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细胞区域。树突状细胞与T细胞相互作用的熟练程度使它们成为启动和增强病毒感染的主要候选者。最近发现DC-SIGN，一种在dc中高表达的表面受体，可促进表达CD4和趋化因子受体的细胞的高效HIV感染，这表明该分子可能在DC-HIV相互作用中起关键作用。在初步研究中，我们证明了DC-SIGN基因（这里被称为DC-SIGN1）和另一个高度同源的基因DC-SIGN2的可塑性，产生了广泛的DC-SIGN样分子。这包括潜在的可溶性异构体以及广泛的膜结合dc - sign样分子，它们的细胞外配体（gp120）结合域不同。我们将验证DC-HIV相互作用是通过大量多态但结构相似的分子介导的假设，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）的替代剪接产生的。将实现三个目标。目的1将确定DC-SIGN1和DC-SIGN2亚型的分子库和细胞分布。Aim #2将确定DC-SIGN1和DC- sign2异构体的gp120粘附性和HIV-1反式感染活性，并阐明缺乏跨膜结构域的天然DC-SIGN1异构体是否是HIV-1结合DC-SIGN1的可溶性抑制剂。为了寻找DC-SIGN1在体内HIV-1发病机制中的作用的遗传证据，在aim #3中，我们将确定DC-SIGN1多态性与hiv感染和未感染个体的大队列传播风险和临床结果之间的关系。我们的期望是，这些研究将澄清和进一步显著我们对dc - sign介导的事件在体外DC-HIV相互作用中的作用和体内HIV发病机制的理解。它们还将为理解DC-HIV和DC-T细胞相互作用（在HIV发病机制中起关键作用的事件）相关的新问题和旧问题提供一个跳板。我们的研究也使我们处于一个独特的位置，以寻求阻断DC-HIV相互作用的策略，这被认为是HIV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.