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.

项目摘要/摘要 尽管联合抗逆转录病毒疗法（CART）取得了显着成功，以控制HIV-1感染，但病毒 储层无限期地持续治疗。这些持续的病毒种群构成了主要负担 对于有效的HIV-1治疗，当治疗失败或分析后导致病毒血症的快速反弹 治疗中断（ATI）。尽管组织中​​持续的病毒群构成了大多数储层，但 由于难以获得组织样品，大多数储层研究不包括组织样品 包含复制的主动焦点，即反弹病毒的部位。因此，我们无法正确学习 这些病毒群体及其主要特征仍然未知。了解性质和特性 反弹的局面应该使我们更近一点，以确定与持久性和快速相关的水库 Ati后反弹。我们以前定义了ATI后反弹早期焦点的研究表明了一个意外 结果是所有检测到的SIV感染细胞均具有髓样形态，并且对CD3和其他T细胞染色为阴性 标记。这些研究的重点是早期储层，该储层是在开始在手推车后4天开始的 挑战。在这些条件下，没有病毒特异性细胞介导或体液免疫反应。 但是，在他的角度很明显，反弹病毒群体被免疫反应过滤了 推车开始。基于批判性考虑和人类更好的模型感染，该项目将 确定先天和适应性免疫压力的影响会影响组织中新兴焦点的环境 利用我们的PET/CT引导的死灵尸体和切除手术工作流程，可以研究病毒反弹 在日食期内组织内。我们打算利用我们的能力将SIV活性病毒性位点定位在感染中 猕猴，对支持反弹的细胞和解剖区室进行详细的识别 持续的SIV。我们将研究先天和适应性免疫系统的效果，并破坏髓样细胞 人群确定反弹期间对动力学，大小和病毒种群动态的影响。 拟议的项目在其创新方法和方法方面与科学相关，因为它将允许 确定主要特性和动力学持续病毒种群反弹的日食阶段 ati。鉴于持续的病毒种群在反弹中的重要性。更好地理解反弹病毒 ATI之后的人群动态是制定成功策略以治愈HIV-1的关键。