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

治疗性HIV疫苗面对的免疫系统的抗病原体反应已经建立， 通常已经发展了很多年。已经产生了针对免疫显性表位的T细胞应答， 并且可能已经死亡-或者可能迫使病毒逃逸并最终使T细胞扩增， 替代性的，原本是次显性的特异性。许多HIV特异性T细胞具有低增殖能力， 使他们在停止抗逆转录病毒治疗时无法作出强有力的反应。而且 已建立的T细胞库未能控制急性感染，因此， 伴随的功能缺陷不可能是治疗有效的。 治疗性疫苗接种的主要目标必须是扩增具有上级免疫原性的新T细胞克隆。 功能，和/或恢复预先存在的存储器单元的功能。我们建议，只有这样的定性 改进可以为宿主提供新的控制病毒的能力。 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细胞对治疗性疫苗接种应答的质量。这 免疫代谢状况预测并可能促进质量上的上级反应？哪一部分 T细胞对疫苗接种的反应由新的和以前未检测到的克隆型代表， 新克隆型的功能能力和分化与先前存在的克隆型不同？ 第二个主要目的是评估不同疫苗方案和代谢产物的相对能力。 因此，我们需要采取干预措施，以扩增具有干细胞样品质的新的HIV/SIV特异性T细胞。我们和其他人已经证明 自然HIV控制者体内的HIV特异性T细胞表达高水平的促进记忆的转录， 因子TCF-1保持增殖能力，并表现出代谢可塑性。我们假设疫苗- 具有干细胞样特性的诱导细胞通常来源于先前未扩增的幼稚T细胞克隆型， 长期暴露于抗原，并且不同的疫苗方案在募集这些细胞的能力上不同。 我们努力的第三个也是中心目标是了解肽特异性、干性和代谢性是如何在体内发挥作用的。 T细胞对疫苗接种的应答能力与ATI期间对病毒血症的控制有关。大 文献支持我们的前提，即高T细胞质量是控制病毒血症所必需的，更具体地说， T细胞记忆或“干性”特征与有效的宿主反应有关。但这些 在治疗性疫苗接种的背景下，这种联系仍然相对未被探索，部分原因是缺乏 大型治疗疫苗研究已经产生了明显的疗效信号。我们将使用来自 人类和非人类灵长类动物治疗性疫苗研究已经显示了T细胞介导的 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 典型的对治疗性疫苗的成功免疫应答。

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.