Mechanism of telomere attrition and premature T cell aging during HIV infection.
HIV 感染期间端粒磨损和 T 细胞过早衰老的机制。
基本信息
- 批准号:10402449
- 负责人:
- 金额:$ 42.8万
- 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:2022-03-01 至 2025-02-28
- 项目状态:未结题
- 来源:
- 关键词:AccountingAcuteAddressAffectAgingApoptosisApoptoticBase Excision RepairsBindingBiomedical ResearchCD4 Positive T LymphocytesCell AgingCell NucleusCell physiologyCellsChromosomesChronicCommunicable DiseasesDNADNA DamageDNA RepairDNA biosynthesisDNA topoisomerase II alphaDown-RegulationElderlyEnzymesEventExhibitsFunctional disorderGenomeGenome StabilityGenomic InstabilityGoalsHIVHIV InfectionsHallmark CellHeat-Shock Proteins 90HumanImmuneImmune responseImmunocompetenceImmunocompromised HostImpairmentIn VitroIndividualInflammatoryLightMediatingMicroRNAsNuclear ImportNuclear Pore ComplexNucleotidesPathway interactionsPatientsPersonsPhenotypePhosphorylationPhosphotransferasesProcessProteinsRNA-Directed DNA PolymeraseRoleSignal TransductionSystemT cell responseT-LymphocyteTERF2 geneTP53 geneTelomeraseTelomere MaintenanceTelomere ShorteningTestingUbiquitinViralVirus DiseasesZinc Fingersage relatedantiretroviral therapyataxia telangiectasia mutated proteinbaseclinically significantexhaustionfunctional disabilityimprovedimproved functioningin vitro Modelin vivonovelnucleaseprematurepreservationpreventreceptorrecruitsenescencestudent trainingtelomeretranslational approachtranslational study
项目摘要
HIV infection appears to drive premature T cell aging, as evidenced by genomic instability and shortened telomeres.
However, how genome or telomere maintenance machineries are dysregulated to drive T cell aging during HIV
infection remains largely unknown. The objective of this study is to elucidate the mechanisms by which HIV infection
accelerates telomere erosion that may cause premature T cell aging, so as to develop effective means to improve
cellular functions in the immunocompromised host. Indeed, telomere integrity is a key feature of linear chromosomes
that preserves genome stability and function, whereas telomere erosion is a hallmark of cell aging or senescence
that drives cell dysfunction or apoptosis. Importantly, we have recently found that CD4 T cells derived from HIV
patients on antiretroviral therapy (ART), and primary CD4 T cells infected with HIV on ART in vitro, both exhibit
enhanced DNA damage and telomere erosion, and both are associated with a profound apoptotic and aging
phenotypes. We have also shown that 1) telomeric DNA damage and repair machineries are impaired; 2) the human
telomerase reverse transcriptase (hTERT - the catalytic unit of telomerase that prolongs telomeric DNA) remains
intact; 3) the telomeric repeat binding factor 2 (TRF2 - a telomere shelterin protein that protects telomeres from DNA
damage) and the ataxia-telangiectasia mutated (ATM - a kinase that repairs the DNA damage) are inhibited; and 4)
the human telomeric zinc-finger associated protein (TZAP - a newly identified telomere-associated protein that can
compete with TRF2 for telomere binding and has nuclease activity in trimming telomeric DNA) is upregulated in CD4
T cells during HIV infection. We thus hypothesize that either an increase in nuclease-mediated telomere trimming
by an aberrant telomeric DNA damage & repair signaling, and/or a compromised telomeric DNA replication and
elongation, are involved in telomere attrition during HIV infection. Elucidating the mechanisms regulating telomere
integrity may open new avenues to protect T cells from unwanted telomere damage, prevent premature T cell aging,
and maintain immune competence. To establish this hypothesis, we will employ a translational approach using
comprehensive ex vivo and in vitro systems: CD4 T cells isolated from acute and chronic HIV-infected subjects with
or without ART; and primary CD4 T cells infected with wild-type HIV with or without ART - an in vitro model mirroring
HIV-infected, ART-controlled patients in vivo. In Aim 1, we will identify the role of TRF2 and TZAP in the telomeric
DNA damage and telomere attrition during HIV infection. In Aim 2, we will elucidate the mechanisms involved in
compromising telomeric DNA elongation during HIV infection. This translational study is novel and clinically
significant in that it will explore mechanisms fundamental to diminishing T cell responses, and will address important
questions as to how telomeric DNA is damaged to accelerate T cell aging and whether interfering with the enzyme
involved in disrupting telomere integrity can remodel T cell function during HIV infection. Understanding such
mechanisms is critical for developing approaches to improve immune responses in the setting of many chronic
infectious diseases, including but not limited to HIV infection.
HIV感染似乎会导致T细胞过早衰老,这可以通过基因组不稳定和端粒缩短来证明。
项目成果
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Juan Zhao其他文献
Juan Zhao的其他文献
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{{ truncateString('Juan Zhao', 18)}}的其他基金
Mechanism of telomere attrition and premature T cell aging during HCV infection
HCV感染过程中端粒磨损和T细胞过早衰老的机制
- 批准号:
10745519 - 财政年份:2022
- 资助金额:
$ 42.8万 - 项目类别:
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