Role of myeloid cells in CNS and systemic reservoirs and rebound

骨髓细胞在中枢神经系统和全身储存库和反弹中的作用

• 批准号: 10540816
• 负责人: Thomas Hope
• 金额: $ 105.57万
• 依托单位: NORTHWESTERN UNIVERSITY AT CHICAGO
• 依托单位国家: 美国
• 财政年份: 2022
• 资助国家: 美国
• 起止时间: 2022-01-01 至 2026-11-30
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10540816
• 关键词: Adaptive Immune System; Anatomy; Animals; Antibody Response; Antiviral Agents; Antiviral Response; Area; Autopsy; Bar Codes; Binding; Biological Assay; Blood; Brain; CD3 Antigens; CD4 Positive T Lymphocytes; Cell Separation; Cells; Cellular Morphology; Characteristics; Dependence; Down-Regulation; Environment; Event; Excision; HIV; HIV-1; Human; Image; Immune; Immune response; Individual; Infection; Innate Immune Response; Innate Immune System; Interferons; Interruption; Intervention; Kinetics; Label; Lead; Light; Location; Macaca; Macaca mulatta; Mediating; Methodology; Microglia; Modeling; Morphology; Myelogenous; Myeloid Cells; Names; Nature; Negative Staining; Operative Surgical Procedures; PET/CT scan; Phase; Play; Population; Population Dynamics; Process; Property; Recovery; Reproducibility; Research; Role; Running; SIV; Shapes; Signal Transduction; Site; Source; Systemic infection; T-Lymphocyte; Thinking; Time; Tissue Sample; Tissues; Transmission Electron Microscopy; Variant; Viral; Viral reservoir; Viremia; Virion; Virus; Visualization; Work; adaptive immune response; antiretroviral therapy; cell type; design; experimental study; fitness; innovation; insight; nonhuman primate; pressure; response; spatial relationship; success; viral rebound

Project Summary/Abstract Despite the remarkable success of the combined antiretroviral therapy (cART) to control HIV-1 infection, viral reservoirs persist indefinitely under treatment. These persisting viral populations constitute the principal burden for an effective HIV-1 cure, as they lead to a rapid rebound in viremia when treatment fails or after analytic treatment interruption (ATI). Although persisting viral populations in tissue comprise most of the reservoir, the majority of the reservoir studies do not include tissue samples due to the difficulties to obtain tissue samples containing active foci of replication, the site of the rebounding virus. Therefore, we are not able to properly study these viral populations and their main characteristics remain unknown. Understanding the nature and properties of rebound should bring us a step closer to identifying the reservoir associated with persistence and rapid rebound after ATI. Our previous studies defining the early foci of rebound after ATI revealed an unexpected result as all detected SIV infected cells has a myeloid morphology and stained negative for CD3 and other T cell markers. Those studies were focused on the early reservoir, established when cART is initiated 4 days post challenge. Under these conditions, there are no virus specific cell mediated or humoral immune responses. However, at his point is clear that rebounding virus populations are filtered by immune responses in play when cART was initiated. Based on critical consideration and better model infection in humans, this project will determine the impact of innate and adaptive immune pressure impacts the milieu of the emerging foci in tissues leveraging our PET/CT guided necropsy and resection surgery workflow allowing the study of viral rebound within tissue during the eclipse phase. We intend to use our ability to localize SIV active viremia sites in infected macaques, to perform a detailed identification of the cells and anatomical compartments that support rebound of persistent SIV. We will study the effect of the innate and adaptive immune system and disrupt myeloid cell populations to determine the impact on the kinetics, magnitude, and viral population dynamics during rebound. The proposed project is scientifically relevant in its innovative approach and methodologies as it will allow to determine the main properties and dynamics the eclipse phase of rebound of persistent viral population after ATI. Given the importance of persistent viral populations in rebound. A better understanding of rebound virus population dynamics after ATI is key to developing successful strategies to cure HIV-1.

项目概要/摘要 尽管联合抗逆转录病毒疗法 (cART) 在控制 HIV-1 感染方面取得了显著成功，但病毒 水库在处理过程中会无限期地持续存在。这些持续存在的病毒种群构成了主要负担 有效治愈 HIV-1，因为当治疗失败或分析后，它们会导致病毒血症迅速反弹 治疗中断（ATI）。尽管组织中​​持续存在的病毒种群构成了病毒的大部分储存库， 由于获取组织样本困难，大多数储库研究不包括组织样本 含有活跃的复制灶，即反弹病毒的位点。因此，我们无法正确地学习 这些病毒种群及其主要特征仍然未知。了解本质和属性 反弹应该使我们更接近确定与持久性和快速性相关的储存库。 ATI之后反弹。我们之前的研究定义了 ATI 后反弹的早期焦点，揭示了一个意想不到的情况 结果是所有检测到的 SIV 感染细胞均具有骨髓形态，且 CD3 和其他 T 细胞染色呈阴性 标记。这些研究的重点是早期储存库，该储存库是在 cART 启动后 4 天后建立的。 挑战。在这些条件下，不存在病毒特异性细胞介导的免疫反应或体液免疫反应。 然而，他的观点很清楚，反弹的病毒种群会被免疫反应过滤掉，当 启动了 cART。基于严格的考虑和更好的人类感染模型，该项目将 确定先天性和适应性免疫压力对组织中新兴病灶环境的影响 利用我们的 PET/CT 引导尸检和切除手术工作流程来研究病毒反弹 在日食阶段的组织内。我们打算利用我们的能力来定位感染者中 SIV 活性病毒血症位点 猕猴，对支持反弹的细胞和解剖结构进行详细识别 持续性 SIV。我们将研究先天性和适应性免疫系统的影响并破坏骨髓细胞 群体以确定反弹期间对动力学、幅度和病毒群体动态的影响。 拟议项目的创新方法和方法具有科学相关性，因为它将允许 确定持续性病毒种群反弹的主要特性和动态 ATI。鉴于持久性病毒种群在反弹中的重要性。更好地了解反弹病毒 ATI 后的人口动态是制定成功治愈 HIV-1 策略的关键。