Follicular dendritic cell activation and HIV pathogenesis

滤泡树突状细胞激活和 HIV 发病机制

• 批准号: 8012521
• 负责人: Gregory F. Burton
• 金额: $ 44.21万
• 依托单位: BRIGHAM YOUNG UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2010
• 资助国家: 美国
• 起止时间: 2010-06-01 至 2014-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8012521
• 关键词: Active Sites; Affect; Antibodies; Antigen-Antibody Complex; Archives; CD32 Antigens; CD4 Positive T Lymphocytes; Cells; Complement; Complement 3d Receptors; Cytokine Signaling; Data; Dendritic cell activation; Disease; Drug resistance; Follicular Dendritic Cells; Future; Genetic Transcription; HIV; HIV Infections; Human; In Vitro; Infection; Interleukin-6; Intervention; Knock-out; Ligation; Lipopolysaccharides; Lymphoid Tissue; Maintenance; Mediating; Nature; Pathogenesis; Play; Protein C Inhibitor; Proviruses; Reporting; Research; Rest; Role; Seminal; Serpins; Source; Stimulus; Structure of germinal center of lymph node; Surface; T-Lymphocyte; Therapeutic Intervention; Time; Viral; Virus; Virus Activation; Virus Replication; cytokine; design; in vivo; neutralizing antibody; public health relevance; receptor; repository

DESCRIPTION (provided by applicant): HIV reservoirs pose significant treatment obstacles and provide a continuing source of genetically diverse, replication-competent virus to perpetuate disease. A major human reservoir of HIV is the follicular dendritic cell (FDC) network, which harbors genetically diverse virus including archived drug-resistance quasispecies that are not found elsewhere. FDCs are confined to the follicles of secondary lymphoid tissues (sLTs) where they trap and retain HIV extracellularly in the form of immune complexes (ICs) comprised of specific antibody (Ab) and/or complement (C') components. FDCs trap ICs (including HIV) using CD32 (Fc?RIIB) and CD21 (Complement Receptor 2), although other as yet unknown receptors may also make contributions in the case of HIV-IC. FDC-trapped HIV is highly infectious and remarkably, remains so even in the presence of high concentrations of neutralizing antibodies (NtAb). Moreover, FDC virus infectivity persists for months to years in the absence of ongoing infection and/or replication. FDCs also produce TNFa (and likely other cytokines) that increases NF?B activation and in turn, HIV replication and contributes to the highly activated state of cells in the germinal center (GC), including CD4+ GC T cells that are frequently infected. The importance of the FDC-HIV reservoir is supported by the observation that active virus replication persists surrounding FDCs throughout the natural course of disease. FDCs are now known to exist in two states, activated and resting. The objective of this proposed research is to determine if activation of FDCs is required: 1) to maintain HIV infectivity over time, 2) to increase HIV expression in infected cells, and 3) to transmit infection in the presence of potent neutralizing antibodies. A better understanding of the FDC reservoir of highly infectious HIV can permit the design of specific intervention strategies that can target this dangerous repository of HIV. PUBLIC HEALTH RELEVANCE: Follicular dendritic cells (FDCs) represent a large, but understudied reservoir of infectious HIV that can contribute to persisting infection. This application focuses on the role of FDC activation upon this cell's ability to maintain the infectious nature of HIV trapped on its surfaces, increase virus expression in CD4+ T cells and transmit infection in the presence of potent neutralizing antibodies. Understanding how the FDC interacts with HIV and how this can be controlled can provide the ability to block this dangerous reservoir of infectious virus.

描述（由申请人提供）：HIV 储存库造成了重大的治疗障碍，并提供了遗传多样性、具有复制能力的病毒的持续来源，使疾病永久化。 HIV 的主要人类储存库是滤泡树突状细胞 (FDC) 网络，该网络包含遗传多样性的病毒，包括其他地方未发现的已存档的耐药准种。 FDC 局限于次级淋巴组织 (sLT) 的滤泡中，以由特异性抗体 (Ab) 和/或补体 (C') 成分组成的免疫复合物 (IC) 的形式将 HIV 捕获并保留在细胞外。 FDC 使用 CD32 (Fc?RIIB) 和 CD21（补体受体 2）捕获 IC（包括 HIV），尽管其他未知受体也可能在 HIV-IC 中发挥作用。 FDC 捕获的 HIV 具有高度传染性，而且值得注意的是，即使存在高浓度的中和抗体 (NtAb)，其传染性仍然如此。此外，在没有持续感染和/或复制的情况下，FDC病毒的感染性持续数月至数年。 FDC 还产生 TNFa（以及可能的其他细胞因子），从而增加 NFκB 激活，进而促进 HIV 复制，并有助于生发中心 (GC) 细胞的高度激活状态，包括经常感染的 CD4+ GC T 细胞。 FDC-HIV 储存库的重要性得到了以下观察结果的支持：在整个疾病的自然病程中，活跃的病毒复制在 FDC 周围持续存在。 目前已知 FDC 存在两种状态：激活状态和静止状态。这项拟议研究的目的是确定是否需要激活 FDC：1) 随着时间的推移维持 HIV 感染性，2) 增加受感染细胞中的 HIV 表达，3) 在存在强效中和抗体的情况下传播感染。更好地了解高传染性 HIV 的 FDC 储存库，可以设计针对这一危险的 HIV 储存库的具体干预策略。 公共卫生相关性：滤泡树突状细胞 (FDC) 是一个巨大但尚未得到充分研究的传染性 HIV 储存库，可导致持续感染。该应用重点关注 FDC 激活对该细胞维持捕获在其表面的 HIV 感染性质、增加 CD4+ T 细胞中的病毒表达以及在强效中和抗体存在的情况下传播感染的能力的作用。了解 FDC 如何与 HIV 相互作用以及如何控制这种相互作用可以提供阻止这种危险的传染性病毒库的能力。