Trained immunity induced by Nef-containing extracellular vesicles

摘要 研究发现，某些感染不仅能诱导对病原体的免疫，而且能对无关的 多年来，病原体一直吸引着研究人员的兴趣。近年来，这一现象的潜在机制 这种现象已经开始显露出来。研究发现，负责异源保护的关键细胞 先天免疫细胞，如自然杀伤细胞(NKs)、树突状细胞和单核/巨噬细胞。这些 细胞通过最初的感染做好准备，使它们能够对随后的感染提供更强的反应 相同或无关的代理。这种先天免疫记忆的现象被称为训练免疫。这个 拟议的训练性免疫机制涉及通过第一刺激激活代谢途径， 导致表观遗传变化，使细胞保持在一种“经过训练”的状态，从而增强对 随后的刺激措施。先天免疫记忆可以导致增强的反应或抑制 随后的反应(耐受性)，取决于最初免疫刺激的强度和长度 细胞。在艾滋病毒感染的背景下，尚不清楚先天记忆是否由感染引起，尽管 有限的证据表明，在接触艾滋病毒后，NK细胞会持续激活。在此应用程序中，我们呈现 携带HIV-1蛋白Nef(ExNef)的细胞外小泡诱导训练免疫的第一个证据 人类单核细胞，其特征是对刺激的反应增强。这种训练的机制出现了 依赖于exNef介导的胆固醇稳态效应。鉴于exNef被释放到血液中 即使在艾滋病病毒复制被ART抑制后，经过训练的单核/巨噬细胞仍可以维持 病毒抑制后很长一段时间。我们建议研究exNef诱导的先天遗传的机制 免疫记忆训练及其对巨噬细胞对HIV感染易感性的影响。建议的目标 回答FOA中的两个科学问题：‘艾滋病毒暴露或感染是否会诱发先天免疫记忆？’ 以及“是什么机制调节了影响艾滋病毒感染的先天免疫记忆？”这项研究还涉及 FOA中提到的一种具体方法：新陈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’.