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

尽管有抗逆转录病毒疗法（ART），但HIV-1继续造成相当大的医疗和经济负担，并且仍然迫切需要HIV-1治愈。该计划的目标是产生一个可以抵抗HIV-1感染的免疫系统，将病毒复制控制在检测限以下，并在没有ART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，正在输注100亿T细胞，这些T细胞已对HIV感染具有抵抗力，并可以识别感染的HIV通过嵌合抗原受体（CAR）感染HIV的人。该联盟的一个主要目标是开发改善这些T细胞的效应子功能、运输和持久性的策略。我们提案的要素是：1）工程改造具有改善功能和持久性的艾滋病毒特异性T细胞（项目1，John Wherry）。该项目将使用特征良好的动物模型来寻找增强T细胞功能和慢性感染持续性的因素或途径。2)在非人类灵长类动物中建模HIV CAR T细胞贩运和持久性（项目2，Hans-Peter Kiem，Chris Peterson和Mike Betts）。该项目旨在了解CAR T细胞如何在整个身体中运输，并探索如何改变这种运输以利于HIV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)在小鼠模型中模拟HIV治愈的联合免疫疗法（项目3，Jim Riley和托德艾伦）。在这里，我们将探讨多种免疫治疗方法如何协同促进T细胞控制HIV复制。4）临床试验引擎，以开发HIV治愈研究，以测试工程T细胞（项目4，Usman Azam，巴勃罗Tebas和Jim Hoxie）。该行业主导的项目将开发一种改进的工艺，从HIV感染者中制造工程化T细胞，然后采用项目1-3开发的最有前途的方法进行I期临床试验。该计划由2个核心支持：核心A是行政核心（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，以促进成本分摊，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.