Delaney AIDS Research Enterprise to Cure HIV

德莱尼艾滋病研究企业治愈艾滋病毒

• 批准号: 9190154
• 负责人: STEVEN Grant DEEKS
• 金额: $ 554.71万
• 依托单位: UNIVERSITY OF CALIFORNIA, SAN FRANCISCO
• 依托单位国家: 美国
• 财政年份: 2016
• 资助国家: 美国
• 起止时间: 2016-07-14 至 2021-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9190154
• 关键词: Acquired Immunodeficiency Syndrome; Adult; Affect; Anti-Retroviral Agents; B-Lymphocytes; CD8B1 gene; Cell physiology; Cells; Clinical Trials; Collaborations; Cytomegalovirus; Cytotoxic T-Lymphocyte-Associated Protein 4; Disease; Disease remission; Effectiveness; Effector Cell; Environment; Future; Generations; Goals; HIV; HIV Infections; HIV vaccine; Helper-Inducer T-Lymphocyte; Human; IRF3 gene; IRF4 gene; Image; Immune; Immune response; Immune system; Immunity; Immunologics; Immunotherapeutic agent; Individual; Infection; Inflammatory; Interruption; Intervention; Laboratories; Life; Link; Location; Lymphoid; Lymphoid Tissue; Macaca; Macaca mulatta; Maintenance; Malignant Neoplasms; Measures; Mediating; Methods; Mission; Modeling; Monkeys; Nature; Pathway interactions; Phase I Clinical Trials; Population; Positron-Emission Tomography; Radiolabeled; Regimen; Research; Research Infrastructure; Residual state; Resources; Role; SIV; Safety; Series; Staging; System; T cell response; T-Lymphocyte; Therapeutic; Time; Tissues; Tracer; Vaccinated; Vaccines; Viral; Viral reservoir; Virus; Work; antiretroviral therapy; base; collaboratory; combinatorial; imaging modality; immune clearance; immunogenicity; improved; industry partner; meetings; nonhuman primate; novel vaccines; programs; radiotracer; response; therapy development; vector; virus characteristic

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.

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来减少 抗逆转录病毒治疗 (ART) 期间病毒库的大小，以及控制 ART 后残留的病毒 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系统 持久且有效的响应。此外，这些响应需要出现在正确的位置 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。我们将定义角色 假定的免疫豁免庇护所，使 SIV/HIV 在 ART 期间持续存在并使用猴子模型 开发突破这些庇护所的疗法（初始研究焦点 1，IRF1）。我们将表征 ART 抑制成人淋巴组织中复制能力病毒的分布并发展 PET 量化该储层的成像方式（IRF2）。我们将定义免疫检查点（PD-1、 其他）及其对猴子和人 T 细胞功能的阻断（IRF3）。最后，我们将定义安全性， 人 CMV (HCMV) 载体 HIV 疫苗对 HIV 感染者的免疫原性和抗 HIV 有效性 成人接受 ART (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。我们预计会遇到以下情况 里程碑和可交付成果：(1) SIV-淋巴组织中具有复制能力的储存库的定义 受感染的猴子和 HIV 感染者接受抑制性 ART，(2) 确定 B 卵泡是否发挥作用 作为感染 CD4+ TFH 的免疫避难所，如果是这样，B 滤泡耗竭是否会减少 (3) 确定具有最佳病毒特异性 CD8+ T 细胞反应的特征 减少储存库和/或 ART 后病毒控制的活性，(4) 确定组织储存库是否可以 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 检查点阻断剂可增强 T 细胞功能和/或逆转 HIV 潜伏期，(6) 安全性和 免疫检查点阻断剂在治疗 SIV 和 HIV 疾病中的免疫原性，(7) 安全性测定 HCMV/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/或免疫检查点封锁可能是该疫苗（或其他类似干预措施）所必需的 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 HCMV/HIV 载体在接受抗逆转录病毒治疗的个体中单独或与 B 组合的临床试验 细胞滤泡破坏和/或免疫检查点阻断。