Role of DC-SIGN in HIV infection

树突状细胞(DC)被认为在HIV-1的传播和感染的建立中起着重要作用。HIV破坏了DC的正常运输过程，使其从粘膜表面运输到引流淋巴组织的T细胞区。树突状细胞与T细胞相互作用的熟练程度使其成为启动和增强病毒感染的首选对象。DC-SIGN是一种在DC中高表达的表面受体，最近的研究发现，DC-SIGN通过反式表达CD4和趋化因子受体的细胞来促进HIV的有效感染，这表明该分子可能在DC-HIV相互作用中发挥关键作用。在初步研究中，我们证明了DC-SIGN基因(这里指定为DC-SIGN1)和另一个高度同源的基因DC-SIGN_2的可塑性，产生了广泛的DC-SIGN样分子。这一谱系包括潜在的可溶异构体以及广泛的膜结合的DC-SIGN样分子，这些分子在细胞外配体(Gp120)结合区域上存在差异。我们将测试这一假设，即DC-HIV相互作用是通过一大类多态但结构相似的分子介导的，这些分子是由两个不同但高度相关的基因，即DC-SIGN1(原始版本)或DC-SIGN2选择性剪接而产生的。我们将追求三个目标。目的#1将确定DC-SIGN1和DC-SIGN2亚型的分子谱系和细胞分布。目的#2将测定DC-SIGN1和DC-SIGN1亚型的gp120粘附性和对HIV-1的反式感染活性，并阐明天然存在的缺乏跨膜区的DC-SIGN1亚型是否是HIV-1与DC-SIGN1结合的可溶性抑制剂。为了寻找DC-SIGN1在体内HIV-1致病机制中作用的遗传学证据，在目标3中，我们将在大量HIV感染者和非感染者中确定DC-SIGN1基因多态与传播风险和临床结局之间的关联。我们的期望是，这些研究将澄清并显著加深我们对DC-SIGN介导的事件在体外DC-HIV相互作用和体内HIV发病机制中的作用的理解。它们还将为构建与理解DC-HIV和DC-T细胞相互作用相关的新问题和旧问题提供跳板，这些事件在HIV发病机制中发挥关键作用。我们的研究还将我们置于一个独特的位置，以寻求阻止DC-HIV相互作用的战略，这些相互作用被认为是艾滋病毒传播所必需的。

Dendritic cells (DCs) are thought to play an important role in the dissemination of HIV-1 and establishment of infection. HIV subverts the normal trafficking process of DCs for its transport from mucosal surfaces to the T cell areas of draining lymphoid tissues. The proficiency of DCs in interacting with T cells makes them prime candidates for initiating and enhancing viral infection. The recent discovery that DC-SIGN, a surface receptor with high expression in DCs promotes efficient HIV infection in trans of cells that express CD4 and chemokine receptors suggests that this molecule might play a key role in DC-HIV interactions. In preliminary studies we demonstrate that plasticity of the DC-SIGN gene (designated here as DC-SIGN1), and another highly homologous gene designated as DC-SIGN2, generates a wide repertoire of DC-SIGN-like molecules. This repertoire includes potentially soluble isoforms as well as a wide array of membrane-bound DC-SIGN-like molecules that differ in their extracellular ligand (gp120) binding domain. We will test the hypothesis that DC-HIV interactions are mediated via a large class of polymorphic, but structurally-similar molecules that are generated by the alternative splicing of two distinct, but highly related genes i.e., DC-SIGN1 (original version) or DC-SIGN2. Three aims will be pursued. Aim #1 will determine the molecular repertoire and cellular distribution of DC-SIGN1 and DC-SIGN2 isoforms. Aim #2 will determine the gp120 adhesivity and HIV-1 trans-infection activity of DC-SIGN1 and DC-SIGN2 isoforms, and elucidate if naturally occurring DC-SIGN1 isoforms lacking the transmembrane domain are soluble inhibitors of HIV-1 binding to DC- SIGN1. To seek genetic evidence for a role of DC-SIGN1 in HIV-1 pathogenesis in vivo, in aim #3 we will determine the association between polymorphisms in DC-SIGN1 and risk of transmission and clinical outcome in large cohorts of HIV-infected and uninfected individuals. Our expectation is that these studies will clarify and further significantly our understanding of the role of DC-SIGN-mediated events in DC-HIV interactions in vitro, and HIV pathogenesis in vivo. They will also provide a springboard for framing new and reframing old problems related to understanding DC-HIV and DC-T cell interactions, events that play key roles in HIV pathogenesis. Our studies also place us in a unique position to pursue strategies to block DC-HIV interactions thought to be necessary for HIV transmission.