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）：艾滋病毒水库构成了重大的治疗障碍，并提供了持续多样的多样化，复制能力的病毒来使疾病永存。 HIV的主要人类储藏是卵泡树突状细胞（FDC）网络，该网络具有遗传多样的病毒，其中包括其他地方找不到的存档药物抗药性准菜。 FDC仅限于继发性淋巴组织（SLT）的卵泡，它们以特定抗体（AB）和/或补体（C'）成分组成的免疫复合物（ICS）的形式捕获并保留HIV细胞外。 FDCS TRAP IC（包括HIV）使用CD32（FC？RIIB）和CD21（补体受体2），尽管其他未知受体也可能在HIV-IC的情况下做出贡献。 FDC捕获的HIV具有高度感染力，而且显着，即使存在高浓度中和抗体（NTAB）的情况。此外，在没有持续的感染和/或复制的情况下，FDC病毒感染持续数月至数年。 FDC还产生了增加NF？B激活的TNFA（以及可能的其他细胞因子），进而将HIV复制复制，并促进生发中心（GC）中高度激活的细胞状态，包括经常感染的CD4+ GC T细胞。 FDC-HIV水库的重要性得到了这样一种观察，即在整个自然疾病过程中，活动病毒复制持续存在于FDC周围。 现在已知FDC存在于两个状态，即激活和休息。这项拟议的研究的目的是确定FDC的激活是否需要：1）维持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，而3）在存在有效的中和抗体的情况下传递感染。更好地了解高度传染性艾滋病毒的FDC水库可以允许设计特定的干预策略，这些干预策略可以针对这种危险的艾滋病毒储存库。 公共卫生相关性：卵泡树突状细胞（FDC）代表了一种大型但正在研究的感染性HIV储层，可以导致持续的感染。该应用的重点是FDC激活在该细胞保持艾滋病毒表面上的艾滋病毒感染性的能力，增加CD4+ T细胞中的病毒表达并在存在有效中和中和抗体的情况下传递感染的能力。了解FDC如何与艾滋病毒相互作用以及如何控制它可以提供阻止这种危险的传染病病毒储层的能力。