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: 9315694
• 负责人: STEVEN Grant DEEKS
• 金额: $ 549.38万
• 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/9315694
• 关键词: Acquired Immunodeficiency Syndrome; Adaptive Immune System; Adult; Affect; Anti-Retroviral Agents; B-Lymphocytes; CD8-Positive T-Lymphocytes; Cell physiology; Cells; Clinical Trials; Collaborations; Cytomegalovirus; Cytotoxic T-Lymphocyte-Associated Protein 4; Disease; Disease remission; Effectiveness; Effector Cell; Future; Generations; Goals; HIV; HIV Infections; HIV vaccine; Helper-Inducer T-Lymphocyte; Human; IRF3 gene; IRF4 gene; Immune; Immune response; Immunity; Immunologics; Immunotherapeutic agent; Individual; Infection; 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; System; T cell response; T-Lymphocyte; Therapeutic; Time; Tissues; Tracer; Vaccinated; Vaccines; Viral; Virus; Work; antiretroviral therapy; base; collaboratory; combinatorial; imaging approach; imaging modality; immune checkpoint; immune checkpoint blockade; immune clearance; immunogenicity; improved; industry partner; inflammatory milieu; meetings; nonhuman primate; novel vaccines; programs; response; therapy development; vector; vector vaccine; 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.

项目摘要/摘要 敢合作的使命是利用自适应免疫系统的力量来减少 抗逆转录病毒疗法（ART）期间储层的大小，并在ART后控制任何残留病毒 中断。我们的总体假设是，耐久的艾滋病毒感染需要强大的免疫 持续且功能性的响应。而且，这些回应需要在正确的位置正确 时间。我们提出了四个高度联系的研究焦点，旨在实现这些目标。我们将定义 推定的免疫特性保护区，使SIV/HIV能够在艺术中持续并使用猴子模型 开发违反这些庇护所的疗法（初始研究灶1，IRF1）。我们将表征 在艺术抑制的成年人的淋巴组织中分配复制能力的病毒并发展PET 成像模式以量化此储层（IRF2）。我们将定义免疫检查点的作用（PD-1， 其他）及其对猴子和人的T细胞功能的封锁（IRF3）。最后，我们将定义安全性， 人类CMV（HCMV）在HIV感染的HIV疫苗的免疫原性和抗HIV效果 成人艺术（IRF4）。所有四个最初的研究焦点都与他们的共同目标联系在一起，以了解如何最好 在人淋巴系统中量化，减少和控制HIV。我们预计会议以下 里程碑和可交付成果：（1）SIV-的淋巴组织中复制能力的储层的定义 受感染的猴子和感染的艾滋病毒感染的人对抑制性艺术，（2）确定B卵泡是否服务 作为感染CD4+ TFH的免疫学庇护所，如果是的，则B卵泡耗竭是否会减小大小 储层，（3）确定具有最佳的病毒特异性CD8+ T细胞反应的特征 储层还原和/或艺术后病毒控制的活性，（4）确定组织储层是否可以 通过放射标记的示踪剂和PET扫描测量（5）鉴定免疫的最佳组合 增强T细胞功能和/或反向艾滋病毒潜伏期的检查点阻滞剂，（6）安全性的定义 治疗的SIV和HIV疾病中免疫检查点阻滞剂的免疫原性，（7）确定安全性 HCMV/HIV疫苗在治疗的HIV疾病中的免疫原性，以及（8）确定B细胞是否破坏 对于这种疫苗（或其他可比较的干预措施）可能需要/或免疫检查点封锁 减少储层和/或持久的缓解。我们的工作将为未来的概念证明奠定基础 抗逆转录病毒治疗个体中HCMV/HIV载体的临床试验，无论是单独还是与B结合 细胞卵泡破坏和/或免疫检查点阻塞。