The intersection of diet, cell metabolic state, and SIV reservoir transcription
饮食、细胞代谢状态和 SIV 储存库转录的交叉点
基本信息
- 批准号:10618546
- 负责人:
- 金额:$ 25.43万
- 依托单位:
- 依托单位国家:美国
- 项目类别:
- 财政年份:2023
- 资助国家:美国
- 起止时间:2023-08-10 至 2025-07-31
- 项目状态:未结题
- 来源:
- 关键词:AgeAnimalsBindingBiological ProductsBloodBlood GlucoseCD4 Positive T LymphocytesCTLA4 blockadeCTLA4 geneCellsClinicalClinical TrialsDNADefectDietDietary FactorsDietary intakeEatingEnzymesFOXO1A geneFRAP1 geneFutureGenderGeneral PopulationGenetic TranscriptionGenomeGlucoseGlycolysisGoalsHIVHIV-1HeterogeneityHormone imbalanceHormonesHourHumanImpairmentInfectionInsulinInsulin ReceptorIntermittent fastingLife Cycle StagesMacaca mulattaMeasurableMeasuresMetabolicMethodsModelingNatureNon-Insulin-Dependent Diabetes MellitusPD-1 blockadePIK3CG genePatientsPersonsPhosphorylationPhosphorylation SitePlasmaPopulationPositioning AttributePrevalenceProcessProductionProvirusesRNARegulationRestRiskRoleSIVSamplingSerumShockSignal PathwaySignal TransductionTestingTimeUp-RegulationViralVirus LatencyWorkanti-CTLA4anti-PD-1antiretroviral therapyclinical implementationcohortcomorbiditydietaryexperimental studyglucose uptakein vivoinsulin signalinginterestmemory CD4 T lymphocytenuclear factors of activated T-cellsphosphoproteomicspre-clinicalpreclinical trialprogrammed cell death protein 1promoterpurgereactivation from latencysynergismtranscription factorviral resistancewestern diet
项目摘要
Project Summary/Abstract
The main obstacle to curing HIV-1 infection is a reservoir that consists of resting memory CD4 T cells whose genomes
contain inducible and replication-competent HIV-1 proviruses. Decay of the reservoir is slow and this has reinforced a
notion that proviral HIV-1 DNA is largely transcriptionally silent. A wide body of recent evidence has pointed to the
contrary. At any point in time, a non-negligible fraction of the HIV-1 reservoir remains transcriptionally active despite
complete suppression with antiretroviral therapy (ART). Moreover, latent HIV-1 transcription can be induced above these
apparent baseline levels with HIV-1 stimulatory compounds, deemed latency reversal agents (LRAs). Some LRAs have
been able to modestly reduce reservoir size in small clinical or pre-clinical trials of HIV-1+ humans or SIV+ rhesus
macaques (RMs). However, a current limitation of LRA use is that to date, these agents have been tested only in very
narrow patient/animal cohorts, not representative of heterogeneity that exists in the HIV-1+ population, and not accounting
for age, gender, or the prevalence of additional co-morbidities associated with HIV-1. Type 2 diabetes in particular is a co-
morbidity that is prevalent in PLWH, and is the result of an imbalance of the dietary hormone insulin. In preliminary
studies, we find that CD4 T cells (which serve as the principle reservoir for HIV-1) express the insulin receptor and respond
to insulin by activating the PI3K signaling pathway. PI3K signaling is known to be upstream of (1) metabolic regulators of
latent HIV-1 transcription (mTORC signaling) and (2) transcription factors involved in binding to the HIV-1 promoter (Sp1
and FOXO1). In these proposed studies, we will take advantage of an existing well-powered cohort of fully ART-suppressed
SIV+ RMs to probe the role of insulin signaling as a regulator of the HIV-1/SIV lifecycle. We will employ cutting-edge
phospho-proteomic methods to examine how the dietary hormone insulin influences transcription of latent SIV in (Aim 1)
the context of LRA-based biologics that share common signaling cascades with insulin and (Aim 2) the context of natural
blood glucose/insulin fluctuations that occur with dietary intake. The application will seek to define on a basic level (1) the
insulin “signalome” in CD4 T cells (2) as-yet explored dietary factors that may influence transcriptional activity of latent
HIV-1 and importantly (3) provide a conceptual framework for future studies on LRA use in settings in which insulin
signaling is impaired.
项目总结/摘要
治愈HIV-1感染的主要障碍是由静息记忆CD 4 T细胞组成的储库,其基因组
含有可诱导和可复制的HIV-1前病毒。水库的衰减是缓慢的,这加强了一个
前病毒HIV-1 DNA在很大程度上是转录沉默的。最近的大量证据表明,
相反。在任何时间点,HIV-1储库的不可忽略的部分保持转录活性,
抗逆转录病毒治疗(ART)完全抑制。此外,潜伏的HIV-1转录可以在这些水平上被诱导。
HIV-1刺激性化合物(视为潜伏期逆转剂(LRA))的表观基线水平。一些LRA有
能够在HIV-1+人类或SIV+恒河猴的小型临床或临床前试验中适度减少储存库大小
猕猴(RM)。然而,目前使用上帝抵抗军的一个局限性是,迄今为止,这些战剂仅在很小的地区进行过测试,
狭窄的患者/动物队列,不代表HIV-1+人群中存在的异质性,并且未考虑
年龄、性别或与HIV-1相关的其他合并症的患病率。2型糖尿病是一种常见的糖尿病。
这是艾滋病毒感染者中普遍存在的一种疾病,是饮食激素胰岛素失衡的结果。初步
研究中,我们发现CD 4 T细胞(作为HIV-1的主要储存库)表达胰岛素受体,
通过激活PI 3 K信号通路而转化为胰岛素。已知PI 3 K信号传导是(1)以下物质的代谢调节剂的上游:
潜伏的HIV-1转录(mTORC信号传导)和(2)参与结合HIV-1启动子(Sp1)的转录因子
和FOXO 1)。在这些拟议的研究中,我们将利用现有的完全ART抑制的良好功效队列,
SIV+ RM用于探测胰岛素信号传导作为HIV-1/SIV生命周期调节剂的作用。我们将聘请最先进的
磷酸化蛋白质组学方法检测饮食激素胰岛素如何影响潜伏SIV的转录(目的1)
与胰岛素共享共同信号级联的基于LRA的生物制剂的背景和(目的2)天然胰岛素的背景。
血糖/胰岛素波动与饮食摄入有关。该应用程序将寻求在基本层面上定义(1)
CD 4 T细胞中的胰岛素“信号组”(2)尚未探索的饮食因素可能影响潜在的
HIV-1,重要的是(3)为未来在胰岛素依赖的环境中使用LRA的研究提供了一个概念框架。
信号被破坏。
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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Joseph Christopher Mudd其他文献
Joseph Christopher Mudd的其他文献
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{{ truncateString('Joseph Christopher Mudd', 18)}}的其他基金
Early intervention with anti-proliferative therapy close to ART initiation to limit long-term SIV persistence
在 ART 开始时进行早期抗增殖治疗干预,以限制 SIV 的长期持续存在
- 批准号:
10849960 - 财政年份:2023
- 资助金额:
$ 25.43万 - 项目类别:
Role of RhCMV in shaping the SIV proviral landscape
RhCMV 在塑造 SIV 前病毒景观中的作用
- 批准号:
10541869 - 财政年份:2022
- 资助金额:
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Role of RhCMV in shaping the SIV proviral landscape
RhCMV 在塑造 SIV 前病毒景观中的作用
- 批准号:
10397879 - 财政年份:2022
- 资助金额:
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Mechanisms and Therapeutic Targeting of CD4 Down regulation in African Green Monkeys
非洲绿猴 CD4 下调的机制和治疗目标
- 批准号:
10378164 - 财政年份:2021
- 资助金额:
$ 25.43万 - 项目类别:
Mechanisms and Therapeutic Targeting of CD4 Down regulation in African Green Monkeys
非洲绿猴 CD4 下调的机制和治疗目标
- 批准号:
10254703 - 财政年份:2021
- 资助金额:
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Innate Lymphoid Cell Loss in HIV-1 and SIV Infection
HIV-1 和 SIV 感染中的先天淋巴细胞损失
- 批准号:
9618331 - 财政年份:2020
- 资助金额:
$ 25.43万 - 项目类别:
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