Can mannosylated dendrimers inhibit HIV-1 infection of DC-SIGN expressing cells

描述(申请人提供)：在皮肤和粘膜组织中发现的树突状细胞(DC)表达凝集素，DC特异性的细胞间黏附分子抓取非整合素(DC-SIGN)，一种甘露糖结合，钙依赖的凝集素。由于DC在粘膜表面被发现，它们是第一批暴露于HIV-1的细胞类型之一，它们的细胞表面DC-SIGN通过附着gp120上的甘露糖残基与其结合。虽然DC-SIGN介导的结合和摄取被认为在免疫反应中发挥着重要作用，但在某些情况下，它促进了病毒感染。它与HIV-1和HIV-2的相互作用就是一个例子。DC-SIGN已被发现与其他病毒结合，包括埃博拉病毒、丙型肝炎病毒、巨细胞病毒和登革病毒，以及不同的细菌。在对表达DC-SIGN的细胞感染埃博拉病毒的研究中，发现由甘露糖残基衍生的超支化树枝状聚合物(树枝状大分子)能够抑制DC凝集素的受体功能。类似的研究还没有对艾滋病毒进行过。这是一个明显的缺陷，因为甘露糖特异性凝集素被发现可以抑制HIV-1对T淋巴细胞的感染，推测是通过结合甘露糖残基和阻断DC-SIGN与gp120的结合来实现的。这些观察结果为甘露糖化树枝状大分子也可能抑制艾滋病毒感染的假设提供了坚实的基础。拟议的实验旨在确定甘露糖化树枝状大分子是否是DC-SIGN的有效配体，如果是，它们是否抑制DC-SIGN与gp120的相互作用。一旦确定了一种有效的抑制剂，将进行实验以确定它是否被细胞摄取。如果如预期的那样，甘露糖化树枝状大分子能够有效地抑制表达DC-SIGN的靶细胞与rgp120的结合，将为HIV-1的预防提供一种新的潜在的治疗途径，并将支持多价甘露糖化化合物可能有效地抑制利用DC-SIGN途径的其他病原体的相互作用的假说。正是这些可能性使这项研究值得冒险。

DESCRIPTION (provided by applicant): Dendritic cells (DCs) found in dermal and mucosal tissue express the lectin, DC-specific intercellular adhesion molecule-grabbing nonintegrin (DC-SIGN), a mannose binding, calcium dependent, lectin. Because DCs are found at mucosal surfaces, they are one of the first cell types exposed to HIV-1 and their cell surface DC-SIGN binds it by adhering to mannose residues present on gp120. While binding and uptake mediated by DC-SIGN is considered to play an important role in the immune response, in some instances it facilitates viral infection. Its interaction with HIV-1 and 2 is an example of this. DC-SIGN has been found to bind other viruses including Ebola, hepatitis C virus, cytomegalovirus and Dengue virus, as well as different bacteria. In studies of infection of DC-SIGN expressing cells by Ebola, it was found that a hyperbranched dendritic polymer (dendrimer) derivatized with mannose residues was able to inhibit the receptor function of the DC lectin . Similar studies have not been carried out with HIV. This is a glaring deficit since mannose- specific lectins were found to inhibit infection of T lymphocytes by HIV-1, presumably by binding the mannose residues and blocking DC-SIGN binding to gp120. These observations provide a solid base for the hypothesis that mannosylated dendrimers might inhibit infection by HIV as well. Proposed experiments are designed to determine whether mannosylated dendrimers are effective ligands for DC-SIGN and if so whether they inhibit the interaction of DC-SIGN with gp120. Once an effective inhibitor is identified, experiments will be carried out to determine whether it is taken up by cells. If as anticipated, mannosylated dendrimers are effective inhibitors of the binding of rgp120 by DC-SIGN-expressing target cells, it will provide a new potential therapeutic approach for the prevention of HIV-1, and would support the hypothesis that multivalent mannosylated compounds might be effective at inhibiting the interaction of other pathogens that utilize the DC-SIGN pathway. It is these possibilities that make this research worth the risk.