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的 HIV 感染。加强临床前测试，重点关注具有经过验证的临床功效的化合物和组合方法，以扩大保护范围，并将极大地促进应对这一挑战。虽然 猕猴模型开创了抗 HIV PrEP 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，新开发的携带人类艾滋病毒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实现了 HIV-1 通过阴道和直肠途径的粘膜传播，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 HIV 预防的药代动力学和药效学 (PK/PD)。 HIV 药物疗效通常在小剂量探索研究中定义，这些研究测量血浆病毒 RNA 等替代标记物，以定义治疗效果并确定正确的剂量、剂量组合和剂量频率。预防作用的替代标记尚未确定。这导致需要进行大规模且昂贵的试验，以艾滋病毒发病率作为结果，以测试各种艾滋病毒化学预防方案的功效。在这方面，人源化小鼠模型具有巨大的优势，因为可以根据 HIV 发病结果快速进行剂量探索研究，以确定 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。借鉴两个主要实验室（PK-PD 的 Kashuba 实验室和人源化小鼠的 Akkina 实验室）的专业知识，该提案的主要目标是对使用 HIV 本身作为攻击病毒的 PrEP 策略进行建模，并获取重要数据以用于在猕猴和临床上进行进一步测试发展。我们在这三年资助期内的具体目标是目标 1：确定 ARV 的最低日剂量（CCR5 抑制剂马拉韦罗、整合酶抑制剂拉替拉韦和 RT 抑制剂替诺福韦和恩曲他滨） 需要提供针对阴道 HIV-1 攻击的完全保护。目标 2. 通过将 PrEP 功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 ARV 的组合和间歇给药 PrEP 策略。 公共卫生相关性（由申请人提供）：针对 HIV 并预防病毒传播的化学预防药物预计将保护全世界数百万高危人群。在这里，我们将系统地评估四种抗HIV药物，即马拉韦罗、拉替拉韦、替诺福韦和FTC，以确定其在血浆和阴道组织中提供充分保护所需的最佳药物暴露水平。这些具有不同作用方式的药物将在新型人源化小鼠艾滋病毒性传播模型中进行测试。除了确定它们作为预防剂的潜在功效外，我们还将测试它们的药物分布 体内。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共同配制，以设计出一种更优越的保护性药物方案，即使针对常见的耐药病毒，也具有广谱效力。如果成功，这些研究将导致制定一种新的有效的艾滋病毒预防策略，这是遏制艾滋病流行所迫切需要的。