Project 2

项目2

基本信息

批准号：
10731714
负责人：
DENNIS J. HARTIGAN-O'CONNOR
金额：
$ 62.53万
依托单位：
UNIVERSITY OF CALIFORNIA AT DAVIS
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：
2023-05-22 至 2028-05-31
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10731714
关键词：
2019-nCoV Affect Aftercare Amino Acids Arginine CD8-Positive T-Lymphocytes CD8B1 gene Catabolism Cell physiology Cells Cellular Metabolic Process Clinical Trials Cohort Studies Data Energy-Generating Resources Enzymes FRAP1 gene Failure Generations HIV Human Immune response Individual Infection Interruption Jaw Link Literature Macaca Macaca mulatta Measures Mediating Memory Metabolic Metabolic Control Metabolic Pathway Metabolism Nucleocapsid Nutrient Pathway interactions Pattern Persons Plasma Population Positioning Attribute Property Regimen Regulation Route SIV SIV Vaccines Sampling Sirolimus Site System T cell differentiation T cell response T memory cell T-Cell Development T-Lymphocyte T-Lymphocyte Subsets Techniques Testing Therapeutic Vaccinated Vaccination Vaccine Therapy Vaccinee Vaccines Variant Viremia Virus Virus Replication arginase design detection of nutrient exhaust experimental study human data inhibitor mTOR inhibition metabolic profile metabolomics multiple omics nonhuman primate pre-clinical recruit response restraint sensor stem success therapeutic vaccine transcriptome sequencing vaccine trial vector vaccine

项目摘要

Project 2 will determine the extent to which metabolic conditions and immunometabolic programming impact the ability to recruit new T-cell clonotypes with memory-like features. HIV-infected individuals harbor pre-existing HIV-specific T cells that were insufficiently potent to control initial infection and that will likely remain ineffective even after expansion in number following therapeutic vaccination. We propose that metabolic control over the response to vaccination can positively bias the response by limiting expansion of exhausted T cells and allowing expansion of long-lived memory cells that can control viral replication after treatment interruption. If so, then control over host and specifically T-cell metabolism may be required to design impactful therapeutic T-cell vaccines that transform the host immune response to HIV. We believe that fully understanding T-cell responses in human populations will require better understanding of how host metabolism controls T-cell differentiation. Furthermore, manipulation of metabolic pathways, especially amino-acid sensing pathways, may offer a mechanism for greater control over the quality of the T- cell response elicited by therapeutic vaccination. This project will use metabolic profiling via plasma metabolomics, RNAseq, and SCENITH to (i) understand the extent to which metabolic profiles are associated with success in completed therapeutic-vaccine trials, and (ii) test if metabolic regulation can alter the trajectory of T-cell development in response to therapeutic vaccines. We hypothesize that successful vaccines leverage immunometabolic programming to restrain pre-existing memory CD8+ T cells from expanding and promote outgrowth of broadly reactive new CD4+ and CD8+ clonotypes with stem-like qualities. Aim 1: Using samples from therapeutically vaccinated humans and non-human primates, identify metabolomic features that predict T-cell differentiation patterns, breadth, and/or control over viremia in ATI. In this aim, we test if rich metabolomic data (plasma analytes, bulk RNAseq, and SCENITH) from macaques and humans can predict both the quality of T-cell responses generated by therapeutic vaccination and the virus control achieved after ATI. Aim 2: Examine the systemic and T cell-specific metabolomic impact of SIV vaccines co-delivered with either supplemental arginine or the arginine-catabolizing enzyme, arginase 1, and the effect on viremia after ART cessation. mTOR regulates cellular metabolism based on integration of nutrient-sensing systems, including those that measure availability of amino acids. Vaccine-mediated modulation of amino-acid catabolism could therefore provide a route to local and limited metabolic regulation that encourages a transformative and effective T-cell response.

项目 2 将确定代谢条件和免疫代谢编程的程度影响招募具有类似记忆功能的新 T 细胞克隆型的能力。 HIV感染者含有预先存在的 HIV 特异性 T 细胞，这些 T 细胞不足以控制初始感染，并且将即使治疗性疫苗接种后数量扩大，也可能仍然无效。我们建议对疫苗接种反应的代谢控制可以通过限制免疫反应的扩展来积极地偏向反应。耗尽的 T 细胞并允许长寿命记忆细胞的扩展，这些细胞可以在之后控制病毒复制治疗中断。如果是这样，那么可能需要控制宿主，特别是 T 细胞的代谢设计有效的治疗性 T 细胞疫苗，改变宿主对 HIV 的免疫反应。我们相信，要充分了解人群中的 T 细胞反应，就需要更好地了解宿主代谢如何控制 T 细胞分化。此外，代谢途径的操纵，特别是氨基酸传感途径，可能提供一种更好地控制 T-质量的机制治疗性疫苗接种引起的细胞反应。该项目将通过血浆代谢组学、RNAseq 和 SCENITH 使用代谢分析来 (i) 了解代谢特征与已完成的治疗性疫苗试验的成功相关的程度，以及（ii）测试代谢调节是否可以改变 T 细胞发育轨迹以响应治疗性疫苗。我们假设成功的疫苗利用免疫代谢编程来抑制预先存在的疾病记忆 CD8+ T 细胞增殖并促进具有广泛反应性的新 CD4+ 和 CD8+ 的生长具有茎样特性的克隆型。目标 1：使用来自治疗性疫苗接种的人类和非人类灵长类动物的样本，鉴定预测 T 细胞分化模式、宽度和/或病毒血症控制的代谢组学特征 ATI。为此，我们测试是否有丰富的代谢组数据（血浆分析物、批量 RNAseq 和 SCENITH）猕猴和人类可以预测治疗性疫苗接种产生的 T 细胞反应的质量以及ATI之后实现的病毒控制。目标 2：检查与 SIV 疫苗共同接种的系统性和 T 细胞特异性代谢组学影响补充精氨酸或精氨酸分解代谢酶精氨酸酶 1 以及对病毒血症的影响 ART 停止后。 mTOR 基于营养传感系统的整合来调节细胞代谢，包括测量氨基酸可用性的那些。疫苗介导的氨基酸调节因此，分解代谢可以提供一条局部和有限代谢调节的途径，从而鼓励变革性且有效的 T 细胞反应。