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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：
8478040
负责人：
Ramesh Akkina
金额：
$ 63.41万
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 2015-05-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8478040
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）：一种有效的化疗暴露前预防（PrEP）策略预计可以预防数百万新的艾滋病毒感染。加强临床前测试，重点是具有临床疗效的化合物和组合方法，以增加保护的广度，并将极大地促进应对这一挑战。而