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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：
Joseph Christopher Mudd
金额：
$ 25.43万
依托单位：
TULANE UNIVERSITY OF LOUISIANA
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：
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

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/文摘