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(申请人提供)：一种有效的抗艾滋病毒阴道杀菌剂可能预防数百万妇女新的艾滋病毒感染。将重点放在具有已知病毒特异性活性的化合物上，增加保护范围和加强临床前测试的组合方法将极大地促进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很有价值，但开发HIV感染的小动物模型将极大地促进对潜在杀微生物剂化合物的大规模快速评估。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。这一令人振奋的发展，加上具有新作用机制的新的抗逆转录病毒化合物的发现，以及有效的广谱中和抗艾滋病毒抗体(BNAb)的鉴定，为我们提供了一个独特的机会来测试预防艾滋病毒性传播的新方法。我们在这些研究中使用HIV本身作为人源化小鼠的挑战病毒的主要目标是确定新的分子类别作为潜在的HIV微杀菌剂，以供进一步开发。我们最近获得了关于马拉韦罗、雷替格列韦和VRC01bNAb作为潜在杀菌剂的有希望的初步数据，这为这里提出的进一步研究奠定了基础。我们的具体目标是：1.开发整合酶抑制剂雷替格列韦和CCR5抑制剂马拉韦罗作为阴道杀菌剂。2.评估广泛中和抗艾滋病毒抗体作为潜在的艾滋病毒杀微剂。3.评价发情期、细胞相关病毒、田间菌株和抗药性突变体等因素对田间杀菌剂使用效果的影响。4.评估使用具有不同作用模式的精选抗艾滋病毒药物的组合杀微生物剂策略。5.在体内评价有希望的杀微生物剂候选药物的安全性和潜在毒性。