CCR5 Targeting to Control HIV/SHIV to Nonhuman Primates

CCR5 旨在控制非人类灵长类动物的 HIV/SHIV

• 批准号: 8202337
• 负责人: HANS-PETER KIEM
• 金额: $ 27.68万
• 依托单位: FRED HUTCHINSON CANCER RESEARCH CENTER
• 依托单位国家: 美国
• 财政年份: 2011
• 资助国家: 美国
• 起止时间: 2011-07-08 至 2016-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8202337
• 关键词: AIDS therapy; AIDS/HIV problem; Acquired Immunodeficiency Syndrome; Address; Adenovirus Vector; Alternative Therapies; Animal Model; Animals; Anti-Retroviral Agents; Antiviral Therapy; Biological Models; CCR5 gene; CD34 gene; Cell Transplants; Cells; Code; Communities; Complement; DNA; Data; Disease Progression; Effectiveness; Engraftment; Gene-Modified; Genetic; Goals; HIV; HIV Infections; HIV therapy; Hematopoietic; Hematopoietic stem cells; Highly Active Antiretroviral Therapy; Human; Infection; Infection prevention; Knock-in Mouse; Lentivirus Vector; Macaca; Macaca nemestrina; Methods; Modeling; Modification; Monkeys; Morbidity - disease rate; Mus; Pathogenesis; Patients; Reagent; Reporting; Resistance; Severity of illness; Site-Directed Mutagenesis; Source; Study models; System; Testing; Toxic effect; Transplantation; Vaccines; Variant; Viral; Zinc Fingers; clinical application; clinically relevant; genetic manipulation; in vivo; mortality; mouse model; nonhuman primate; novel; nuclease; receptor; reconstitution; simian human immunodeficiency virus

The goal of this project is to evaluate strategies to eliminate HIV and latent reservoirs in a monkey model of HIV/SHIV infection. Recent promising vaccine trials have failed to protect from HIV, emphasizing the importance of developing alternative therapies. One such alternative therapy is the genetic modification of hematopoietic cells to make them resistant to HIV infection. Genetic modification of hematopoietic stem cells (HSCs) with zinc finger nucleases targeting the CCR5 gene loci have been shown to reduce the severity of disease in an HIV mouse model system. Thus, we propose a study aimed at determining the potential clinical application of a gene modifying approach targeting CCR5 as an antiviral therapy with the overall goal being the eradication of the viral reservoir in HIV[+] patients. We will study the effect of CCR5[-/-] repopulating cells on the latent reservoir using a clinically relevant nonhuman primate AIDS model, the pigtailed macaque (M. nemestrina). This model will allow us to carefully and thoroughly analyze the impact of CCR5[-/-] hematopoietic reconstitution on the control of HIV/SHIV. Here we will address several crucial questions regarding the feasibility and translatability of this approach. We will evaluate methods to efficiently modify HSCs in a large animal model, determine the engraftment potential of ZFN-modified HSCs and the level of ZFN-modified repopulating cells necessary for efficient control of HIV. Given the high clinical relevance of the SHIV macaque model, these studies should be readily translatable to the understanding of latency in HIV/AIDS patients. This project complements and interacts closely with the other projects and cores. Specifically, data from Project 1 will serve as a baseline for the latent reservoir in monkeys, Project 2 will provide and develop novel reagents. Project 4 will develop anti HIV strategies that can be incorporated into the monkey studies and Project 5 will develop novel delivery approaches which can also be tested in monkeys. This project will make use of all the cores. We propose the following four aims: 1) Determine the optimal approach for genetically modifying hematopoietic stem cells with zinc finger nucleases. 2) Determine the engraftment potential of ZFN-modified CCR5[-/-] repopulating cells in macaques. 3) Establish means to efficiently and safely increase the percentage of CCR5-modified cells. 4) Determine if transplantation with CCR5[-/-] CD34[+] cells can prevent infection and provide long-term control.

该项目的目标是评估在猴子模型中消除艾滋病毒和潜伏病毒库的策略。 HIV/SHIV 感染。最近有希望的疫苗试验未能预防艾滋病毒，这强调了 开发替代疗法的重要性。其中一种替代疗法是基因改造 造血细胞，使其抵抗艾滋病毒感染。造血干细胞的基因改造 具有针对 CCR5 基因位点的锌指核酸酶的 (HSC) 已被证明可以减轻 HIV小鼠模型系统中的疾病。因此，我们提出一项旨在确定潜力的研究 以 CCR5 为靶点的基因修饰方法作为抗病毒治疗的临床应用，总体目标 消除 HIV[+] 患者体内的病毒库。我们将研究 CCR5[-/-] 重新填充的效果 使用临床相关的非人类灵长类艾滋病模型（猪尾猕猴）对潜伏病毒库上的细胞进行研究 （M. nemestrina）。该模型将使我们能够仔细、彻底地分析 CCR5 的影响[-/-] 造血重建对 HIV/SHIV 控制的影响。在这里我们将解决几个关键问题 关于该方法的可行性和可移植性。我们将评估有效修改的方法 大型动物模型中的 HSC，确定 ZFN 修饰的 HSC 的植入潜力以及 ZFN 修饰的再生细胞是有效控制 HIV 所必需的。鉴于该研究的高度临床相关性 SHIV 猕猴模型，这些研究应该很容易转化为对潜伏期的理解 艾滋病毒/艾滋病患者。 该项目与其他项目和核心互补并密切互动。具体来说，数据来自 项目 1 将作为猴子潜在储存库的基线，项目 2 将提供和开发新的 试剂。项目 4 将开发可纳入猴子研究的抗 HIV 策略 项目 5 将开发新颖的递送方法，也可以在猴子身上进行测试。该项目将使 使用所有核心。 我们提出以下四个目标：1）确定基因改造的最佳方法 具有锌指核酸酶的造血干细胞。 2) 确定ZFN修饰的植入潜力 CCR5[-/-] 在猕猴中重新填充细胞。 3) 建立有效、安全地提高百分比的方法 CCR5 修饰的细胞。 4) 确定移植CCR5[-/-] CD34[+]细胞是否可以预防感染和 提供长期控制。