Delaney AIDS Research Enterprise to Cure HIV

项目概要/摘要 DARE合作实验室的使命是利用适应性免疫系统的力量， 在抗逆转录病毒治疗（ART）过程中的水库的大小，并控制任何残留的病毒后， 打断我们的总体假设是，艾滋病毒感染的持久缓解需要强大的免疫系统， 反应是持久的和功能。此外，这些反应需要在正确的位置， 时间我们提出了四个高度相关的研究重点，旨在实现这些目标。我们将定义 假定的免疫特权庇护所，使SIV/HIV在ART期间持续存在，并使用猴模型 开发突破这些庇护所的疗法（初始研究焦点1，IRF 1）。我们将描述 ART抑制成人淋巴组织中复制能力病毒的分布并发展PET 成像模式来量化该储库（IRF 2）。我们将定义免疫检查点（PD-1， 其他人）及其对猴子和人的T细胞功能的阻断（IRF 3）。最后，我们将定义安全性， 人巨细胞病毒（HCMV）载体HIV疫苗在HIV感染者中免疫原性和抗HIV有效性 成人ART（IRF 4）。所有这四个最初的研究重点都是由他们的共同目标联系在一起的，即了解如何最好地 量化、减少和控制人类淋巴系统中的HIV。我们预计将举行以下会议： 里程碑和可交付成果：（1）定义SIV淋巴组织中的复制能力储库- 感染的猴子和HIV感染的人进行抑制性ART，（2）确定B卵泡是否 作为感染的CD 4 + TFH的免疫保护区，如果是这样，是否B滤泡耗竭减少了 （3）确定具有最佳免疫应答的病毒特异性CD 8 + T细胞应答的特征， 用于储库减少和/或ART后病毒控制的活性，（4）确定组织储库是否可以被 通过放射性示踪剂和PET扫描测量，（5）确定免疫的最佳组合， 增强T细胞功能和/或逆转HIV潜伏期的检查点阻断剂，（6）安全性的定义， 免疫检查点阻断剂在治疗的SIV和HIV疾病中的免疫原性，（7）安全性测定 HCMV/HIV疫苗在治疗的HIV疾病中的免疫原性，和（8）确定B细胞破坏 和/或免疫检查点阻断可能是这种疫苗（或其他类似干预）所必需的， 实现储库减少和/或持久缓解。我们的工作将为未来的概念验证奠定基础 HCMV/HIV载体在单独或与B联合抗逆转录病毒治疗个体中的临床试验 细胞卵泡破坏和/或免疫检查点阻断。

PROJECT SUMMARY/ABSTRACT The mission of the DARE Collaboratory is to harness the power of the adaptive immune system to reduce the size of the reservoir during antiretroviral therapy (ART) and to control any residual virus after ART is interrupted. Our overall hypothesis is that that durable remission of HIV infection will require a robust immune response that is persistent and functional. Moreover, these responses need to be in the right place at the right time. We propose four highly linked research foci aimed at reaching these goals. We will define the role of putative immune-privileged sanctuaries that enable SIV/HIV to persist during ART and use the monkey model to develop therapies to breach these sanctuaries (Initial Research Foci 1, IRF1). We will characterize the distribution on replication-competent virus in lymphoid tissues of ART-suppressed adults and develop PET imaging modalities to quantify this reservoir (IRF2). We will define the role of immune checkpoints (PD-1, others) and their blockade on T cell function in monkeys and people (IRF3). Finally, we will define the safety, immunogenicity, and anti-HIV effectiveness of a human CMV (HCMV) vectored HIV vaccine in HIV-infected adults on ART (IRF4). All four initial research foci are linked by their shared goal to understand how best to quantify, reduce, and control HIV in the human lymphoid system. We anticipate meeting the following milestones and deliverables: (1) definition of the replication-competent reservoir in lymphoid tissues from SIV- infected monkeys and HIV-infected humans on suppressive ART, (2) determination of whether B follicles serve as a immunologic sanctuary for infected CD4+ TFH and, if so, whether B follicular depletion reduces the size of the reservoir, (3) determination of the characteristics of virus-specific CD8+ T cell responses that have optimal activity for reservoir reduction and/or post-ART viral control, (4) determination if the tissue reservoir can be measured by radiolabeled tracers and PET scanning, (5) identification of the optimal combination of immune checkpoint blockers that enhance T-cell function and/or reverse HIV latency, (6) definition of the safety and immunogenicity of immune checkpoint blockers in treated SIV and HIV disease, (7) determination of the safety and immunogenicity of the HCMV/HIV vaccine in treated HIV disease, and (8) determination if B cell disruption and/or immune checkpoint blockade might be necessary for this vaccine (or other comparable interventions) to achieve reservoir reduction and/or durable remission. Our work will set the stage for a future proof-of-concept clinical trial of the HCMV/HIV vector in antiretroviral-treated individuals, either alone or in combination with B cell follicle disruption and/or immune checkpoint blockade.