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/文摘
项目成果
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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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