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

项目1 -摘要 慢性感染，如乙型肝炎病毒、丙型肝炎病毒、艾滋病毒、结核病、疟疾等，是发病和死亡的主要原因。 药理学和免疫学治疗的最新进展揭示了治愈的新机会 一些持续感染一个病人，蒂莫西·布朗，用骨髓（BM）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 这些方法的可行性得到了证实，但没有治愈。然而，催化的部分原因是 这些在艾滋病毒中的初步观察和癌症免疫治疗的进展，现在有相当大的努力， 专注于艾滋病毒的过继细胞疗法（ACT）。尽管ACT在某些癌症中取得了重大成功， 成功治疗癌症，特别是艾滋病毒的主要障碍是T细胞耗竭。事实上，当CAR-T细胞在 对于癌症患者，T细胞耗竭是一种主要的潜在机制7 -9，T细胞耗竭是免疫应答的核心。 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细胞活化的分子途径。 可以靶向T细胞耗竭以改善T细胞在细胞增殖期间的功能和/或耐久性。 治疗慢性病毒感染。我们的目标是确定T细胞耗竭的机制， 提高抗艾滋病毒青蒿素综合疗法的功能和持久性。我们将首先在慢性病毒感染的小鼠模型中测试这些想法。 感染，然后将有希望的候选人在HIV感染的人源化小鼠中进行测试，同时还解剖 潜在的分子机制。我们将测试整体假设，分子途径相关 随着T细胞的耗竭，可以通过基因工程有效地针对性地提高下 制定艾滋病毒的ACT方法。我们将通过以下目标来检验这一假设： SA 1.在体内识别和检测改善功能和/或归巢的关键基因和途径 T细胞在慢性病毒感染和艾滋病病毒的行为。我们假设调节 可以靶向效应子功能和/或归巢以改善慢性病毒感染的ACT期间的T细胞功效。 SA 2.为了识别和测试体内基因和途径，将提高长期耐久性， 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细胞耗竭中有缺陷特异性持久性和/或记忆相关途径 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， SA 2是识别和靶向改善最佳长期持久性，分化和回忆的途径 慢性病毒感染的ACT中T细胞的能力。 项目1的长期目标是改善下一代CAR T细胞疗法。研究 提出的建议不仅将确定艾滋病毒ACT的重要新目标并剖析潜在机制，而且将 还为未来改善基于预防或逆转T细胞的细胞疗法的努力建立了平台。 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.