Follicular dendritic cell activation and HIV pathogenesis

描述(由申请人提供)：艾滋病毒宿主构成了重大的治疗障碍，并提供了遗传多样性、复制能力强的病毒的持续来源，从而使疾病永久化。人类艾滋病毒的一个主要宿主是滤泡树突状细胞(FDC)网络，该网络含有遗传多样性的病毒，包括其他地方没有的存档耐药准种。FDCs局限于次级淋巴组织(SLT)的滤泡，在那里它们以免疫复合体(IC)的形式捕获和保留HIV，IC由特异性抗体(Ab)和/或补体(C‘)组成。FDC使用CD32(Fc？RIIb)和CD21(补体受体2)捕获IC(包括HIV)，尽管其他未知的受体也可能在HIV-IC中发挥作用。 FDC诱捕的艾滋病毒具有很强的传染性，即使在高浓度的中和抗体(NtAb)存在的情况下也是如此。此外，在没有持续感染和/或复制的情况下，口蹄疫病毒的传染性可持续数月至数年。FDCs还产生TNFa(和可能的其他细胞因子)，增加核因子B的激活，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的支持：在整个自然病程中，活跃的病毒复制在FDDC周围持续存在。 目前已知FDDC存在两种状态：激活状态和休眠状态。这项拟议的研究的目的是确定是否需要激活FDCs：1)随着时间的推移保持HIV的传染性，2)增加感染细胞中HIV的表达，3)在强大的中和抗体存在的情况下传播感染。更好地了解FDC的高传染性艾滋病毒储存库可以设计针对这一危险的艾滋病毒储存库的具体干预策略。 与公共卫生相关：滤泡树突状细胞(FDCs)是一个巨大的、但未被充分研究的传染性艾滋病毒储存库，可能导致持续感染。这项应用着重于FDC激活对该细胞维持其表面捕获的HIV的感染性、增加CD4+T细胞中的病毒表达以及在强大的中和抗体存在下传播感染的能力所起的作用。了解FDC如何与艾滋病毒相互作用以及如何控制这一作用，可以提供阻断这一危险的传染性病毒储存库的能力。

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.