Trained immunity induced by Nef-containing extracellular vesicles

摘要 发现某些感染不仅诱导对致病因子的免疫，而且还诱导对不相关因子的免疫。 病原体已经吸引了研究人员多年。近年来，这一现象的潜在机制 现象开始显现。发现负责异源保护的关键细胞 是先天免疫细胞，如自然杀伤细胞（NK）、树突细胞和单核细胞/巨噬细胞。这些 细胞通过最初的感染“启动”，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 所提出的训练免疫力的机制涉及通过代谢途径的第一刺激激活， 导致表观遗传变化，使细胞保持在一个“训练”的状态，允许增强对一个 后续刺激。先天免疫记忆可以导致增强的反应或抑制免疫应答。 随后的反应（“耐受性”），这取决于免疫系统初始刺激的强度和长度。 细胞在艾滋病毒感染的背景下，仍然不清楚先天记忆是否是由感染引起的，尽管 有限的证据表明，在HIV暴露后NK细胞的持久活化。在本申请中，我们提出 携带HIV-1蛋白Nef（exNef）的细胞外囊泡诱导训练免疫的第一个证据是， 人单核细胞，其特征在于对刺激的反应增加。这种训练的机制似乎 依赖于exNef介导的对胆固醇稳态的作用。考虑到前Nef被释放到血液中 即使在HIV复制被ART抑制后，训练的单核细胞/巨噬细胞也可以维持 在病毒抑制后很长一段时间。我们建议研究exNef诱导的先天性 免疫记忆训练及其对巨噬细胞对HIV感染易感性影响拟议目标 解决FOA中的两个科学问题：“HIV暴露或感染是否会诱导先天免疫记忆？” 以及“什么机制调节影响HIV获得的先天免疫记忆？”。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系统的重新编程， 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’.