Engineering T cells to Provide Durable Control of HIV-1 Replication

尽管有抗逆转录病毒疗法(ART)，但艾滋病毒-1继续造成相当大的医疗和经济负担，仍然迫切需要治愈艾滋病毒-1。该计划的目标是产生一种免疫系统，能够抵抗艾滋病毒-1感染，将病毒复制控制在检测极限以下，并在没有抗逆转录病毒治疗的情况下保持高功能能力。我们目前正在进行一项I期临床试验，将100亿个对艾滋病毒感染产生抵抗力的T细胞注入艾滋病毒感染者体内，这些T细胞可以识别通过嵌合抗原受体(CAR)感染的艾滋病毒。该联盟的一个主要目标是制定策略，改善这些T细胞的效应器功能、运输和持久性。我们建议的要素是：1)设计具有改善功能和持久性的HIV特异性T细胞(项目1，John Wherry)。该项目将使用具有良好特性的动物模型来寻找增强T细胞功能和对慢性感染的持久性的因素或途径。2)在非人类灵长类动物中模拟HIV-CAR T细胞的贩运和持久性(项目2，Hans-Peter Kiem，Chris Peterson和Mike Betts)。这个项目试图了解CAR T细胞是如何在体内运输的，并探索如何改变这种贩运以有利于艾滋病毒的清除。此外，还探索了HIV CAR T细胞成为组织驻留记忆T细胞的能力。3)建立联合免疫疗法治愈艾滋病毒的小鼠模型(项目3，Jim Riley和Todd Allen)。在这里，我们将探索各种免疫治疗方法如何协同作用，以促进T细胞对艾滋病毒复制的控制。4)临床试验引擎开发艾滋病毒治愈研究，以测试工程T细胞(项目4，Usman Azam，Pablo Tebas和Jim Hoxie)。这个行业主导的项目将开发一种改进的工艺，从艾滋病毒感染者中制造工程T细胞，然后采用项目1-3开发的最有希望的方法来进行I期临床试验。该计划由两个核心支持：核心A是管理核心(PI，Jim Riley)；核心B是基因组工程核心(PI，Rick Bushman)。此外，我们的计划利用现有的医学院和CFAR核心，促进成本分担，避免资源重复。

Despite anti-retroviral therapies (ART), HIV-1 continues to cause a considerable medical and economic burden, and there continues to be a pressing need for an HIV-1 cure. The goal of this Program is to generate an immune system that can resist HIV-1 infection, control viral replication below the limit of detection and persist at high functional competency in the absence of ART. We are currently performing a Phase I clinical trial that is infusing 10 billion T cells that have been made resistant to HIV infection and can recognize HIV infected via a chimeric antigen receptor (CAR) into HIV infected individuals. A major goal of this consortium to develop strategies that improve the effector function, trafficking and persistence of these T cells. The elements of our proposal are: 1) Engineering HIV-specific T cells that have improved function and persistence (Project 1, John Wherry). This project will use well-characterized animal models to search for factors or pathways that augment T cell function and persistence to chronic infection. 2) Modeling HIV CAR T cell trafficking and persistence in Non-Human Primates (Project 2, Hans-Peter Kiem, Chris Peterson and Mike Betts). This project seeks to understand how CAR T cells traffic throughout the body and explores ways to alter this trafficking to favor HIV clearance. Additionally, the ability of HIV CAR T cells to become tissue resident memory T cells is explored. 3) Modeling combination immunotherapy for HIV Cure in a mouse models (Project 3, Jim Riley and Todd Allen). Here, we will explore how a wide array of immunotherapy approaches synergize to promote T cell control of HIV replication.4) Clinical trials engine to develop an HIV Cure study to test engineered T cells (Project 4, Usman Azam, Pablo Tebas and Jim Hoxie). This industry led project will develop an improved process to manufacture engineered T cells from HIV infected individuals and then take the most promising approaches developed by Projects 1-3 to conduct a Phase I clinical trial. The Program is supported by 2 Cores: Core A is the administrative Core (PI, Jim Riley); Core B is the Genome Engineering Core (PI, Rick Bushman). In addition, our Program takes advantage of existing School of Medicine and CFAR Cores to promote cost sharing and avoid duplication of resources.