CBF-1 role in regulating HIV reservoir in microglial cells
CBF-1在调节小胶质细胞中HIV储存库中的作用
基本信息
- 批准号:10626867
- 负责人:
- 金额:$ 23.4万
- 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:2022-06-01 至 2024-05-31
- 项目状态:已结题
- 来源:
- 关键词:AddressAnti-HIV TherapyAreaAutopsyBindingBinding SitesBiological ModelsBlood VesselsBrainCD4 Positive T LymphocytesCellsCentral Nervous SystemChromatin StructureComplexDropsEconomic BurdenEnzymesEpigenetic ProcessExploratory/Developmental GrantFailureFunctional disorderGene ExpressionGenerationsGenetic TranscriptionGoalsGrantHIVHIV Long Terminal RepeatHIV-1HIV-associated neurocognitive disorderHeterochromatinHighly Active Antiretroviral TherapyHumanIndividualInflammationInvestigationKnowledgeKnowledge acquisitionLong Terminal RepeatsLymphocyteLymphoid CellMacrophageMaintenanceMediatingMicrogliaModificationMolecularMyelogenousMyeloid CellsNuclearPaperPatientsPhasePlayProductivityProvirusesPublic HealthPublishingResearchRestRoleSeriesSiteSpecimenStructureTargeted ResearchTestingTimeViral reservoirbrain cellcell typechromatin modificationdesignepigenetic silencingexperimental studygene repressiongenetic corepressorhistone modificationinhibitorinnovationknock-downlatent HIV reservoirmemory CD4 T lymphocytenovelnovel therapeuticspromoterreactivation from latencyrecruittargeted treatmenttherapeutic targettranscription factortreatment optimization
项目摘要
Project Summary: Although the resting memory CD4+ T cells are the best-recognized long-lived reservoirs of
latent HIV provirus, it is now well accepted that the myeloid cells, especially of the central nervous system (CNS)-
-including perivascular macrophages and microglial cells--can also contribute to viral reservoirs.
The molecular mechanisms relevant to HIV latency are primarily defined by analyzing HIV latency in latently
infected CD4+ lymphoid cells. However, very little is known about HIV latency/persistence in myeloid cells.
Notably, the presence of HIV-harboring myeloid cells in the CNS are documented to be the key factor contributing
to CNS inflammation and promoting HIV-associated neurocognitive disorder (HAND) in HIV patients. Microglial
cells are the main HIV reservoir in the CNS, yet a gap in the knowledge regarding our understanding of the
molecular mechanisms that maintains HIV reservoirs in those cells. Our long term goal is identifying and
characterizing the underlying molecular mechanisms that regulate HIV latency in microglial cells. The important
role of CBF-1-mediated transcriptional inhibition during HIV latency is well established in lymphoid cells. The
objective of this grant is to characterize the role of CBF-1 during HIV latency in microglial cells. Based on our
published and preliminary findings, we have hypothesized that, similar to lymphocytes, in microglial cells CBF-
1 promotes HIV latency/slowdown by inducing the generation of transcriptionally-repressive heterochromatin
structures at HIV LTR. Our rationale is that since HIV latency is primarily regulated at the transcriptional level,
defining the precise mechanism(s) that regulate HIV transcription in microglial cells will offer new therapeutic
opportunities to target HIV reservoirs in the CNS. In Aim 1, we will examine the role of CBF-1-induced epigenetic
changes in restricting HIV transcription and their eventual impact on the establishment and the maintenance
phases of HIV latency. In Aim 2, we will characterize the corepressor complexes that CBF-1 recruits at HIV LTR
and their functional significance in promoting HIV reservoir in microglial cells. Upon conclusion, we will be able
to define the CBF-1-mediated mechanisms that facilitate the establishment and maintenance of HIV latency in
microglial cells. These studies will also provide a well-defined therapeutic target in the form of CBF-1 and its
corepressor complexes in order to relieve multiple repressive epigenetic modifications simultaneously.
Proposed research is innovative because it uses human primary microglial cells, and a novel ex vivo model
system for HIV latency in microglial cells that, for the first time, allows the studies of the molecular correlates for
HIV entry and exit into latency in microglial cells, which is otherwise an impossible task due to insufficient
availability of brain autopsy specimens. This contribution is significant since the identified mechanisms, which
regulate HIV transcription and latency in microglial cells, will facilitate the designing of optimized therapies
targeting CNS reservoirs of HIV, contributing to cure approaches.
项目总结:虽然静息记忆CD4+ T细胞是公认的最长寿的
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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Mudit Tyagi其他文献
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{{ truncateString('Mudit Tyagi', 18)}}的其他基金
CBF-1 role in regulating HIV reservoir in microglial cells
CBF-1在调节小胶质细胞中HIV储存库中的作用
- 批准号:
10403065 - 财政年份:2022
- 资助金额:
$ 23.4万 - 项目类别:
Characterization of cocaine induced signaling pathways that enhances HIV transcription
可卡因诱导的增强 HIV 转录的信号通路的表征
- 批准号:
9554849 - 财政年份:2017
- 资助金额:
$ 23.4万 - 项目类别:
Characterization of cocaine induced signaling pathways that enhances HIV transcription
可卡因诱导的增强 HIV 转录的信号通路的表征
- 批准号:
10399877 - 财政年份:2017
- 资助金额:
$ 23.4万 - 项目类别:
Characterization of cocaine induced signaling pathways that enhances HIV transcription
可卡因诱导的增强 HIV 转录的信号通路的表征
- 批准号:
9926231 - 财政年份:2017
- 资助金额:
$ 23.4万 - 项目类别:
Characterization of cocaine induced signaling pathways that enhances HIV transcription
可卡因诱导的增强 HIV 转录的信号通路的表征
- 批准号:
10611835 - 财政年份:2017
- 资助金额:
$ 23.4万 - 项目类别:
Cocaine induced selective epigenetic and signaling pathways enhance HIV replicati
可卡因诱导选择性表观遗传和信号通路增强 HIV 复制
- 批准号:
8610274 - 财政年份:2013
- 资助金额:
$ 23.4万 - 项目类别:
Cocaine induced selective epigenetic and signaling pathways enhance HIV replicati
可卡因诱导选择性表观遗传和信号通路增强 HIV 复制
- 批准号:
8330018 - 财政年份:2013
- 资助金额:
$ 23.4万 - 项目类别:
Cocaine enhances HIV replication by inducing transcriptionally active chromatin s
可卡因通过诱导转录活性染色质增强 HIV 复制
- 批准号:
8329932 - 财政年份:2012
- 资助金额:
$ 23.4万 - 项目类别:
Cocaine enhances HIV replication by inducing transcriptionally active chromatin s
可卡因通过诱导转录活性染色质增强 HIV 复制
- 批准号:
8586519 - 财政年份:2012
- 资助金额:
$ 23.4万 - 项目类别:
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