Developing RANTES analogues as topical strategies to prevent HIV transmission

项目3：没有得到证实的杀微生物剂策略，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， 应探讨战略，因为迄今没有一项战略取得成功，而且每项正在制定的战略都有一些 潜在的缺陷和挑战。我们的团队已经成功地证明了目标锁定的可能性 CCR5使用改良的RANTES类似物作为一种策略来防止艾滋病毒感染的粘膜传播。 虽然这些开创性的研究有助于修订专题预防战略的范式，但在 氨基末端修饰的RANTES类似物的应用仍然存在几个潜在的障碍 预防艾滋病毒感染通过粘膜传播的局部策略。这些潜在的障碍中有许多是 已提出的其他专题艾滋病毒预防战略也有相同之处。面临的潜在挑战 这些策略包括：一些RANTES类似物的潜在激动剂活性，效力，效果的持久性， 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：确定介导炎性细胞因子诱导的信号通路 PSC-RANTES(和其他RANTES类似物)在阴道/宫颈组织中的表达并干扰这些信号转导 途径作为一种机制减少对RANTES类似物的炎症反应 抗艾滋病病毒的活动。 SP.目的#2：评估联合策略的抗病毒活性(和免疫学效果) 与RANTES类似物一起提供添加剂或协同抗病毒保护。 SP.目的#3：探索新的水凝胶制剂策略，使阴道内更持久 接触RANTES类似物和其他化合物。 SP.目的#4：建立高规模GMP级合成重组RANTES的方法 类似物(6P4-RANTES、5P12-RANTES和5P14-RANTES-完全重组试剂 体外活性作为PSC-RANTES在艾滋病毒抑制方面)，将允许负担得起的局部应用 预防战略。 由这个经验丰富的团队成功完成这些研究可能会导致澄清 制定这一前景看好的局部预防艾滋病毒传播战略的途径。

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.