Mechanisms of Trained Immunity in HIV Immune Responses

项目总结/摘要 急性HIV感染的特征是强大的先天免疫反应，决定了最终的临床 病程。先天免疫激活和转录变化可以持续超过急性感染 期先天免疫系统的细胞可以通过先前的暴露进行重新编程或“训练”， 持久的变化会影响未来的免疫反应。这种现象被称为训练免疫或先天免疫。 免疫记忆，是表观遗传编码，允许刺激依赖性转录因子结合，不仅 可利用的细胞类型特异性增强子，而且还可利用细胞中以前无法进入的染色质区域。 基因组尽管早期先天反应在确定HIV病程中的重要性， 训练免疫力在HIV感染中的作用还没有被探索过。此外，物质使用对这些 早期的先天免疫应答是未知的。该项目将利用艾滋病毒免疫学方面的专业知识， 物质使用（Fulcher博士），先天免疫记忆表观遗传机制（Cheng博士）和HIV 免疫学和细胞毒性T淋巴细胞（杨博士），以探讨机制的训练免疫形成 HIV免疫反应以及HIV本身如何重新编程先天免疫细胞。我们假设 在单核细胞分化期间暴露于某些刺激将导致产生细胞因子的不同能力 并刺激HIV特异性CD 8 + T细胞反应。在艾滋病毒感染的背景下，我们假设艾滋病毒 暴露诱导单核细胞重编程，导致可能有助于 慢性炎症和免疫衰竭为了验证这些假设，我们将：（1）识别先天免疫 刺激，训练单核细胞的最佳艾滋病毒特异性免疫反应，包括检查的影响， 滥用药物对这些反应的影响，以及（2）表征HIV产生的先天免疫记忆 感染，并确定病毒因子和宿主信号转导途径所需的培训。我们将训练 从使用或不使用药物的人获得的原代人单核细胞，在使用药物期间具有不同的配体。 分化为巨噬细胞，然后暴露于HIV，并使用功能性免疫测定比较结果。 将使用RNAseq询问途径。我们接下来将用HIV培养单核细胞， 以及使用RNAseq和ATACseq的次级刺激（LPS）后的转录变化。结果 这些研究将促进对训练的免疫力如何塑造艾滋病毒免疫反应的理解， HIV可能会影响后期的免疫反应。这些知识可以为治疗带来新的免疫靶点， 改善艾滋病毒预防和治疗。

PROJECT SUMMARY / ABSTRACT Acute HIV infection is characterized by a robust innate immune response that determines the ultimate clinical disease course. Innate immune activation and transcriptional changes can persist beyond the acute infection period. Cells of the innate immune system can be reprogrammed or “trained” by prior exposures, and this lasting changes influence future immune responses. This phenomenon, termed trained immunity or innate immune memory, is epigenetically encoded, allowing stimulus-dependent transcription factors to bind not only to available cell type-specific enhancers, but also to previously inaccessible regions of the chromatin in the genome. Despite the importance of early innate responses in determining HIV disease course, the role of trained immunity in HIV infection has not been explored. Moreover, the effects of substance use on these early innate immune responses are not known. This project will leverage expertise in HIV immunology and substance use (Dr. Fulcher), innate immune memory epigenetic mechanisms (Dr. Cheng), and HIV immunology and cytotoxic T lymphocytes (Dr. Yang) to investigate mechanisms of trained immunity in shaping HIV immune responses and how HIV itself may reprogram innate immune cells. We hypothesize that exposure to certain stimuli during monocyte differentiation will lead to differential ability to produce cytokines and stimulate HIV-specific CD8+ T cell responses. In the setting of HIV infection, we hypothesize that HIV exposure induces monocyte reprogramming resulting in heightened secondary responses that may contribute to chronic inflammation and immune exhaustion. To test these hypotheses we will: (1) identify innate immune stimuli that train monocytes for optimal HIV-specific immune responses, including examining the effects of drugs of abuse on these responses and (2) characterize the innate immune memory produced by HIV infection and determine the viral factors and host signaling pathways required for training. We will train primary human monocytes, obtained from persons who do or do not use drugs, with different ligands during differentiation to macrophages then expose to HIV and compare outcomes using functional immune assays. Pathways will be interrogated using RNAseq. We will next train monocytes with HIV then examine epigenetic and transcription changes following secondary stimulus (LPS) using RNAseq and ATACseq. Results from these studies will advance understanding of how trained immunity shapes HIV immune responses, and how HIV may affect later immune responses. This knowledge can lead to novel immune targets for therapeutics to improve HIV prevention and treatment.