Development of Gamma delta CAR-T cells to target CNS HIV reservoir
Development of Gamma delta CAR-T cells to target CNS HIV reservoir
批准号:
10620021
负责人:
Namita Rout
金额:
$28.46万
依托单位国家:
美国
项目类别:
财政年份:
2023
资助国家:
美国
项目状态:
已结题
起止时间:
2023-01-01 至 2024-12-31
关键词:
AddressAdoptive TransferAutopsyBar CodesBiodistributionBrainCAR T cell therapyCD4 Positive T LymphocytesCell modelCellsCellular StressCentral Nervous SystemDataDevelopmentEngineeringEngraftmentFoundationsFunctional disorderFutureGenesGenetic EngineeringGoalsGranzymeHIVHIV-associated neurocognitive disorderHematologic NeoplasmsImmuneImpaired cognitionIn VitroInfectionInflammationInnovative TherapyLentivirus VectorLocationMacacaMacaca mulattaMacrophageMicrogliaModelingModernizationMutationMyelogenousMyeloid CellsNervous System TraumaNeurocognitiveNeurocognitive DeficitNeuronsPathogenesisPatientsPersonsPharmaceutical PreparationsPropertyResearchResistanceRetroviral VectorRhesusRiskSIVSafetySiteSpecificityStressT-LymphocyteTestingTherapeuticTissuesViralVirusVirus Replicationantiretroviral therapybrain tissuecancer immunotherapycell transformationchimeric antigen receptorchimeric antigen receptor T cellsclinically relevantcytotoxicitydesignfeasibility testingimprovedin vitro Assayin vivoin vivo evaluationinsightlatent HIV reservoirlymph nodesmigrationmonocyteneuroAIDSneuroinflammationnovelnovel strategiespreventpurgesimian human immunodeficiency virustransmission processγδ T cells
中文摘要
项目总结
英文摘要
PROJECT SUMMARY
HIV persistence in reservoir tissues remains a major barrier to achieving a therapeutic cure despite effective
antiretroviral therapy (ART). Eradicating HIV-infected cells in the central nervous system (CNS) is particularly
challenging since it is a site of immune privilege and is poorly accessible to ART drugs. While cognitive
impairment among people living with HIV has significantly reduced in the era of modern HIV treatment, about
30% of ART-suppressed HIV patients still display conditions of HIV-associated neurocognitive disorder (HAND),
suggesting that even low levels of HIV persisting in the brain can cause neurological damage. Thus, functional
cure strategies that can safely eradicate replicating virus the CNS reservoir are urgently needed. Emerging
evidence suggests that myeloid cells, including brain macrophages (Mf), are sanctuaries of HIV persistence in
the CNS, and that HIV-infected macrophages are more resistant to CTLs than CD4 T cells. The goal of this
project is to develop a universal gamma delta (γδ) CAR-T platform with dual HIVenv/Mf-targeting for HIV-
infected myeloid cells in the CNS reservoir. Our central hypothesis is that adding Mf specific CAR to anti-HIV γδ
CAR-T cells will enable efficient targeting of HIV-infected cells in the CNS reservoir. Our data in rhesus
macaques show enhanced in vitro killing of HIV-infected monocytic cells by γδ CD4-CAR-T cells and greater
Granzyme B cytotoxicity, which has been shown to be critical for CTL killing of HIV-infected primary
macrophages. Based on the unique functional properties of γδ T cells, including (i) well-documented CTL activity
in immunotherapy of cancer, (ii) ability to migrate to sites of neuroinflammation, and (iii) innate anti-HIV/SIV CTL
functions; we hypothesize that the dual γδ CAR-T cells will induce more effective targeting of myeloid HIV
reservoirs. In Aim 1, we will develop approaches for generating retroviral and lentiviral vector-based γδ CD4-
CAR-T cells toward enhanced targeting of SHIV-infected primary Mf and microglial cells. In Aim 2, we will test
the in vivo potential of the optimized γδ CAR-T cell to migrate and engraft in the CNS during viremic infection
with the novel macrophage-tropic TF SHIV.D model of CNS pathogenesis. The proposed research is significant
because its successful completion will lead to the development of a universal γδ CAR-T cell model with enhanced
targeting of tissue macrophage reservoirs including the CNS in a clinically relevant model of SHIV.D infected
rhesus macaques.
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会议论文
Innate immune mechanisms of epithelial barrier disruption during treated HIV and SIV infections
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批准号:10668086
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项目类别:
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资助金额:$55.48万
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财政年份:2022
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负责人:Namita Rout
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依托单位:
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批准号:10548685
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项目类别:
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依托单位:
Gamma Delta T cell and microbial modulation to target chronic SIV-associated inflammation
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批准号:10666598
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项目类别:
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资助金额:$72.49万
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依托单位:
Genetically Modified Gamma Delta T Cells to Target SIV Reservoirs
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批准号:10065758
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项目类别:
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资助金额:$50.87万
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财政年份:2018
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负责人:Namita Rout
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依托单位:
Genetically Modified Gamma Delta T Cells to Target SIV Reservoirs
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批准号:10314034
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项目类别:
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资助金额:$49.47万
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财政年份:2018
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负责人:Namita Rout
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依托单位:
Genetically Modified Gamma Delta T Cells to Target SIV Reservoirs
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批准号:10077819
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项目类别:
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资助金额:$50.28万
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财政年份:2018
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负责人:Namita Rout
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依托单位:
Role of Lipid Antigen-Specific T Cells in the Anti-mycobacterial Immune Response of BCG/SIV Infected Macaques
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批准号:9767660
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项目类别:
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资助金额:$21.25万
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财政年份:2018
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依托单位:
Role of Innate Immunity and Microbiome in the Inflammation of Aging and Long-Term Antiretroviral Therapy
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批准号:10402502
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项目类别:
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资助金额:$13.19万
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财政年份:2012
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负责人:Namita Rout
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依托单位:
海外基金