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: 9224985
• 负责人: Kirston Mandy Lang Barton
• 金额: $ 1.26万
• 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 2017-04-18
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9224985
• 关键词: Address; Adverse effects; Affect; Alpha Cell; Anatomy; 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; Genome; Gut associated lymphoid tissue; HIV; HIV Infections; HIV-1; Helper-Inducer T-Lymphocyte; Immobilized Cells; Immunohistochemistry; Individual; Infection; Location; Lymph Node Tissue; Maintenance; Microscopy; Modern Medicine; Morphology; Nature; Obstruction; Participant; Patients; Pharmacology; Phylogenetic Analysis; Population; Proviruses; Research Project Grants; Role; Source; Surface; 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; public health relevance; small molecule inhibitor; trafficking

 DESCRIPTION (provided by applicant): 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 cels (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.

 描述（由申请人提供）：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。杀菌或功能性治疗方法的开发将解决其中许多限制。治愈的主要障碍是ART患者中存在持续的、有复制能力的HIV。最近，几项临床试验表明，他们可以用小分子抑制剂靶向持续的HIV。然而，这项工作的大部分都集中在病毒，这是非常容易获得的循环系统。下一个重要的步骤是具体确定持续性HIV的储存库存在于患者中， ART，以便新的疗法可以针对这些部位。该项目的重点是淋巴结滤泡，这是一个已知的持久性HIV-1的来源。然而，淋巴结滤泡中单个细胞类型在HIV持续存在中的作用尚未完全确定。淋巴结滤泡含有滤泡-树突状细胞（follicular-dendriticcells，FDC），其可以将有复制能力的病毒隔离在其细胞表面，然后这些病毒可以潜在地感染易感的滤泡T辅助细胞（follicular T helper cells，TFH）。根据淋巴结中持续存在的HIV是否主要由靶细胞中的潜伏HIV前病毒接种，或者FDC相关病毒粒子是否有助于持续存在，这将极大地影响未来如何制定旨在清除这种病毒的策略。为了解决这个问题，我们收集了长期ART研究参与者的淋巴结滤泡，并将使用显微镜表征FDC和TFH的形态。然后，我们将使用激光捕获显微切割分离FDC和TFH，并使用单基因组测序和单前病毒测序来表征这些细胞中的病毒，并确定FDC上隔离的HIV是否作为ART患者中感染性病毒的储存库，以及这种病毒是否可以传播到其他已知的持续性HIV储存库。通过定义FDC在长期ART患者中HIV持续存在和传播中的作用，这项重要的工作将有助于未来HIV根除临床试验的发展，并使他们能够将治疗重点和指导指向与持续HIV最相关的解剖位置。此外，该项目将专门针对NIAID的重点领域，即“治愈艾滋病毒感染”的优先事项，以确定是否存在其他艾滋病毒感染源。