Efficacy Testing of HIV-Specific Microbicides in Humanized Mice

HIV特异性杀微生物剂在人源化小鼠中的功效测试

• 批准号: 8410283
• 负责人: Ramesh Akkina
• 金额: $ 44.49万
• 依托单位: COLORADO STATE UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2012
• 资助国家: 美国
• 起止时间: 2012-02-15 至 2015-01-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8410283
• 关键词: AIDS prevention; Affect; Animal Model; Anti-HIV Agents; Anti-Retroviral Agents; CCR5 gene; Cells; Clinical Trials; Data; Development; Drug Formulations; Drug resistance; Epidemic; Estrus; Evaluation; Goals; HIV; HIV Antibodies; HIV Infections; HIV-1; Human; Inflammation; Integrase Inhibitors; Lead; Licensing; Macaca; Modeling; Mus; Pharmaceutical Preparations; Preclinical Testing; Route; Safety; Satellite Viruses; Sexual Transmission; Surface; Tenofovir; Testing; Toxic effect; Vagina; Viral; Virus; Woman; anti-HIV microbicide; base; combinatorial; efficacy testing; in vivo; inhibitor/antagonist; meetings; microbicide; mouse model; mutant; neutralizing monoclonal antibodies; novel; novel strategies; prevent; prophylactic; rectal; stem; success; transmission process; vaginal microbicide

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.

描述（由申请人提供）：有效的抗HIV阴道微生物可能会预防女性数百万新的HIV感染。专注于具有已知病毒特异性活性的化合物，结合方法可以增加保护和加强临床前测试的广度，这将极大地促进开发广泛有效的杀criperticide的挑战。尽管猕猴模型对于小尺度杀菌剂测试很有价值，但对艾滋病毒感染的小动物模型的开发将极大地促进对潜在杀菌剂化合物的大规模快速评估。在这方面，新开发的人性化的小鼠模型藏有人类艾滋病毒靶细胞显示出巨大的希望。在这些模型中，我们和其他人最近成功地通过阴道和直肠路线实现了HIV-1粘膜传播。这一令人兴奋的发展以及发现新的抗逆转录病毒化合物，具有新颖的作用机理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，可以测试预防HIV性传播的新方法。在这些研究中，我们在人性化小鼠中采用艾滋病毒作为挑战病毒的主要目标是将新的分子鉴定为潜在的艾滋病毒杀菌剂，以进一步发展。最近，我们获得了有关Maraviroc，Raltegravir和VRC01 BNAB的有希望的初步数据，作为潜在的微生物，这构成了此处提出的进一步研究的基础。我们的具体目的是1。开发整合酶抑制剂Raltegravir和CCR5抑制剂Maraviroc作为阴道菌皮。 2。评估广泛中和抗HIV抗体作为潜在的HIV杀菌剂。 3。评估重要因素，例如发情周期，细胞相关病毒，野外菌株和耐药突变体，以成功地在野外生体。 4。使用具有不同作用模式的选择的抗HIV药物评估组合杀菌剂策略。 5。评估体内有前途的杀菌剂候选物的安全性和潜在毒性。