Developing RANTES analogues as topical strategies to prevent HIV transmission

项目3：没有经过验证的杀微生物剂策略，最近的大规模试验未能显示 保护虽然有许多发展战略正在酝酿之中，但至关重要的是， 应探讨各种战略，因为迄今为止没有一项战略取得成功，而且每一项战略都有一些 潜在的缺点和挑战。我们的团队已经成功地证明了 CCR 5使用修饰的RANTES类似物作为预防HIV感染粘膜传播的策略。 虽然这些开创性的研究有助于修改局部预防战略的模式， 氨基末端修饰的RANTES类似物的应用仍然存在一些潜在的障碍， 预防HIV感染的粘膜传播的局部策略。这些潜在障碍中有许多是 其他已提出的艾滋病毒预防战略也有类似的情况。潜在的挑战 这些策略包括：某些RANTES类似物的潜在激动剂活性，效力，作用的持久性， 和成本 因此，该协作应用程序的项目#3将尝试通过以下方式解决这些限制 具体目标： SP目标#1：确定通过以下途径介导炎症细胞因子诱导的信号传导途径： PSC-RANTES（和其他RANTES类似物）在阴道/宫颈组织中的作用，并破坏这些信号传导 通路作为一种机制，以减少炎症反应的RANTES类似物，同时保留 抗HIV活性。 Sp.目的#2：评估可能导致免疫缺陷的联合策略的抗病毒活性（和免疫学效应）， 与RANTES类似物一起提供相加或协同的抗病毒保护。 Sp.目的#3：探索可允许更持久的阴道内注射的新型水凝胶制剂策略 暴露于RANTES类似物和其他化合物。 Sp.目的#4：开发用于重组RANTES的高规模GMP级合成的方法 类似物（6P 4-RANTES和5 P12-RANTES和5 P14-RANTES -完全重组的试剂，其作为 在HIV抑制方面具有PSC-RANTES的体外活性），这将允许负担得起的这种局部应用 预防战略。 这个经验丰富的团队成功完成这些研究可能会澄清 这是一种有希望的局部预防艾滋病毒传播策略的发展途径。

Project 3: There is no proven microbicide strategy, and recent large scale trials have failed to show protection. While there are numerous strategies in the pipeline for development, it is essential that promising strategies be explored, as none to date have succeeded and each strategy in development has some potential drawbacks and challenges. Our group has successfully demonstrated the plausibility of targeting CCR5 using modified RANTES analogues as a strategy to prevent mucosal transmission of HIV infection. While these seminal studies have helped to revise the paradigm of topical prevention strategies, there remain several potential obstacles to the application of amino terminus modified RANTES analogues as topical strategies to prevent mucosal transmission of HIV infection. Many of these potential obstacles are shared by other topical HIV prevention strategies that have been proposed. The potential challenges to these strategies include: potential agonist activity of some RANTES analogues, potency, durability of effect, and cost. Thus Project #3 of this collaborative application will attempt to resolve these limitations with the following specific aims: Sp Aim #1: to determine the signaling pathways that mediate the induction of inflammatory cytokines by PSC-RANTES (and other RANTES analogues) in vaginal/cervical tissue and to disrupt these signaling pathways as a mechanism to reduce the inflammatory responses to RANTES analogues while preserving anti-HIV activity. Sp. Aim #2: to evaluate the antiviral activities (and immunologic effects) of combination strategies that may provide additive or synergistic antiviral protection together with RANTES analogues. Sp. Aim #3: to explore novel hydrogel formulation strategies that may permit more durable intravaginal exposure to RANTES analogues and other compounds. Sp. Aim #4: to develop methods for the high scale GMP grade synthesis of recombinant RANTES analogues (6P4-RANTES, and 5P12-RANTES, and 5P14-RANTES - fully recombinant agents that are as active in vitro as PSC-RANTES in terms of HIV inhibition) that will permit affordable application of this topical prevention strategy. Successful completion of these studies by this experienced team will likely result in clarifying the pathways to development of this promising strategy for topical prevention of HIV transmission.