Testing practical microbicides in macaques

在世界范围内，超过80%的艾滋病毒感染是由于阴道传播而发生的。有一个绝望的 需要一种安全有效的杀微生物剂，以防止艾滋病毒传播给妇女。的目标 研究项目3是确定融合抑制剂的最佳组合和配方， 证明了最高水平的安全性，有效性和对阴道HIV的保护持续时间 使用非人灵长类动物阴道传播模型进行传播。在过去的几年里，我们 已经证明，几种融合抑制剂可以完全防止阴道传播， 与HIV-1传播高度相关的多种猴/免疫缺陷病毒（SHIV）毒株。我们 现在建议确定这些抑制剂的最佳组合，其提供最大水平的 对多种病毒株的效力和用不同病毒株的重复攻击。我们还将测试 设计用于在粘膜组织中提供延长保护的持续递送系统（阴道环） 在一次应用之后。最后，我们将严格评估这些抑制剂的安全性， 系统来确定这些可以应用多长时间而不会引起炎症或不良反应。 因此，我们的实验设计用于测试融合抑制剂单独在以下情况下的功效和安全性： 组合，特别是在持续释放制剂中，以确定以下的最佳组合： 融合抑制剂，可以安全和经济地用作杀微生物剂，以减缓艾滋病毒的传播 感染，特别是在流行病传播最快的地区。的具体目标 研究项目3是： 具体目标1。确定最有效的融合抑制剂组合， 保护猕猴免受SIV/SHIV不同毒株的粘膜传播; 具体目标2。比较融合抑制剂的疗效和保护持续时间， 体内持续递送装置，以及; 具体目标3。评估多剂量和缓释制剂的安全性 阴道和直肠粘膜中的抑制剂。 该项目的最终目标是确定一种HIV融合抑制剂组合， 应用于持续释放配方，将始终保护妇女免受重复暴露 高度分化的艾滋病毒株。

Worldwide, over 80% of HIV infections occur as a result of vaginal transmission. There is a desperate need for a safe and effective microbicide than can prevent the transmission of HIV to women. The goal of Research Project 3 is to identify the optimal combination and formulation of fusion inhibitors that demonstrates the greatest level of safety, efficacy, and duration of protection against vaginal HIV transmission using the nonhuman primate model of vaginal transmission. Over the last several years, we have demonstrated that several fusion inhibitors can completely protect against vaginal transmission of multiple simian/immunodeficiency virus (SHIV) strains that are highly relevant to HIV-1 transmission. We now propose to determine optimal combinations of these inhibitors that provide the greatest level of efficacy against multiple strains and repeated challenge with divergent strains of virus. We will also test sustained delivery systems (vaginal rings) designed to confer extended protection in mucosal tissues after a single application. Finally, we will rigorously assess the safety of these inhibitors and delivery systems to determine how long these may be applied without inducing inflammation or adverse effects. Our experiments are thus designed to test the efficacy and safety of fusion inhibitors, alone, in combination, and particularly in sustained release formulations to identify the optimal combination of fusion inhibitors that can be safely and economically used as a microbicide to slow the spread of HIV infection, particularly in areas where the epidemic is spreading the fastest. The specific aims of Research Project 3 are to: Specific Aim 1. Determine the most effective combination of fusion inhibitors that provides optimal protection against mucosal transmission of diverse strains of SIV/SHIV in macaques; Specific Aim 2. Compare the efficacy and duration of protection of fusion inhibitors administered in sustained delivery devices in vivo, and; Specific Aim 3. Assess the safety of multiple dosing and sustained release formulations of fusion inhibitors in both the vaginal and rectal mucosa. The ultimate goal of this project is to identify a combination of HIV fusion inhibitors that can be safely applied in a sustained release formulation that will consistently protect women against repeated exposure to highly divergent strains of HIV.