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.

项目总结/摘要 尽管联合抗逆转录病毒疗法（cART）在控制HIV-1感染方面取得了显着的成功，但病毒感染仍然存在。 储层在处理下无限期地存在。这些持续存在的病毒群构成了 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群体构成了大部分的宿主， 由于难以获得组织样本，大多数储层研究不包括组织样本 含有活跃的复制灶，即病毒反弹的场所。因此，我们无法正确地研究 这些病毒群体及其主要特征仍然未知。了解自然和属性 反弹应该使我们更接近于确定与持久性和快速相关的储层 ATI后反弹。我们以前的研究定义了ATI后早期反弹的病灶，发现了一个意想不到的 结果所有检测到的SIV感染细胞具有髓样形态，并且CD 3和其他T细胞染色阴性 标记。这些研究集中于早期储库，在cART开始后4天建立 挑战.在这些条件下，不存在病毒特异性细胞介导的或体液免疫应答。 然而，在他的观点是明确的，反弹的病毒种群被过滤的免疫反应在发挥作用时， 启动了cART。基于批判性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出现病灶的环境的影响 利用我们的PET/CT引导尸检和切除手术工作流程， 在组织中的变化我们打算利用我们的能力定位SIV活动的病毒血症网站， 猕猴，以执行支持反弹的细胞和解剖隔室的详细识别 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、幅度和病毒群体动力学的影响。 拟议的项目在其创新方法和手段方面具有科学相关性，因为它将允许 确定持续性病毒种群反弹的主要性质和动力学， ATI考虑到持续的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。