Re-educating T cell-mediated immunity in SIV by modulating metabolic pathways
通过调节代谢途径重新训练 SIV 中 T 细胞介导的免疫
基本信息
- 批准号:10481246
- 负责人:
- 金额:$ 19.13万
- 依托单位:
- 依托单位国家:美国
- 项目类别:
- 财政年份:2022
- 资助国家:美国
- 起止时间:2022-04-01 至 2024-12-31
- 项目状态:已结题
- 来源:
- 关键词:AIDS/HIV problemAffectAnatomyAnimalsAntigensAutopsyBacillusBiological AssayBloodCD8-Positive T-LymphocytesCell SurvivalCell physiologyCellsCellular ImmunityCellular Indexing of Transcriptomes and Epitopes by SequencingCellular Metabolic ProcessChronicCommunicable DiseasesComplexDisease ProgressionEnergy MetabolismEnvironmentExhibitsFDA approvedFatty AcidsFlow CytometryGenus HippocampusGlycolysisGoalsHIVHIV AntigensHIV InfectionsHIV/TBHost DefenseHumanImmuneImmunityImmunologicsImpairmentIndividualInfectionInvestigationMacaca fascicularisMeasuresMediatingMetabolicMetabolic PathwayMetabolismMetforminMitochondriaModalityModelingMonitorMycobacterium tuberculosisOpportunistic InfectionsOxidative PhosphorylationPET/CT scanPathologyPathway interactionsPatientsPeptidesPeripheralPersonsPharmaceutical PreparationsPhenotypePlasmaPlayPredispositionPrevalenceProcessRoleSIVSamplingSignal TransductionStressT-LymphocyteTestingTimeTissuesTuberculosisViral Load resultViral reservoirVirus DiseasesX-Ray Computed Tomographyantiretroviral therapyco-infectionexhaustexhaustionglobal healthimmune activationimprovedlymph nodesnonhuman primateoxidationpathogenprogrammed cell death protein 1programsreceptorresponsesingle-cell RNA sequencingtooluptake
项目摘要
Project Summary/Abstract
HIV/AIDS is a chronic infectious disease that affects around 37 million people worldwide. CD8 T cells play a
critical role in controlling HIV infection. However, CD8 T cells become exhausted over time due to continuous
stimulation. Exhausted HIV-specific CD8 T cells, characterized by elevated expression of inhibitory receptors
(e.g. PD-1), positively correlate with higher viral load, impaired T cell function, and disease progression. In HIV
and other chronic viral infections, exhausted antigen-specific CD8 T cells expressing PD-1 can create a
suppressive environment suggesting that such cells not only have a direct role in disease progression but can
cross-talk with other immune cells to impair their function. Chronic HIV infection dysregulates T cell energy
metabolism. HIV-specific CD8 T cells isolated from infected individuals exhibit elevated mitochondrial stress
which is still apparent years after antiretroviral therapy (ART). PD-1 expression on T cells is associated with
mitochondrial stress. PD-1-mediated signaling dysregulates T cell mitochondrial energetics by reducing
glycolysis and shifting towards fatty acid b-oxidation and oxidative phosphorylation (OxPhos). Metformin is an
FDA-approved drug that dampens OxPhos by inhibiting mitochondrial complex I. To date, most studies
investigating metformin use in HIV+ individuals are often in the presence of ART. It has yet to be explored how
modulating energy metabolism with metformin impacts host immunity in an ART-naïve setting. HIV not only
impairs immune control of the viral infection, but also increases susceptibility to opportunistic infections. People
living with HIV are incredibly susceptible to the tuberculosis-causing bacilli, Mycobacterium tuberculosis (Mtb).
We previously showed SIV-infected Mauritian cynomolgus macaques (MCM) to be more susceptible to Mtb,
which we attributed to immunologic impairment by preexisting SIV infection. Therefore, Mtb challenge is a
stringent assessment of host defenses and, given the prevalence of HIV/Mtb co-infection, has great relevance
to global health.
In this K01 proposal, we will identify pathways involved in energy metabolism in CD8 T cells during chronic HIV
infection and reveal their role in T cell exhaustion using our established MCM model of HIV. We will use a
comprehensive analytic approach that combines single cell RNA sequencing, metabolic assays, and flow
cytometry to assess the role of T cell metabolism in SIV-infected MCM. We will alter metabolism using metformin
to reprogram CD8 T cells and determine whether this metabolic reprogramming improves host immunity by
challenging SIV+ animals with Mtb.
项目总结/摘要
艾滋病毒/艾滋病是一种慢性传染病,影响着全世界约3 700万人。CD 8 T细胞发挥着
在控制艾滋病毒感染方面发挥重要作用。然而,CD 8 T细胞随着时间的推移由于持续的免疫应答而变得耗尽。
刺激.耗尽的HIV特异性CD 8 T细胞,特征为抑制性受体表达升高
(e.g. PD-1),与较高的病毒载量、受损的T细胞功能和疾病进展正相关。艾滋病毒
和其他慢性病毒感染时,表达PD-1的耗尽的抗原特异性CD 8 T细胞可以产生一种免疫应答。
抑制性环境,这表明这些细胞不仅在疾病进展中起直接作用,
与其他免疫细胞相互干扰,损害它们的功能。慢性HIV感染使T细胞能量失调
新陈代谢.从感染个体中分离的HIV特异性CD 8 T细胞表现出线粒体应激升高
这在抗逆转录病毒治疗(ART)后的几年仍然很明显。T细胞上的PD-1表达与
线粒体应激PD-1介导的信号转导通过减少T细胞线粒体能量失调
糖酵解和向脂肪酸b-氧化和氧化磷酸化(OxPhos)转变。二甲双胍是一种
FDA批准的药物,通过抑制线粒体复合物I来抑制OxPhos。迄今为止,大多数研究
研究二甲双胍在HIV+个体中的使用通常是在ART存在的情况下进行的。
二甲双胍调节能量代谢影响ART初治环境中的宿主免疫力。艾滋病不仅
削弱对病毒感染的免疫控制,但也增加对机会性感染的易感性。人
艾滋病毒感染者对结核杆菌(Mtb)非常敏感。
我们先前显示SIV感染的猕猴(MCM)对Mtb更敏感,
我们将其归因于先前存在的SIV感染引起的免疫损伤。因此,Mtb挑战是一种
严格评估宿主防御能力,并考虑到艾滋病毒/结核病合并感染的流行,
to global全球health健康.
在这个K 01提案中,我们将确定慢性HIV感染期间CD 8 T细胞中参与能量代谢的途径。
感染,并使用我们建立的HIV MCM模型揭示它们在T细胞耗竭中的作用。我们将使用一个
结合单细胞RNA测序、代谢测定和流式细胞仪的综合分析方法
流式细胞术以评估T细胞代谢在SIV感染的MCM中的作用。我们将使用二甲双胍改变代谢
重编程CD 8 T细胞,并确定这种代谢重编程是否通过以下方式提高宿主免疫力:
用Mtb攻击SIV+动物。
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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ERICA CHRISTINE LARSON其他文献
ERICA CHRISTINE LARSON的其他文献
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{{ truncateString('ERICA CHRISTINE LARSON', 18)}}的其他基金
Re-educating T cell-mediated immunity in SIV by modulating metabolic pathways
通过调节代谢途径重新训练 SIV 中 T 细胞介导的免疫
- 批准号:
10596151 - 财政年份:2022
- 资助金额:
$ 19.13万 - 项目类别:
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