Multi-omic understanding of the transformed host T-cell response to HIV following therapeutic vaccination

治疗性疫苗接种后转化宿主 T 细胞对 HIV 反应的多组学理解

• 批准号: 10731710
• 负责人: DENNIS J. HARTIGAN-O'CONNOR
• 金额: $ 149.42万
• 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/10731710
• 关键词: Activities of Daily Living; Antigens; Cells; Chronic; Clinical; Clinical Trials; Clone Cells; Cytomegalovirus; DNA; Exhibits; Exposure to; Fostering; Frequencies; Goals; HIV; HIV vaccine; Human; Immune; Immune response; Immune system; Immunodominant Epitopes; Infection; Infection Control; Interruption; Intervention; Intuition; Learning; Link; Literature; Mediating; Memory; Metabolic; Peptides; Persons; Property; RNA; Regimen; Research; Residual state; SIV; Sampling; Sampling Studies; Signal Transduction; Specificity; T cell receptor repertoire sequencing; T cell response; T memory cell; T-Lymphocyte; Testing; Therapeutic; Vaccination; Vaccine Therapy; Vaccines; Viral; Viremia; Virus; acute infection; antiretroviral therapy; chronic infection; effector T cell; exhaust; immune function; improved; metabolomics; multiple omics; next generation; nonhuman primate; novel therapeutics; pathogen; programs; recruit; response; restoration; stem; stemness; success; therapeutic vaccine; therapeutically effective; transcription factor; vaccine trial; vector

Therapeutic HIV vaccines confront an immune system whose anti-pathogen responses are established and have usually been evolving for years. T-cell responses to immunodominant epitopes have been generated and may have been maintained—or could have forced viral escape and eventual expansion of T cells with alternative, originally sub-dominant specificities. Many HIV-specific T cells have low proliferative capacity, rendering them incapable of a robust response when antiretroviral treatment is stopped. Furthermore, the established T-cell repertoire failed to control acute infection, so expansion of pre-existing T cells with their attendant functional deficiencies is unlikely to be therapeutically effective. The primary goal of therapeutic vaccination must instead be expansion of new T-cell clones with superior function, and/or the restoration of function to pre-existing memory cells. We suggest that only such qualitative improvements can provide the host with new capacity for control over the virus. A central objective of our program is to understand the extent to which pre-existing host immune and metabolic features constrain the quality of T-cell responses to therapeutic vaccination. Which immunometabolic conditions predict and perhaps foster qualitatively superior responses? What fraction of the T-cell response to vaccination is represented by new and previously undetected clonotypes, and how do the functional capacities and differentiation of the new clonotypes differ from pre-existing ones? A second major objective is to evaluate the relative ability of different vaccine regimens and metabolic interventions to expand new HIV/SIV-specific T cells with stem-like qualities. We and others have shown that HIV-specific T cells in natural HIV controllers express high levels of the memory-promoting transcription factor, TCF-1, retain proliferative capacity, and exhibit metabolic plasticity. We hypothesize that vaccine- induced cells with stem-like properties often derive from naïve T-cell clonotypes not previously expanded or chronically exposed to antigen, and that different vaccine regimens differ in their ability to recruit such cells. A third and central objective of our effort is to learn how peptide specificity, stemness, and metabolic capacities of T cells responding to vaccination are related to control over viremia during ATI. A large literature supports our premise that high T-cell quality is required for control over viremia, and more specifically that T cell memory, or “stemness”, features are associated with effective host responses. However, these connections remain relatively unexplored in the context of therapeutic vaccination, in part due to scarcity of large therapeutic-vaccine studies that have yielded an appreciable efficacy signal. We will use samples from human and non-human primate therapeutic-vaccine studies that have shown evidence for T cell-mediated virologic suppression to understand if the T-cell features previously linked to control over infection are also typical of successful immune responses to therapeutic vaccines.

治疗性艾滋病毒疫苗面对的是免疫系统，其抗病原体反应是建立的，并且 通常已经进化了好几年。已经产生了对免疫优势表位的T细胞反应 并可能被维持--或者可能迫使病毒逃脱并最终通过 另类的，最初是次要的特性。许多HIV特异性T细胞的增殖能力很低， 使他们在抗逆转录病毒治疗停止时无法做出强有力的反应。此外， 已建立的T细胞谱系未能控制急性感染，因此用其扩增先前存在的T细胞 随之而来的功能缺陷不太可能在治疗上有效。 治疗性疫苗接种的主要目标必须是扩大新的T细胞克隆，具有更好的 功能，和/或恢复到先前存在的存储单元的功能。我们认为，只有这样的定性 改进可以为宿主提供控制病毒的新能力。 我们计划的一个中心目标是了解预先存在的宿主免疫和 代谢特征限制了T细胞对治疗性疫苗的反应质量。哪一个 免疫代谢条件预测并可能促进质量优越的反应？其中有多少是 T细胞对疫苗接种的反应表现为新的和以前未检测到的克隆型，以及 新克隆类型的功能能力和分化与先前存在的克隆类型不同？ 第二个主要目标是评估不同疫苗方案和代谢的相对能力。 干预措施，以扩增具有干细胞性质的新的HIV/SIV特异性T细胞。我们和其他人已经展示了 天然HIV控制者中HIV特异性T细胞表达高水平的记忆促进转录 因子，TCF-1，保持增殖能力，并显示代谢可塑性。我们假设疫苗- 具有干细胞样特性的诱导细胞通常来自幼稚的T细胞克隆型，以前没有扩增或 不同的疫苗方案招募这类细胞的能力也不同。 我们努力的第三个也是中心目标是了解多肽的特异性、干性和代谢 T细胞对疫苗的应答能力与ATI期间病毒血症的控制有关。大号 文献支持我们的假设，即控制病毒血症需要高质量的T细胞，更具体地说 这种T细胞记忆或“干性”特征与有效的宿主反应有关。然而，这些 在治疗性疫苗接种方面，联系仍然相对未被探索，部分原因是缺乏 已经产生了明显疗效信号的大型治疗性疫苗研究。我们将使用来自 人类和非人类灵长类治疗性疫苗研究表明存在T细胞介导的证据 病毒学抑制以了解以前与控制感染有关的T细胞特征是否也 对治疗性疫苗的成功免疫反应的典型代表。