化
也可能导致受损的细胞信号传导,并解释了广泛不同的再激活反应谱
单个细胞之间。对于原代T细胞,我们证明了LOY细胞中潜伏的HIV-1感染事件是
在很大程度上抵抗TCR/CD 3复合物激活介导的再激活,而潜伏感染的T细胞在
它们的Y染色体的拥有促进了TCR/CD 3活化后的HIV-1再活化。失去Y-
因此,染色体现象可以解释一个抗再活化的水库的存在,
由Siliciano集团描述。由于LOY是不可逆的,这是第一次报告的生物分子改变,
可以从机制上解释HIV-1潜伏期的稳定性和再激活的惰性,我们认为这是主要的障碍
到病毒根除在这个应用中,我们将扩展我们的研究相关性的LOY和再活化
抗HIV-1潜伏期。我们的发现为我们提供了一个独特的机会,
基于具有功能后果的因果机制(LOY)的潜在水库的部分
(再活化抗性),这将允许探索和开发治疗策略,
使用单细胞分析方法单独靶向这些储层组分(目标1)。同时,我们将
研究是否可以在来自女性供体的T细胞中发现类似的潜伏表型,以及
X染色体(LOX)是女性中最常见的染色体数目畸变,
HIV-1潜伏期控制优于LOY(目的2)。从这一建议中产生的见解应该提供基本的
对HIV-1潜伏期控制的新见解,并指导新的治疗策略的发展,以针对
潜伏的HIV-1储库,特别是HIV-1储库的再活化抗性部分。
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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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
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:
$ 42.43万 - 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:
$ 42.43万 - 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:
10223169 - 财政年份:2017
- 资助金额:
$ 42.43万 - 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:
$ 42.43万 - 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:
$ 42.43万 - 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:
$ 42.43万 - 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:
$ 42.43万 - 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:
$ 42.43万 - 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:
$ 42.43万 - 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:
$ 42.43万 - 项目类别:
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