Project 2

项目2将确定新陈代谢条件和免疫代谢规划的程度 影响招募具有记忆样特征的新T细胞克隆类型的能力。感染艾滋病毒的个人 窝藏先前存在的HIV特异性T细胞，这些T细胞不足以控制初始感染，这将 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扩展来积极地偏向反应 耗尽T细胞并允许长期记忆细胞的扩张，这些记忆细胞可以控制病毒在 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，改变宿主对艾滋病毒的免疫反应。 我们认为，充分了解人类群体中的T细胞反应将需要更好地理解 宿主代谢如何控制T细胞分化。此外，代谢途径的操纵， 尤其是氨基酸感应通路，可能提供一种更好地控制T- 由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使用代谢概况，以(I)了解 代谢特征与已完成的治疗性疫苗试验的成功有关的程度，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限制先前存在的 记忆CD8+T细胞的扩增和促进广泛反应的新的CD4+和CD8+的生长 具有茎状特征的克隆型。 目标1：使用来自经治疗接种疫苗的人类和非人类灵长类动物的样本，识别 预测T细胞分化模式、广度和/或控制病毒血症的代谢特征 ATI。在这个目标中，我们测试丰富的代谢数据(血浆分析物、批量RNAseq和SCENITH)是否来自 猕猴和人类都可以预测治疗性疫苗接种产生的T细胞反应的质量 并在ATI后实现了病毒控制。 目的2：检查与SIV疫苗联合交付的系统和T细胞特异性代谢的影响 补充精氨酸或精氨酸分解代谢酶精氨酸酶1对病毒血症的影响 在艺术停止之后。MTOR基于营养传感系统的集成来调节细胞代谢， 包括那些衡量氨基酸可利用性的指标。疫苗介导的氨基酸调控 因此，分解代谢可以提供一条局部和有限的代谢调节途径，从而鼓励 变革性和有效的T细胞反应。

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.