Modeling Next Generation HIV PrEP in Humanized Mice

在人源化小鼠中模拟下一代 HIV PrEP

基本信息

批准号：
8662692
负责人：
Ramesh Akkina
金额：
$ 67.47万
依托单位：
COLORADO STATE UNIVERSITY
依托单位国家：
美国
项目类别：
财政年份：
2012
资助国家：
美国
起止时间：
2012-06-01 至 2017-12-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8662692
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

项目摘要

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.

描述（由申请人提供）：预测有效的化学预防预防（PREP）策略可以防止数百万个新的HIV感染。强化临床前测试，重点是具有可靠的临床功效和组合方法，以增加保护的广度，并将极大地促进应对这一挑战。而猕猴模型已经开创了抗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评估潜在的准备化合物，组合，剂量，剂量和给药策略。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。我们和其他人最近通过这些模型中的阴道和直肠途径实现了HIV-1粘膜传播，并获得了概念证明数据，因此可以在该系统中有效测试PREP策略。 PREP领域的主要知识差距是用于预防HIV的药代动力学和药效学（PK/PD）。通常在小剂量的研究研究中定义了HIV的药物疗效，该研究测量了替代标志物，例如等离子体病毒RNA，以定义治疗作用并建立正确的剂量，剂量组合和剂量频率。尚未确定预防作用的替代标记。这导致需要进行大型且昂贵的试验，该试验以HIV发病率为结果，以测试各种HIV化学预防治疗方案的功效。在这方面，人源化的小鼠模型具有巨大的优势，因为可以通过HIV发病率迅速进行剂量研究研究，以定义PK/PD并为进一步的PREP研究提供理性剂量，组合和剂量频率。利用两个主要实验室的专业知识（PK-PD上的Kashuba Lab和Akkina Lab on handizate小鼠）的一个主要目标是对采用HIV本身作为挑战病毒的PREP策略进行建模，并得出重要数据，以进一步测试猕猴和临床开发。我们在这三年赠款期间的具体目的是目标1。确定ARV的最低每日剂量（CCR5抑制剂maraviroc，Integrase抑制剂Raltegravir和RT抑制剂Tenofovir和Emtricitabine）要求完全保护阴道HIV-1挑战。 AIM 2。通过将PRES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，并在小鼠中开发出药物暴露和预防的PK-PD模型。目标3。评估使用具有不同作用模式的ARV的组合和间歇性给药准备策略。