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.
项目概要/摘要
治愈 HIV-1 感染的主要障碍是由静息记忆 CD4 T 细胞组成的储存库,其基因组
含有可诱导且具有复制能力的 HIV-1 原病毒。水库的腐烂速度很慢,这加强了
HIV-1 前病毒 DNA 在转录上很大程度上是沉默的。最近的大量证据表明
相反。在任何时间点,HIV-1 储存库的不可忽略的部分仍然保持转录活性,尽管
通过抗逆转录病毒治疗(ART)完全抑制。此外,潜在的 HIV-1 转录可以在这些之上被诱导
HIV-1 刺激化合物的明显基线水平,被视为潜伏逆转剂 (LRA)。一些圣主抵抗军有
在 HIV-1+ 人类或 SIV+ 恒河猴的小型临床或临床前试验中,能够适度减小病毒库的大小
猕猴(RM)。然而,目前上帝抵抗军使用的一个限制是,迄今为止,这些制剂仅在非常有限的环境中进行了测试。
狭窄的患者/动物群体,不代表 HIV-1+ 人群中存在的异质性,也不考虑
年龄、性别或与 HIV-1 相关的其他合并症的患病率。 2 型糖尿病尤其是一种
感染者中普遍存在的疾病,是饮食激素胰岛素失衡的结果。在初步
研究中,我们发现 CD4 T 细胞(作为 HIV-1 的主要储存库)表达胰岛素受体并做出反应
通过激活 PI3K 信号通路转化为胰岛素。已知 PI3K 信号传导是 (1) 代谢调节因子的上游
潜在的 HIV-1 转录(mTORC 信号传导)和 (2) 参与与 HIV-1 启动子结合的转录因子 (Sp1
和 FOXO1)。在这些拟议的研究中,我们将利用现有的完全抑制 ART 的强大队列
SIV+ RM 探索胰岛素信号作为 HIV-1/SIV 生命周期调节剂的作用。我们将聘用最尖端的
磷酸蛋白质组学方法检查膳食激素胰岛素如何影响潜在 SIV 的转录(目标 1)
基于 LRA 的生物制剂与胰岛素共享共同的信号级联,以及(目标 2)天然药物的背景
饮食摄入引起的血糖/胰岛素波动。该应用程序将寻求在基本层面上定义 (1)
CD4 T 细胞中的胰岛素“信号组”(2) 尚未探索可能影响潜在胰岛素转录活性的饮食因素
HIV-1 和重要的是 (3) 为未来在胰岛素注射环境中使用 LRA 的研究提供了一个概念框架
信号传导受损。
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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