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.

尽管抗逆转录病毒疗法（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。一个发展 消毒或功能固化将解决许多这些局限性。主要障碍 治愈是ART患者的持续性，复制能力的HIV的存在。最近，几个 临床试验表明，它们可以靶向具有小分子抑制剂的持续性HIV。 但是，这项工作的大部分都集中在病毒上，该病毒在药理学上很容易获得 循环系统。下一个重要步骤是专门确定储层的位置 ART患者存在持续的HIV，因此可以针对这些位置的新疗法。 该项目着重于淋巴结卵泡，这是持续性HIV-1的已知来源。 但是，单个细胞类型在淋巴结卵中的作用在HIV持续性中 未完全定义。淋巴结卵泡包含卵泡树突细胞（FDC），可以 在其细胞表面上的隔离复制能力的病毒，然后可能感染 易感滤泡T辅助细胞（TFHS）。取决于淋巴中持续的HIV是否 节点主要由靶细胞中潜在的HIV原病毒播种，或者是否与FDC相关 病毒体有助于持久性极大地影响未来的策略旨在清除 该病毒应开发。为了解决这个问题，我们收集了淋巴结卵泡 从研究参与者长期艺术的参与者，并将描述FDC的形态和 使用显微镜的TFH。然后，我们将使用激光捕获量隔离FDC和TFHS 显微解剖，将使用单基因组测序和单病毒测序 表征这些细胞中的病毒，并确定在FDC上隔离的HIV是否充当 ART患者的感染病毒的储层以及该病毒是否可以传播到 其他已知的持续艾滋病毒的水库。通过定义FDC在持久性和 在长期艺术中，艾滋病毒在患者中传播艾滋病毒，这项重要的工作将有助于 开发未来的艾滋病毒根除临床试验，并允许他们集中精力和指导 解剖位置是最相关的持续艾滋病毒来源的治疗方法。 此外，该项目将专门针对“治愈艾滋病毒的NIAID”领域 感染优先级，以确定是否存在艾滋病毒感染的其他储藏。