Trained immunity induced by Nef-containing extracellular vesicles

摘要 研究发现，某些感染不仅能诱导针对致病因子的免疫力，还能针对不相关的病原体产生免疫力 多年来，这种病原体一直引起研究人员的兴趣。近年来，这一现象的潜在机制 现象开始显露出来。发现负责异源保护的关键细胞 是先天免疫细胞，例如自然杀伤细胞 (NK)、树突状细胞和单核细胞/巨噬细胞。这些 细胞通过初始感染而“启动”，从而使它们能够对随后的感染提供增强的反应 相同或不相关的代理人。这种先天免疫记忆现象被称为训练免疫。的 拟议的训练免疫机制涉及通过代谢途径的第一个刺激来激活 导致表观遗传变化，使细胞保持在“训练”状态，从而增强对 随后的刺激。先天免疫记忆可以导致增强反应或抑制 随后的反应（“耐受性”），取决于免疫初始刺激的强度和持续时间 细胞。在艾滋病毒感染的情况下，先天记忆是否是由感染引起的仍不清楚，尽管 有限的证据表明 NK 细胞在暴露于 HIV 后会持续激活。在这个应用程序中，我们提出 第一个证据表明携带 HIV-1 蛋白 Nef (exNef) 的细胞外囊泡可诱导训练有素的免疫力 人类单核细胞，其特征是对刺激的反应增强。本次培训机制显现 依赖于 exNef 介导的对胆固醇稳态的影响。鉴于 exNef 被释放到血液中 即使在 ART 抑制 HIV 复制后，经过训练的单核细胞/巨噬细胞仍可维持 病毒被抑制后可以持续很长时间。我们建议研究 exNef 诱导的先天性机制 免疫记忆训练及其对巨噬细胞HIV感染易感性的影响。拟议目标 解决了 FOA 中的两个科学问题：“HIV 暴露或感染是否会诱发先天免疫记忆？” 以及“哪些机制调节影响艾滋病毒感染的先天免疫记忆？”。该研究还涉及 FOA 中提到的一种具体方法：“代谢变化导致先天免疫重新编程” 细胞’。

Abstract Findings that certain infections induce immunity not only against the causing agent, but also against an unrelated pathogen have intrigued investigators for many years. During recent years, underlying mechanisms of this phenomenon have started to come to light. It was found that the key cells responsible for heterologous protection are innate immune cells such as natural killer cells (NKs), dendritic cells, and monocytes/macrophages. These cells are ‘primed’ by initial infection, allowing them to provide enhanced response to subsequent infection by the same or unrelated agent. This phenomenon of innate immune memory was termed trained immunity. The proposed mechanism for trained immunity involves activation by the first stimulus of metabolic pathways that lead to epigenetic changes, which maintain the cell in a "trained" state allowing enhanced responses to a subsequent stimulus. Innate immune memory can lead either to enhanced responses or to suppression of subsequent responses (‘tolerance’), depending on the strength and length of the initial stimulation of the immune cells. In the context of HIV infection, it remains unknown whether innate memory is induced by infection, although limited evidence suggests a lasting activation of NK cells following HIV exposure. In this application, we present the first evidence that extracellular vesicles carrying the HIV-1 protein Nef (exNef) induce trained immunity in human monocytes, characterized by increased response to stimulation. The mechanism of this training appears to depend on exNef-mediated effect on cholesterol homeostasis. Given that exNef are released into the blood even after HIV replication had been suppressed by ART, trained monocytes/macrophages can be maintained for a long time after virus suppression. We propose to investigate the mechanism of exNef-induced innate immune memory training and its effect on susceptibility of macrophages to HIV infection. The proposed aims address the two scientific questions in the FOA: ‘Does HIV exposure or infection induce innate immune memory?’ and ‘What mechanisms regulate innate immune memory which impact HIV acquisition?’. The study also involves a specific approach mentioned in the FOA: ‘Metabolic changes leading to reprogramming of innate immune cells’.