Project 2

项目2

• 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
• 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

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 影响招募具有记忆样特征的新T细胞克隆型的能力。hiv感染者 携带预先存在的HIV特异性T细胞，这些细胞不足以控制初始感染， 即使在治疗性疫苗接种后数量增加后也可能仍然无效。我们建议 对疫苗接种反应的代谢控制可以通过限制免疫应答的扩增而使免疫应答产生正偏差。 耗尽的T细胞，并允许长寿命记忆细胞的扩增，这些记忆细胞可以控制病毒复制， 治疗中断。如果是这样，那么可能需要控制宿主和特别是T细胞代谢， 设计有效的治疗性T细胞疫苗，改变宿主对HIV的免疫反应。 我们认为，要充分了解人类群体中的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，操纵代谢途径， 特别是氨基酸传感途径，可能提供了一种机制，更好地控制T细胞的质量， 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使用代谢谱来（i）了解 代谢谱与已完成的治疗疫苗试验成功相关的程度，以及（ii） 测试代谢调节是否可以改变T细胞对治疗性疫苗的反应轨迹。 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 记忆性CD 8 + T细胞的扩增和促进广泛反应性新的CD 4+和CD 8 + T细胞的生长 具有茎状特性的克隆型。 目的1：使用来自治疗性疫苗接种的人和非人灵长类动物的样品，鉴定 代谢组学特征，预测T细胞分化模式，宽度，和/或控制病毒血症， ATI在这个目标中，我们测试了是否有来自于来自于基因组的丰富的代谢组学数据（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细胞应答的质量， 以及ATI后达到的病毒控制。 目的2：检查与SIV共递送的SIV疫苗的全身和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基于营养物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，卡他霉素可以提供一种局部和有限的代谢调节途径， 转化和有效的T细胞反应。