Project 1

项目1

• 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
• 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

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.

摘要 为了在ART停止后有效地控制HIV，HIV特异性T细胞对 治疗性疫苗接种不仅必须在规模上增加，而且必须是长期的， 活着，有能力回到储存库持久性位点，具有T细胞记忆样 响应抗原而稳健增殖和执行效应子功能的能力（即，他们 需要克服残留的T细胞耗竭，这种耗竭持续存在于预先存在的HIV特异性T细胞中 尽管ART抑制了病毒载量），并重新关注显性应答， 靶向脆弱表位。由于标准T细胞测定的限制，并且尽管 临床试验的新数据显示，接种疫苗后至少部分控制了艾滋病毒， 了解艾滋病毒治疗性疫苗方案转化为无效的机制， 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。本课题 将利用我们的经验进行综合多模式系统免疫学分析 利用配对的单细胞转录组和TCR测序（scRNA/TCRseq）数据， 三维流式细胞术数据。我们将对HIV/SIV治疗药物进行克隆水平分析， 来自高度独特和临床相关的人和猕猴的疫苗诱导的CD 8 + T细胞 治疗性疫苗对改变艾滋病毒/SIV感染者的 治疗中断后的病毒载量动力学，以询问：在何种程度上是目前的首选 能够募集新的和/或预先存在的T细胞克隆的治疗性疫苗方案， 最佳记忆类属性（功能和微分状态;目标1和2），以及 疫苗引发的T细胞应答的记忆样特征（或其他特征）的程度 与治疗后艾滋病毒控制相关（目标3）？这些研究将使我们能够描述 在前所未有的深度，不同的治疗性疫苗方案的影响， 以前无法测量的-病毒特异性T细胞应答质量的方面。我们的结果 这将为我们开发可靠的病毒特异性T细胞克隆的测量方法奠定基础。 结构和分化状态，这将为人类和猕猴的迭代研究提供信息。