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）：艾滋病毒储库构成重大治疗障碍，并提供遗传多样性，复制能力病毒的持续来源，使疾病永久化。人类HIV的一个主要宿主是滤泡树突状细胞（FDC）网络，其中包含遗传多样性病毒，包括在其他地方未发现的存档耐药准种。FDC局限于次级淋巴组织（sLT）的滤泡，在那里它们以由特异性抗体（Ab）和/或补体（C '）组分组成的免疫复合物（IC）的形式在细胞外捕获和保留HIV。FDC使用CD 32（Fc？RIIB）和CD 21（补体受体2），尽管其他尚不清楚的受体也可能在HIV-IC的情况下做出贡献。 FDC捕获的HIV具有高度传染性，即使在高浓度中和抗体（NtAb）存在下也仍然如此。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。FDCs也产生TNF α（和可能的其他细胞因子），增加NF？B活化，进而HIV复制，并有助于生发中心（GC）细胞的高度活化状态，包括经常感染的CD 4 + GC T细胞。FDC-HIV储库的重要性得到以下观察结果的支持：在疾病的整个自然过程中，活跃的病毒复制持续围绕FDCs。 FDCs现在已知存在于两种状态，激活和休息。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储存库可以允许设计针对HIV危险储存库的特定干预策略。 公共卫生相关性：滤泡树突状细胞（FDCs）代表了一个大的，但未充分研究的水库感染性艾滋病毒，可以有助于持续感染。该申请的重点是FDC活化对该细胞维持其表面捕获的HIV的感染性、增加CD 4 + T细胞中的病毒表达以及在存在强效中和抗体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断这种危险的传染性病毒库的能力。