The Role of Follicular Dendritic Cells in Maintenance of Persistent HIV

滤泡树突状细胞在维持持续性 HIV 中的作用

• 批准号: 9224032
• 负责人: Kirston Mandy Lang Barton
• 金额: $ 1.16万
• 依托单位: UNIVERSITY OF SYDNEY
• 依托单位国家: 美国
• 财政年份: 2016
• 资助国家: 美国
• 起止时间: 2016-01-18 至 2019-01-17
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9224032
• 关键词: Address; Adverse effects; Affect; Anti-Retroviral Agents; Antigen-Antibody Complex; Area; CD4 Positive T Lymphocytes; Cardiovascular system; Cell surface; Cells; Clinical Trials; Development; Epidemic; Follicular Dendritic Cells; Frequencies; Future; Genetic Drift; Genome; Gut associated lymphoid tissue; HIV; HIV Infections; HIV-1; Helper-Inducer T-Lymphocyte; Immunohistochemistry; Individual; Infection; Location; Lymph Node Tissue; Maintenance; Microscopy; Modern Medicine; Morphology; Nature; Obstruction; Participant; Patients; Phylogenetic Analysis; Population; Proviruses; Research Project Grants; Role; Source; Surface; T-Lymphocyte Subsets; Therapeutic; Tissue Sample; Translational Research; Viral; Viral Genome; Viral reservoir; Virion; Virus; Work; antiretroviral therapy; cell type; clinically relevant; cost; effective therapy; genome sequencing; in vivo; laser capture microdissection; light microscopy; lymph nodes; novel therapeutics; peripheral blood; small molecule inhibitor; trafficking

Although anti-retroviral therapy (ART) effectively controls HIV-1 infection, it has several limitations including uncomfortable side effects, low accessibility, and high cost. The development of a sterilizing or functional cure would address many of these limitations. The primary obstruction to a cure is the presence of persistent, replication-competent HIV in patients on ART. Recently, several clinical trials have shown that they can target persistent HIV with small-molecule inhibitors. However, most of this work has focused on virus that is pharmacologically easily accessible in the circulatory system. The next important step is to specifically determine where reservoirs of persistent HIV exist in patients on ART so that new therapies can be targeted to these locations. This project focuses on the lymph node follicles, which are a known source of persistent HIV-1. However, the role of the individual cell types in the lymph node follicles in the persistence of HIV is not fully defined. The lymph node follicles contain follicular-dendritic cells (FDCs) that can sequester replication competent virus on their cell surface, which could then potentially infect susceptible follicular T helper cells (TFHs). Depending on whether the persistent HIV in the lymph nodes is primarily seeded by latent HIV proviruses in target cells or whether FDC-associated virions are contributing to persistence drastically affects how future strategies aimed at clearing this virus should be developed. To address this question, we have collected lymph node follicles from study participants on long-term ART and will characterize the morphology of the FDCs and TFHs using microscopy. Then, we will isolate both the FDC and the TFHs using laser-capture microdissection and will use single-genome sequencing and single-proviral sequencing to characterize the virus in these cells and determine whether HIV sequestered on FDCs acts as a reservoir of infectious virus in patients on ART and whether this virus can then disseminate to other known reservoirs of persistent HIV. By defining the role of FDCs in the persistence and dissemination of HIV in patients on long-term ART, this important work will contribute to the development of future HIV eradication clinical trials and allow them to focus and direct therapeutics to the anatomical locations that are the most relevant sources of persistent HIV. Additionally, this project will specifically address the NIAIDs area of emphasis to “Cure HIV Infection” priority one to determine if additional reservoirs of HIV infection exist.

虽然抗逆转录病毒疗法(Art)有效地控制了hiv-1感染，但它有几个局限性。 包括不舒服的副作用、低可及性和高成本。开发一种新的 消毒或功能治愈将解决许多这些限制。主要的障碍物是 治愈是在接受抗逆转录病毒治疗的患者中存在持续的、具有复制能力的艾滋病毒。最近，有几个 临床试验表明，它们可以通过小分子抑制剂靶向持久性艾滋病毒。 然而，这项工作的大部分都集中在药物上很容易在 循环系统。下一个重要的步骤是具体确定哪里的水库 持续的艾滋病毒存在于接受抗逆转录病毒治疗的患者中，因此新的治疗方法可以针对这些地区。 这个项目的重点是淋巴滤泡，这是一个已知的来源，持久的艾滋病毒-1。 然而，淋巴滤泡中的单个细胞类型在艾滋病毒持续存在中的作用是 没有完全定义。淋巴结滤泡含有滤泡-树突状细胞(FDCs)，它可以 在它们的细胞表面隔离具有复制能力的病毒，然后可能感染 易感滤泡T辅助细胞(TFHs)。取决于淋巴中是否存在持续的艾滋病毒 结节主要由靶细胞中潜伏的HIV病毒或是否与FDC相关 病毒粒子对持久性的贡献极大地影响了未来旨在清除 应该开发这种病毒。为了解决这个问题，我们收集了淋巴结滤泡 来自长期ART的研究参与者，并将表征FDDC的形态和 在显微镜下观察TFHs。然后，我们将使用激光捕获分离FDC和TFH 并将使用单基因组测序和单前病毒测序来 确定病毒在这些细胞中的特征，并确定隔离在FDCs上的艾滋病毒是否起到了 接受抗逆转录病毒治疗的患者中的传染性病毒宿主，以及这种病毒是否会随后传播到 其他已知的持久性艾滋病毒宿主。通过定义FDDC在持久化和 对艾滋病患者传播艾滋病病毒的长期抗逆转录病毒治疗，这项重要工作将有助于 开发未来根除艾滋病毒的临床试验，并使他们能够专注和指导 治疗到与持久性艾滋病毒来源最相关的解剖位置。 此外，该项目将特别针对NIAIDs的重点领域，即“治愈艾滋病毒” 感染“的首要任务是确定是否存在更多的艾滋病毒感染者。