Mechanisms of Trained Immunity in HIV Immune Responses

HIV 免疫反应中的训练免疫机制

• 批准号: 10535270
• 负责人: Quen J Cheng
• 金额: $ 23.4万
• 依托单位: UNIVERSITY OF CALIFORNIA LOS ANGELES
• 依托单位国家: 美国
• 财政年份: 2022
• 资助国家: 美国
• 起止时间: 2022-07-14 至 2024-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10535270
• 关键词: AIDS prevention; ATAC-seq; Acute; Address; Affect; Antigen Presentation; Antigen-Presenting Cells; Antiinflammatory Effect; Binding; Biological Assay; Blood; CD8-Positive T-Lymphocytes; Cannabis; Cells; Cellular Immunity; Chromatin; Chronic; Clinical; Clinical Course of Disease; Cytotoxic T-Lymphocytes; Disease; Disease Progression; Drug user; Enhancers; Epigenetic Process; Epitopes; Exposure to; Future; Gene Expression Profile; Genes; Genetic Transcription; Genome; HIV; HIV Infections; Health; Human; Immune; Immune Targeting; Immune response; Immune system; Immunity; Immunologic Memory; Immunology; Immunology procedure; In Vitro; Inflammation; Innate Immune Response; Innate Immune System; Integrase; Interferon Type II; Interferon-beta; Knowledge; Lead; Ligands; Methamphetamine; Molecular; Myelogenous; Opioid; Outcome; Pathway interactions; Peptides; Persons; Pharmaceutical Preparations; Play; Production; Protease Inhibitor; Reverse Transcriptase Inhibitors; Role; Secondary to; Shapes; Signal Pathway; Stimulant; Stimulus; T cell response; T-Lymphocyte; TNF gene; Testing; Training; Up-Regulation; Vaccine Design; Viral; Viral Proteins; Yang; acute infection; beta-Glucans; cell type; cytokine; drug of abuse; ds-DNA; epigenomics; exhaustion; experimental study; exposed human population; immune activation; immunoregulation; improved; inhibitor; macrophage; monocyte; novel; prevent; response; secondary infection; substance use; targeted treatment; therapeutic target; transcription factor; transcriptome sequencing; transcriptomics

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.

项目摘要 /摘要 急性艾滋病毒感染的特征是坚固的先天免疫响应，该免疫力决定了最终的临床 疾病课程。先天免疫激活和转录变化可以持续超出急性感染 时期。先天性免疫系统的细胞可以通过先前的暴露重新编程或“训练”，这 持久的变化会影响未来的免疫调查。这种现象，被称为受过训练的免疫学或先天性 免疫记忆是表观遗传编码的 对于可用的细胞类型特异性增强剂，但也要在先前无法获得的染色质区域 基因组。尽管早期先天反应在确定艾滋病毒疾病病程中的重要性，但 尚未探索受过训练的艾滋病毒感染免疫力。而且，使用物质对这些的影响 早期的先天免疫调查尚不清楚。该项目将利用HIV免疫学方面的专业知识和 药物使用（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（Yang博士）研究训练的免疫抑制机制 HIV免疫复杂以及HIV本身如何重新编程先天免疫细胞。我们假设这一点 在单核细胞分化过程中暴露于某些刺激将导致产生细胞因子的差异能力 并刺激HIV特异性CD8+ T细胞反应。在HIV感染的情况下，我们假设HIV 暴露会引起单核细胞重编程，从而产生增强的次级反应，这可能有助于 为了检验这些假设，我们将：（1）确定先天免疫 训练单核细胞以进行最佳HIV特异性免疫复杂的刺激，包括检查 这些反应上的滥用药物和（2）表征艾滋病毒产生的先天免疫记忆 感染并确定训练所需的病毒因素和宿主信号通路。我们将训练 主要的人类单核细胞，是从使用药物或不使用药物的人获得的，并具有不同的配体 然后，与巨噬细胞的区分暴露于HIV并使用功能免疫测定法比较结果。 将使用RNASEQ询问途径。我们接下来将使用HIV训练单核细胞，然后检查表观遗传学 使用RNASEQ和ATACSEQ后次级刺激（LPS）后转录变化。结果 这些研究将促进对受过训练的免疫抑制如何促进艾滋病毒免疫调查的理解，以及如何 艾滋病毒可能会影响以后的免疫反应。这些知识可以导致新的免疫靶标进行治疗 改善艾滋病毒预防和治疗。