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的程度 影响具有内存式特征的新型T细胞clonotypes的能力。艾滋病毒感染者 港口先前存在的HIV特异性T细胞，这些细胞不足以控制初始感染，这将 即使在治疗疫苗接种后数量扩大后，也可能仍然无效。我们提出了这一点 对疫苗接种反应的代谢控制可以通过限制扩展的反应阳性 耗尽的T细胞并允许扩大长寿记忆细胞，这些记忆细胞可以控制病毒复制 治疗中断。如果是这样，则可能需要控制主机，特别是T细胞代谢 设计有影响力的治疗性T细胞疫苗，可将宿主免疫反应转化为HIV。 我们认为，人口中的T细胞反应完全了解将需要更好地理解 宿主代谢如何控制T细胞分化。此外，操纵代谢途径， 尤其是氨基酸感测途径，可能提供了一种机制，可以更大地控制T-的质量 通过治疗疫苗引起的细胞反应。 该项目将通过等离子体代谢组学，RNASEQ和Scenith使用代谢分析，以了解（i） 代谢特征与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对治疗疫苗的T细胞发育的轨迹。 我们假设成功的疫苗利用免疫代谢编程来限制现有的 记忆CD8+ T细胞从扩展和促进广泛反应的新CD4+和CD8+的生长 具有类似茎状品质的克隆型。 目标1：使用来自治疗疫苗的人和非人类灵长类动物的样品，识别 预测T细胞分化模式，广度和/或控制病毒血症的代谢组学特征 ati。在此目的中，我们测试了来自丰富的代谢组数据（等离子体分析，散装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 ATI后获得的病毒控制。 目标2：检查与SIV疫苗共同传递的系统性和T细胞特异性代谢组影响 补充精氨酸或精氨酸促酶，精氨酸酶1，以及对病毒血症的影响 在戒酒之后。 MTOR根据营养感应系统的整合来调节细胞代谢， 包括测量氨基酸的可用性的。疫苗介导的氨基酸调节 因此，分解代谢可以为当地和有限的新陈代谢法规提供一条途径，以鼓励 变换且有效的T细胞响应。