Modeling Next Generation HIV PrEP in Humanized Mice

在人源化小鼠中模拟下一代 HIV PrEP

• 批准号: 8330552
• 负责人: Ramesh Akkina
• 金额: $ 68.89万
• 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: 2012-06-01 至 2015-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8330552
• 关键词: AIDS prevention; Acquired Immunodeficiency Syndrome; Animal Model; Anti-HIV Agents; Anti-Retroviral Agents; CCR5 gene; Cells; Characteristics; Chemoprophylaxis; Clinical; Clinical Trials; Data; Development; Dose; Drug Design; Drug Exposure; Drug Kinetics; Drug effect disorder; Effectiveness; Epidemic; Evaluation; Frequencies; Goals; Grant; HIV; HIV Infections; HIV-1; Human; Incidence; Infection; Integrase Inhibitors; Knowledge; Lead; Licensing; Macaca; Measures; Modeling; Mus; Outcome; Pharmaceutical Preparations; Pharmacodynamics; Plasma; Preclinical Testing; Prevent viral transmission; Prevention; Prevention strategy; Prophylactic treatment; Protective Agents; Regimen; Risk; Route; Schedule; Sexual Transmission; Speed; Surrogate Markers; System; Tenofovir; Testing; Therapeutic Effect; Tissues; Vagina; Virus; base; clinical efficacy; combinatorial; design; drug distribution; drug efficacy; drug resistant virus; efficacy testing; emtricitabine; in vivo; inhibitor/antagonist; meetings; mouse model; next generation; novel; prevent; prophylactic; rectal; transmission process; viral RNA

DESCRIPTION (provided by applicant): An effective chemo pre-exposure prophylaxis (PrEP) strategy is predicted to prevent millions of new HIV infections. Intensifying preclinical testing with emphasis on compounds with proven clinical efficacy and combinatorial approaches to increase the breadth of protection and will greatly facilitate in meeting this challenge. While the macaque model has pioneered the anti-HIV PrEP concept and paved the way to the present ongoing clinical trials, a small animal model of HIV infection will speed-up the evaluation of potential PrEP compounds, combinations, doses, and dosing strategies. In this regard, the newly developed humanized mouse models that harbor human HIV target cells show great promise. We and others have recently achieved HIV-1 mucosal transmission via both vaginal and rectal routes in these models and have derived proof-of-concept data so that PrEP strategies can be efficiently tested in this system. A major knowledge gap in the PrEP field is pharmacokinetics and pharmacodynamics (PK/PD) for HIV prevention. Drug efficacy for HIV has usually been defined in small dose finding studies that measure surrogate markers such as plasma viral RNA to define therapeutic effects and establish the correct doses, combinations of doses, and dose frequencies. Surrogate markers of prophylactic effects have not been identified. This has led to the need for large and costly trials having HIV incidence as an outcome to test the efficacy of various HIV chemoprophylaxis regimens. In this regard, the humanized mouse model offers a tremendous advantage in that the dose finding studies can be conducted rapidly with HIV incidence outcomes to define PK/PD and inform rational doses, combinations, and dose frequencies for further PrEP studies. Drawing on expertise from two major labs (Kashuba lab on PK-PD and Akkina lab on humanized mice) a major goal in this proposal is to model PrEP strategies employing HIV itself as the challenge virus and derive important data for further testing in macaques and clinical development. Our specific aims for this three year grant period are to Aim 1. Determine the minimum daily dose of ARVs (CCR5 inhibitor maraviroc, integrase inhibitor raltegravir and RT inhibitors tenofovir and emtricitabine) required to confer complete protection against vaginal HIV-1 challenge. Aim 2. Define PK-PD parameters of the above ARVs by correlating PrEP efficacy with drug concentrations in plasma and vaginal tissues and develop a PK-PD model of drug exposure and prevention in mice. Aim 3. Evaluate combinatorial and intermittent dosing PrEP strategies employing ARVs with different modes of action. PUBLIC HEALTH RELEVANCE (provided by applicant): Chemo-prophylactic drugs that act against HIV and prevent viral transmission are expected to protect millions of at-risk people worldwide. Here we will systematically evaluate four anti-HIV drugs namely, maraviroc, raltegravir, tenofovir and FTC to determine their optimal drug exposure levels needed in plasma and vaginal tissue to confer full protection. These drugs with different modes of action will be tested in a novel humanized mouse model of HIV sexual transmission. In addition to determining their potential efficacy as prophylactics, we will also test their drug distribution in vivo. After determining their efficacy, we will identify the best dosing levels and schedules convenient for widespread use. In addition, we will evaluate if these drugs can be co-formulated with each other in different combinations to design a far superior protective drug regimen with broad spectrum effectiveness even against commonly encountered drug resistant viruses. If successful, these studies will lead to the development of a new potent HIV prevention strategy which is urgently needed to restrain the ongoing AIDS epidemic.

描述（由申请人提供）：预计有效的化疗暴露前预防（PrEP）策略可预防数百万新发HIV感染。加强临床前试验，重点是具有已证实临床疗效的化合物和组合方法，以增加保护的广度，并将大大有助于应对这一挑战。而 猕猴模型开创了抗HIV PrEP的概念，并为目前正在进行的临床试验铺平了道路，HIV感染的小动物模型将加快对潜在PrEP化合物、组合、剂量和给药策略的评估。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前景。我们和其他人最近在这些模型中通过阴道和直肠途径实现了HIV-1粘膜传播，并获得了概念验证数据，以便可以在该系统中有效地测试PrEP策略。PrEP领域的一个主要知识缺口是用于HIV预防的药代动力学和药效学（PK/PD）。HIV的药物疗效通常在小剂量发现研究中确定，这些研究测量替代标志物，如血浆病毒RNA，以确定治疗效果并确定正确的剂量、剂量组合和给药频率。尚未确定预防作用的替代标志物。这导致需要进行以艾滋病毒发病率为结果的大型和昂贵的试验，以测试各种艾滋病毒化学预防方案的功效。在这方面，人源化小鼠模型提供了巨大的优势，因为剂量探索研究可以快速进行，HIV发病率结果可以定义PK/PD，并为进一步的PrEP研究提供合理的剂量、组合和剂量频率。利用两个主要实验室（Kashuba实验室对PK-PD和Akkina实验室对人源化小鼠）的专业知识，该提案的主要目标是采用HIV本身作为挑战病毒来模拟PrEP策略，并为猕猴和临床开发的进一步测试获得重要数据。我们在这三年的资助期内的具体目标是目标1。确定抗逆转录病毒药物（CCR 5抑制剂马拉韦罗、整合酶抑制剂雷特格韦和RT抑制剂替诺福韦和恩曲他滨）的最低日剂量 需要提供针对阴道HIV-1攻击的完全保护。目标2.通过将PrEP疗效与血浆和阴道组织中的药物浓度相关联，定义上述ARV的PK-PD参数，并建立小鼠药物暴露和预防的PK-PD模型。目标3.评估采用不同作用模式的抗逆转录病毒药物的组合和间歇给药PrEP策略。 公共卫生相关性（由申请人提供）：对抗艾滋病毒和预防病毒传播的化学预防药物预计将保护全球数百万高危人群。在这里，我们将系统地评估四种抗HIV药物，即马拉韦罗，雷特格韦，替诺福韦和FTC，以确定其在血浆和阴道组织中提供全面保护所需的最佳药物暴露水平。这些具有不同作用模式的药物将在一种新型的HIV性传播人源化小鼠模型中进行测试。除了确定它们作为药物的潜在功效外，我们还将测试它们在体内的药物分布。 vivo.在确定其功效后，我们将确定便于广泛使用的最佳剂量水平和时间表。此外，我们将评估这些药物是否可以以不同的组合相互共配制，以设计具有广谱有效性的远优于上级保护性药物方案，即使是针对常见的耐药病毒。如果成功，这些研究将导致制定一项新的有效的艾滋病毒预防战略，这是遏制艾滋病流行的迫切需要。