Delaney AIDS Research Enterprise to Cure HIV

项目摘要/摘要 DARE合作实验室的任务是利用适应性免疫系统的力量来减少 在抗逆转录病毒治疗(ART)期间的储存库大小以及在ART后控制任何残留病毒的方法是 被打断了。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力。 持久且有效的响应。此外，这些回应需要在正确的地方、正确的地方 时间到了。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 假定的免疫特权避难所，使SIV/HIV能够在ART期间持续存在，并使用猴子模型 开发突破这些避难所的治疗方法(初始研究焦点1，IRF1)。我们将描述 ART抑制的成人淋巴组织中复制能力病毒的分布及PET的发展 成像方式来量化这个储集层(IRF2)。我们将定义免疫检查点(PD-1， 以及它们对猴子和人类T细胞功能的阻断(IRF3)。最后，我们将定义安全性， 人巨细胞病毒(HCMV)载体HIV疫苗在HIV感染者中的免疫原性和抗HIV效果 成人接受抗逆转录病毒治疗(IRF4)。所有四个最初的研究重点都通过他们的共同目标联系在一起，以了解如何最好地 量化、减少和控制人类淋巴系统中的艾滋病毒。我们预计将满足以下要求 里程碑和交付成果：(1)来自SIV的淋巴组织中复制能力储存库的定义- 被感染的猴子和HIV感染的人抑制ART，(2)B卵泡是否起作用的确定 作为感染的CD4TFH的免疫学避难所，如果是的话，B卵泡衰竭是否会减少 (3)病毒特异性CD8 T细胞反应特性的测定 用于储集物减少和/或术后病毒控制的活性，(4)确定组织储存物是否可以 通过放射性标记示踪剂和PET扫描进行测量，(5)确定免疫的最佳组合 增强T细胞功能和/或逆转HIV潜伏期的检查点阻滞剂，(6)安全性和 免疫检查点阻滞剂在治疗SIV和HIV疾病中的免疫原性(7)安全性测定 和巨细胞病毒/HIV疫苗在治疗HIV疾病中的免疫原性，以及(8)确定B细胞是否被破坏 和/或免疫检查点封锁对于该疫苗(或其他类似干预措施)可能是必要的 实现水库减少和/或持久缓解。我们的工作将为未来的概念验证奠定基础 人巨细胞病毒/HIV载体单独或联合B组抗逆转录病毒治疗的临床试验 细胞卵泡破裂和/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.