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

• 批准号: 10618546
• 负责人: Joseph Christopher Mudd
• 金额: $ 25.43万
• 依托单位: TULANE UNIVERSITY OF LOUISIANA
• 依托单位国家: 美国
• 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: https://reporter.nih.gov/project-details/10618546
• 关键词: Age; Animals; Binding; Biological Products; Blood; Blood Glucose; CD4 Positive T Lymphocytes; CTLA4 blockade; CTLA4 gene; Cells; Clinical; Clinical Trials; DNA; Defect; Diet; Dietary Factors; Dietary intake; Eating; Enzymes; FOXO1A gene; FRAP1 gene; Future; Gender; General Population; Genetic Transcription; Genome; Glucose; Glycolysis; Goals; HIV; HIV-1; Heterogeneity; Hormone imbalance; Hormones; Hour; Human; Impairment; Infection; Insulin; Insulin Receptor; Intermittent fasting; Life Cycle Stages; Macaca mulatta; Measurable; Measures; Metabolic; Methods; Modeling; Nature; Non-Insulin-Dependent Diabetes Mellitus; PD-1 blockade; PIK3CG gene; Patients; Persons; Phosphorylation; Phosphorylation Site; Plasma; Population; Positioning Attribute; Prevalence; Process; Production; Proviruses; RNA; Regulation; Rest; Risk; Role; SIV; Sampling; Serum; Shock; Signal Pathway; Signal Transduction; Testing; Time; Up-Regulation; Viral; Virus Latency; Work; anti-CTLA4; anti-PD-1; antiretroviral therapy; clinical implementation; cohort; comorbidity; dietary; experimental study; glucose uptake; in vivo; insulin signaling; interest; memory CD4 T lymphocyte; nuclear factors of activated T-cells; phosphoproteomics; pre-clinical; preclinical trial; programmed cell death protein 1; promoter; purge; reactivation from latency; synergism; transcription factor; viral resistance; western diet

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。