Efficacy Testing of HIV-Specific Microbicides in Humanized Mice

描述（由申请人提供）：一种有效的抗艾滋病毒阴道杀微生物剂可能会防止数百万新的艾滋病毒感染的妇女。关注具有已知病毒特异性活性的化合物，增加保护范围和加强临床前测试的组合方法将大大有助于应对开发广泛有效的杀微生物剂的挑战。虽然猕猴模型对于小规模杀微生物剂测试是有价值的，但是利用HIV感染的小动物模型将极大地促进潜在杀微生物剂化合物的大规模快速评价。在这方面，新开发的含有人类HIV靶细胞的人源化小鼠模型显示出巨大的前景。我们和其他人最近在这些模型中成功地实现了HIV-1通过阴道和直肠途径的粘膜传播。这一令人兴奋的发展，以及发现具有新作用机制的新型抗逆转录病毒化合物和鉴定有效的广泛中和抗HIV抗体（bNAb），为我们提供了一个独特的机会来测试预防HIV性传播的新方法。我们在这些研究中使用HIV本身作为人源化小鼠中的攻击病毒的主要目标是鉴定作为潜在的HIV杀微生物剂的新类型的分子以供进一步开发。我们最近获得了关于马拉韦罗、雷特格韦和VRC 01 bNAb作为潜在杀微生物剂的有希望的初步数据，这些数据构成了本文提出的进一步研究的基础。我们的具体目标是1.开发整合酶抑制剂雷特格韦和CCR 5抑制剂马拉韦罗作为阴道杀菌剂。2.评价广泛中和的抗HIV抗体作为潜在的HIV杀微生物剂。3.评价重要因素，如发情期、细胞相关病毒、田间菌株和抗药性突变体，以确保杀微生物剂在田间取得成功。4.使用具有不同作用模式的选定抗艾滋病毒药物评价组合杀微生物剂策略。5.评价有前途的杀微生物剂候选物在体内的安全性和潜在毒性。

DESCRIPTION (provided by applicant): An effective anti-HIV vaginal microbicide is likely to prevent millions of new HIV infections in women. Focusing on compounds with known viral specific activity, combinatorial approaches to increase the breadth of protection and intensifying preclinical testing will greatly facilitate in meeting the challenge of developing a broadly effective microbicide. While the macaque model has been valuable for small scale microbicide testing, exploitation of a small animal model of HIV infection will greatly facilitate large scale rapid evaluation of potential microbicide compounds. In this regard, the newly developed humanized mouse models that harbor human HIV target cells show great promise. We and others have recently succeeded in achieving HIV-1 mucosal transmission via both vaginal and rectal routes in these models. This exciting development together with the discovery of new anti-retroviral compounds with novel mechanisms of action and identification of potent broadly neutralizing anti-HIV antibodies (bNAb) provides us with a unique opportunity to test new approaches for prevention of HIV sexual transmission. Our major goal in these studies employing HIV itself as a challenge virus in humanized mice is to identify new classes of molecules as potential HIV microbicides for further development. We recently obtained promising preliminary data on maraviroc, raltegravir and VRC01 bNAb as potential microbicides which form a basis for further studies proposed here. Our specific aims are to 1. Develop the integrase inhibitor raltegravir and CCR5 inhibitor maraviroc as vaginal microbicides. 2. Evaluate broadly neutralizing anti-HIV antibodies as potential HIV microbicides. 3. Evaluate important factors such as estrus period, cell-associated virus, field strains and drug resistant mutants for the success of microbicides in the field. 4. Evaluate a combinatorial microbicide strategy using select anti-HIV agents with different modes of action. 5. Evaluate the safety and potential toxicities of promising microbicide candidates in vivo.