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菌剂可能会防止数百万妇女新感染艾滋病毒。专注于已知病毒特异性活性的化合物，组合方法来增加保护的广度和加强临床前测试将极大地促进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的杀菌剂测试是有价值的，但利用HIV感染的小动物模型将极大地促进大规模快速评估潜在的杀菌剂化合物。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很大的希望。我们和其他人最近在这些模型中成功地通过阴道和直肠途径实现了HIV-1粘膜传播。这一令人兴奋的进展，加上发现了具有新的作用机制的新型抗逆转录病毒化合物，以及发现了有效的广泛中和性抗艾滋病毒抗体（bNAb），为我们测试预防艾滋病毒性传播的新方法提供了一个独特的机会。我们在人源化小鼠中使用HIV本身作为挑战病毒的这些研究的主要目标是确定新的分子类别，作为进一步开发的潜在的HIV杀微生物剂。我们最近获得了关于马拉韦洛克、雷替重力韦和VRC01 bNAb作为潜在杀菌剂的初步数据，为进一步的研究奠定了基础。我们的具体目标是：开发整合酶抑制剂雷替格拉韦和CCR5抑制剂马拉维洛克作为阴道杀菌剂。2. 评价广泛中和的抗HIV抗体作为潜在的HIV杀菌剂。3. 评估诸如发情期、细胞相关病毒、田间菌株和耐药突变体等重要因素，以确定杀微生物剂在田间的成功。4. 评估组合杀菌剂策略使用选择抗艾滋病毒药物与不同的作用模式。5. 评估有前途的杀菌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.