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: 10403380
• 负责人: Thomas Hope
• 金额: $ 106.45万
• 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/10403380
• 关键词: Adaptive Immune System; Anatomy; Animals; Antibody Response; Antiviral Agents; Antiviral Response; Area; Autopsy; Bar Codes; Biological Assay; Blood; Brain; CD3 Antigens; CD4 Positive T Lymphocytes; Cells; Cellular Morphology; Characteristics; Dependence; Down-Regulation; Environment; Event; Excision; HIV; HIV-1; Human; Image; Immune; Immune response; Individual; Infection; 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; Positron-Emission Tomography; Process; Property; Recovery; Research; Role; Running; SIV; Signal Transduction; Site; Source; Systemic infection; T-Lymphocyte; Thinking; Time; Tissue Sample; Tissues; Transmission Electron Microscopy; Variant; Viral; Viral reservoir; Viremia; Virion; Virus; Work; adaptive immune response; antiretroviral therapy; base; 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)在控制艾滋病毒-1感染方面取得了显著成功，但病毒 在处理的情况下，水库会无限期地持续存在。这些持续的病毒种群构成了主要的负担 对于有效的HIV-1治疗，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构成了主要的储存库，但 由于获取组织样本的困难，大多数水库研究不包括组织样本 含有活跃的复制中心，反弹病毒的位置。因此，我们不能适当地研究 这些病毒种群及其主要特征尚不清楚。了解其性质和性质 反弹应该会让我们更接近于确定与持久性和快速相关的储藏库 ATI后反弹。我们之前定义ATI后反弹早期焦点的研究揭示了一个意想不到的 结果所有检测到的SIV感染细胞均呈髓样形态，CD3等T细胞染色均为阴性 记号笔。这些研究集中在早期水库，在CART开始后4天建立 挑战。在这种情况下，没有病毒特异性的细胞免疫反应或体液免疫反应。 然而，在这一点上，很明显，当免疫反应发挥作用时，反弹的病毒群是被过滤掉的 Cart启动了。基于对人类感染的关键考虑和更好的模型，该项目将 确定先天和获得性免疫压力对组织中新出现的病灶环境的影响 利用我们的PET/CT引导的尸检和切除手术工作流程，允许研究病毒反弹 在日食阶段的组织内。我们打算利用我们的能力在感染的患者中定位SIV活跃的病毒血症部位 猕猴，对支持反弹的细胞和解剖隔间进行详细识别 持之以恒的SIV。我们将研究先天和获得性免疫系统的影响，并破坏髓系细胞 以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式和方法方面具有科学相关性，因为它将允许 确定持续病毒种群反弹的主要特征和动态 ATI。鉴于病毒种群持续反弹的重要性。对反弹病毒有更好的认识 ATI后的人口动态是制定成功治愈HIV-1战略的关键。