Nonhuman Primate Core

核心C：项目摘要/摘要 造血干细胞和祖细胞移植是唯一已知的HIV-1病例的基础 功能性治愈。然而，在这一开创性的临床案例研究12年后，实质性的改善是 为了将这一案例研究应用于更广泛的艾滋病毒个人，需要开展这项研究。我们的首要目标是 U19联盟将确定候选策略，以安全有效地修改患者自己的HSPC以抵抗 同时增强他们识别和摧毁受感染细胞的能力。非人类 灵长类(NHP)核心将在组织各自提出的方法的临床前方面发挥核心作用 项目，将重点放在最适合未来试验的翻译相关功能上 在病人身上。在项目1(厨房)中，我们将生成一系列12个NHP，这些NHP与自体、 基因修饰的HSPC。这些细胞将表达一种有希望的病毒特异性免疫效应分子，称为 CD4CAR，结合其他有希望的治疗方法，如广谱中和抗体(BNAbs)，以及 治疗性疫苗接种。CD4CAR修饰的HSPC子代与bNAbs和疫苗特异性结合 细胞，代表了一种针对病毒持久性的强大和协同的方法。在项目2(Morizono)中，我们 将专注于在不将HSPC从体内移除的情况下对其进行基因修饰的方法，总共研究了9个 NHP。所谓的“体内递送”方法将显著提高抗HIV基因的适用性 为世界各地的患者提供治疗。在项目3(AN)中，我们将在总共6个NHP中测试另一个重要方面： 精确调控基因修饰的HSPC及其后代体外和体内水平的能力。每个人 NHP核心项目的具体功能的评估将着眼于临床，并进行密切磋商 与我们在项目4(西蒙兹)中的长期合作伙伴。国家核电计划核心提出的目标是实施 上述每一项NHP研究都使用有效的慢病毒生产基因修饰的NHP HSPC产品 载体，并在每个项目中为动物提供支持性护理，包括HSPC基因治疗和 感染类似艾滋病毒的病毒。我们联合体中的四个项目都具有很强的互补性。我们会 在每个项目监督的大型动物研究之间架起桥梁，对关于协同效应的讨论做出有意义的贡献 在项目之间进行评估，并在新出现的有前景的疗法出现时对其进行评估。

Core C: Project Summary/Abstract Transplantation of hematopoietic stem and progenitor cells (HSPCs) underlies the only known case of HIV-1 functional cure. Over 12 years after this pioneering clinical case study, however, substantial improvements are needed in order to apply this case study to a broader spectrum of HIV+ individuals. The overarching goal of our U19 consortium is to identify candidate strategies to safely and effectively modify a patient's own HSPCs to resist HIV infection, and simultaneously enhance their ability to recognize and destroy infected cells. The Nonhuman Primate (NHP) Core will play a central role in organizing preclinical aspects of the approaches proposed by each project in our group, maintaining a focus on translationally relevant features that are best suited for future trials in patients. In Project 1 (Kitchen), we will generate a series of 12 NHPs that are transplanted with autologous, gene-modified HSPCs. These cells will express a promising virus-specific immune effector molecule known as CD4CAR, in combination with other promising therapies such as broadly neutralizing antibodies (bNAbs), and therapeutic vaccination. CD4CAR-modified HSPC progeny, in combination with bNAbs and vaccine-specific cells, represent a formidable and synergistic approach to target virus persistence. In Project 2 (Morizono), we will focus on approaches to gene-modify HSPCs without removing them from the body, studying a total of 9 NHP. So-called “in vivo delivery” approaches will significantly enhance the applicability of anti-HIV gene therapies to patients around the world. In Project 3 (An), we will test another important aspect in a total of 6 NHP: the ability to precisely regulate the levels of gene-modified HSPCs and their progeny ex vivo and in vivo. Each of the NHP Core's project-specific functions will be assessed with an eye towards the clinic, in close consultation with our longstanding partners in Project 4 (Symonds). The goals set forth by the NHP Core are to implement each of the NHP studies described above, produce gene-modified NHP HSPC products using potent lentiviral vectors, and to provide supportive care for animals in each project, both following HSPC gene therapy and infection with HIV-like viruses. Each of the four projects in our consortium are highly complementary. We will bridge large animal studies overseen by each project, contribute meaningfully to discussions regarding synergies between projects, and evaluate new and promising therapies as they emerge.