Engineering HIV-specific T cells that have improved function and persistence

项目1-摘要 慢性感染，如乙肝病毒、丙型肝炎病毒、艾滋病毒、结核病、疟疾和其他，是发病率和死亡率的主要原因。 药物和免疫治疗的最新进展揭示了治愈的新机会 其中一些持续性感染。一位名叫蒂莫西·布朗的患者用骨髓治愈了艾滋病毒。 2008年的移植证明了治愈艾滋病毒是可能的。随后使用细胞疗法的试验 证明了这种方法的可行性，但没有实现任何治疗方法。然而，部分催化作用是由 这些对艾滋病毒的初步观察和癌症免疫治疗的进展，现在已经有了相当大的努力 专注于艾滋病毒的过继细胞疗法(ACT)。尽管ACT在治疗某些形式的癌症方面取得了重大成功，但 癌症成功的主要障碍是T细胞耗尽，尤其是艾滋病毒。事实上，当CAR T细胞在 癌症患者，T细胞耗竭是一种主要的潜在机制7-9，T细胞耗尽是免疫的中心 艾滋病毒控制失败11，12，64。因此，项目1的中心目标是确定T细胞的分子途径 可靶向改善T细胞在细胞周期中的功能和/或耐久性的衰竭 慢性病毒感染的治疗。我们的目标是确定T细胞耗尽的机制，这是可以针对的 提高抗HIV药物ACT的功能和耐受性。我们将首先在慢性病毒感染的小鼠模型上测试这些想法 然后将有希望的候选者转移到感染艾滋病毒的人源化小鼠身上进行测试，同时还解剖 潜在的分子机制。我们将测试整个假设，分子途径与 随着T细胞的耗竭，可以有效地通过基因工程来改善下一步 针对艾滋病毒的ACT方法的产生。我们将通过以下目标来检验这一假设： SA1.在体内识别和测试将改善功能和/或归巢的关键基因和途径 在慢性病毒感染和HIV感染的过程中T细胞的变化。我们假设调控的通路 在慢性病毒感染的ACT治疗中，可以针对效应器功能和/或归巢来提高T细胞的疗效。 SA2.为了识别和测试体内将提高长期耐久性的基因和途径， 慢性病毒感染和HIV感染时T细胞对ACT的分化和回忆能力。我们 假设在T细胞耗竭过程中有缺陷的特定持久性和/或记忆相关通路 可以有针对性地提高ACT在慢性病毒感染中的持久性和有效性。因此，目标是 SA2是识别和定位改善最佳长期持久性、差异性和回忆的途径 慢性病毒感染患者外周血中T细胞的功能 项目1的长期目标是改进针对艾滋病毒的下一代CAR T细胞疗法。这些研究 提议不仅将为艾滋病毒的ACT确定重要的新目标并剖析潜在的机制，而且将 也为基于预防或逆转T细胞的改进细胞疗法的未来努力建立一个平台 疲惫不堪。

Project 1 - Abstract Chronic infections, such as HBV, HCV, HIV, Tb, malaria and others, are major causes of morbidity and mortality. Recent advances in pharmacological and immunological treatments have revealed new opportunities to cure some of these persisting infections. A single patient, Timothy Brown, cured of HIV using a bone marrow (BM) transplant in 2008 is proof of concept that cure for HIV is possible. Subsequent trials using cellular therapies demonstrated feasibility of such approaches, but no cures were achieved. Nevertheless, catalyzed in part by these initial observations in HIV and by progress in immunotherapy of cancer, there are now considerable efforts focused on adoptive cell therapies (ACT) for HIV. Despite major successes of ACT for some forms of cancer, a major barrier to success for cancers and especially for HIV is T cell exhaustion. Indeed, when CAR T cells fail in cancer patients, T cell exhaustion is a major underlying mechanism7-9 and T cell exhaustion is central to immune failures in HIV control11,12,64. Thus, the central goal of Project 1 is to identify molecular pathways of T cell exhaustion that can be targeted to improve the function and/or durability of T cells during cellular therapy of chronic viral infection. Our goal is to identify mechanisms of T cell exhaustion that can be targeted to improve function and durability of ACT for HIV. We will first test these ideas in a mouse model of chronic viral infection and then move promising candidates to testing in HIV infected humanized mice while also dissecting underlying molecular mechanisms. We will test the overall hypothesis that molecular pathways associated with T cell exhaustion can be effectively targeted through genetic engineering to improve the next generation of ACT approaches for HIV. We will test this hypothesis through the following Aims: SA1. TO IDENTIFY AND TEST IN VIVO KEY GENES AND PATHWAYS THAT WILL IMPROVE THE FUNCTION AND/OR HOMING OF T CELLS DURING ACT OF CHRONIC VIRAL INFECTION AND HIV. We hypothesize that pathways that regulate effector function and/or homing can be targeted to improve T cell efficacy during ACT of chronic viral infection. SA2. TO IDENTIFY AND TEST IN VIVO GENES AND PATHWAYS THAT WILL IMPROVE LONG-TERM DURABILITY, DIFFERENTIATION AND RECALL CAPACITY OF T CELLS FOR ACT DURING CHRONIC VIRAL INFECTION AND HIV. We hypothesize that specific persistence and/or memory related pathways that are defective in T cell exhaustion can be targeted to improve the durability and effectiveness of ACT in chronic viral infection. Thus, the goal of SA2 is to identify and target pathways that improve the optimal long-term persistence, differentiation and recall capacity of T cells in ACT of chronic viral infection. The long-term goal of Project 1 is to improve the next generation of CAR T cell therapies for HIV. The studies proposed will not only identify important new targets for ACT of HIV and dissect underlying mechanisms, but will also establish a platform for future efforts at improving cellular therapies based on preventing or reversing T cell exhaustion.