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 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。