Programming Long Term Durable HIV-1 Specific T cell Responses

许多慢性病毒感染导致T细胞耗竭。T细胞功能差与未能控制 HIV感染和T细胞免疫的崩溃是艾滋病的先兆。目前的抗逆转录病毒疗法（ART）可以包含 艾滋病毒，但未能完全根除病毒。因此，实现艾滋病毒的真正治愈仍然是一个最重要的目标。2008年， 蒂莫西·布朗通过骨髓移植有效地治愈了艾滋病毒感染。供体BM CCR 5中的Δ32突变可预防HIV感染。随后的有希望的试验，虽然未能 实现真正的治愈，推动改善，并了解这种艾滋病毒控制的机制，使用T 细胞被改造以抵抗感染。因此，这种U19的主要原理是测试改进的趋化因子受体- 基于HIV进入拮抗剂的人类工程T细胞。具体地，将HR 2 C34肽融合至 CXCR 4是一种非常有效的HIV进入抑制剂，与以前的方法相比，它在低摩尔浓度下起作用。 抑制CXCR 4和CCR 5介导的HIV感染。适应性免疫可能是至关重要的， 甚至使用抗感染ACT治疗HIV的有效性和可持续性。因此，这个问题的核心 该项目旨在确定CD 4 T细胞应答的功能障碍或“耗竭”如何受到或能够 在ACT期间预防。T细胞耗竭是包括HIV在内的许多慢性感染的共同特征 并且通过不良的效应器功能、抑制性受体的持续和升高的表达以及 改变的转录程序因此，一个主要的问题是， 在ACT期间，CD 4 T细胞被耗尽。因此，我们将检验分子途径 与减少的耗竭和有效的CD 4 T细胞应答相关， ACT治疗艾滋病毒，这些途径可以作为下一步合理改善的基础。 一代ACT方法。为了验证这一假设，我们提出以下目标： SA 1：确定与持续存在的功能性病毒特异性CD 4 T相关的分子途径 慢性病毒感染期间的细胞。我们假设，具有强效抗病毒作用的病毒特异性CD 4 T细胞 功能，帮助活动和长期持久性可以从那些被耗尽， 艾滋病毒治愈后无法提供保护。 SA 2：确定ACT治疗HIV后工程化CD 4 T细胞的转录程序。在这里， 我们将检验C34：CXCR 4修饰的CD 4 T细胞在ACT中不会因HIV而耗竭的假设。 SA 3：直接测试工程化CD 4 T细胞以抵抗耗竭是否可以增强病毒特异性免疫应答。 慢性感染期间的CD 4 T细胞反应。我们将测试特定的汽车可以提供 增强慢性病毒感染期间病毒特异性CD 4 T细胞应答的功能和/或持久性的信号 感染

Many chronic viral infections result in T cell exhaustion. Poor T cell function is associated with failure to contain HIV infection and collapse of T cell immunity precedes AIDS. Current antiretroviral therapies (ART) can contain HIV, but fail to fully eradicate the virus. Thus, achieving true cure of HIV remains a paramount goal. In 2008, Timothy Brown was effectively cured of HIV infection using a bone marrow (BM) transplant. The donor BM contained the Δ32 mutation in CCR5 preventing HIV infection. Subsequent promising trials, while failing to achieve true cure, give impetus to improve upon, and understand the mechanisms of this HIV control using T cells engineered to resist infection. Thus, the main principle of this U19 is to test improved chemokine receptor- based HIV entry antagonists in engineered T cells in humans. Specifically, the HR2 C34 peptide fused to CXCR4 is a highly effective inhibitor of HIV entry that, in contrast to previous approaches, works at low molar ratios to inhibit HIV infection mediated by both CXCR4 and CCR5. Adaptive immunity is likely essential to the efficacy and sustainability of HIV cure even using infection resistant ACT. Thus, the central question of this project is to determine how dysfunction or “exhaustion” of CD4 T cell responses is impacted by or can be prevented during ACT. T cell exhaustion is a common feature of many chronic infections including HIV and is defined by poor effector function, sustained and elevated expression of inhibitory receptors and an altered transcriptional program. A major question, therefore, is to what extent engineered, infection-resistant CD4 T cells become exhausted during ACT. Thus, we will test the hypothesis that molecular pathways associated with reduced exhaustion and effective CD4 T cell responses can be identified, monitored in ACT for HIV cure and that these pathways can serve as the foundation for rational improvement of next generation ACT approaches. To test this hypothesis, we propose the following Aims: SA1: To define the molecular pathways associated with persisting, functional virus-specific CD4 T cells during chronic viral infection. We hypothesize that virus-specific CD4 T cells with potent antiviral function, help activity and long-term persistence can be distinguished from those that are exhausted and unable to provide protection following HIV cure. SA2: To define the transcriptional program of engineered CD4 T cells following ACT for HIV cure. Here, we will test the hypothesis that C34:CXCR4 modified CD4 T cells will not undergo exhaustion in ACT for HIV. SA3: To directly test whether engineering CD4 T cells to resist exhaustion can enhance virus-specific CD4 T cell responses during chronic infection. We will test the hypothesis that specific CARs can deliver signals that enhance function and/or persistence of virus-specific CD4 T cell responses during chronic infection.