Project 1

项目1

基本信息

批准号：
10731713
负责人：
DENNIS J. HARTIGAN-O'CONNOR
金额：
$ 55.12万
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/10731713
关键词：
Activities of Daily Living Adenoviruses Aftercare Alleles Antigens Antiviral Response Binding Blinded Blood Blood specimen CD8-Positive T-Lymphocytes Cells Cellular Assay Chad Clinical Data Clinical Trials Clone Cells DNA Data Elements Enrollment Epitopes Exhibits Flow Cytometry Genetic Transcription HIV Home Human Immunity Immunology Individual Interferon Type II Interruption Kinetics Macaca Measurable Measurement Memory Modality Participant Persons Phenotype Placebos Proliferating Property Randomized Receptor Signaling Regimen Reporting Residual state Route SIV Sampling Site Specificity Structure System T cell receptor repertoire sequencing T cell response T memory cell T-Cell Receptor T-Lymphocyte Testing Vaccination Vaccine Therapy Vaccinee Vaccines Viral Viral Load result Virus antiretroviral therapy clinically relevant cohort efficacy evaluation exhaustion experience high dimensionality improved lymph nodes multimodality multiple omics peripheral blood recruit response therapeutic candidate therapeutic vaccine transcriptome vaccine candidate vaccine delivery

项目摘要

ABSTRACT In order to effectively control HIV after ART is stopped, HIV-specific T cell responses to therapeutic vaccination must not only be increased in magnitude, but they also must be long- lived, have the capacity to home to sites of reservoir persistence, have the T cell memory-like capacity to robustly proliferate and execute effector functions in response to antigen (i.e., they need to overcome the residual T cell exhaustion that persists in pre-existing HIV-specific T cells despite viral load suppression with ART), and be refocused to have dominant responses that target vulnerable epitopes. Due to the limitations of standard T cell assays, and despite emerging data from clinical trials showing at least partial control of HIV post-vaccination, little is known about the mechanisms by which HIV therapeutic vaccine regimens transform ineffective pre-existing HIV-specific T cell immunity into an effective antiviral response. In this Project, we will leverage our experience performing integrated multi-modal systems immunology analysis with paired single cell transcriptome and TCR sequencing (scRNA/TCRseq) data and high- dimensional flow cytometry data. We will perform clonal-level analysis on HIV/SIV therapeutic vaccine-elicited CD8+ T cells from highly unique and clinically relevant human and macaque HIV/SIV cohorts in which therapeutic vaccines have exerted a measurable effect on altering viral load kinetics after treatment interruption to ask: to what extent are current top-candidate therapeutic vaccine regimens capable of recruiting new and/or pre-existing T cell clones with optimal memory-like properties (function and differentiation state; Aims 1 and 2), and to what extent do memory-like features (or other features) of the vaccine-elicited T cell response correlate with post-treatment control of HIV (Aim 3)? These studies will allow us to characterize in unprecedented depth the impact of different therapeutic vaccine regimens on critical – and previously unmeasurable – facets of the quality of the virus-specific T cell response. Our results will lay the groundwork for us to develop reliable measurements of virus-specific T cell clonal structure and differentiation state that will inform iterative studies in humans and macaques.

抽象的为了在ART停止后有效控制HIV，HIV特异性T细胞对治疗性疫苗接种不仅必须增加疫苗接种的强度，而且还必须长期有效存在，有能力驻留在储存库持续存在的位点，具有类似记忆的 T 细胞响应抗原而强有力地增殖和执行效应器功能的能力（即，它们需要克服先前存在的 HIV 特异性 T 细胞中持续存在的残余 T 细胞耗竭问题尽管通过 ART 抑制了病毒载量），并重新集中精力以做出显性反应由于标准 T 细胞测定的局限性，尽管如此，临床试验的新数据显示，疫苗接种后至少部分控制了艾滋病毒，但几乎没有什么进展。了解 HIV 治疗性疫苗方案无效的机制在这个项目中，我们将预先存在的 HIV 特异性 T 细胞免疫转化为有效的抗病毒反应。将利用我们执行集成多模式系统免疫学分析的经验具有配对的单细胞转录组和 TCR 测序 (scRNA/TCRseq) 数据和高我们将对 HIV/SIV 治疗进行克隆水平分析。疫苗从高度独特且临床相关的人类和猕猴中诱导出 CD8+ T 细胞 HIV/SIV 队列中治疗性疫苗对改变产生了可测量的影响治疗中断后的病毒载量动力学问题：当前的最佳候选者在多大程度上能够招募新的和/或预先存在的 T 细胞克隆的治疗性疫苗方案最佳的类似记忆的特性（功能和分化状态；目标 1 和 2），以及什么疫苗引发的 T 细胞反应的类似记忆特征（或其他特征）的程度与 HIV 治疗后控制（目标 3）相关吗？这些研究将使我们能够表征不同治疗性疫苗方案对关键和关键疾病的影响前所未有的深入以前无法测量的——病毒特异性 T 细胞反应质量的各个方面。将为我们开发可靠的病毒特异性 T 细胞克隆测量方法奠定基础结构和分化状态将为人类和猕猴的迭代研究提供信息。