An AAV-mediated functional cure and its impact on the reservoir

AAV 介导的功能性治愈及其对储存库的影响

• 批准号: 9891590
• 负责人: Michael R. Farzan
• 金额: $ 293.89万
• 依托单位: SCRIPPS FLORIDA
• 依托单位国家: 美国
• 财政年份: 2020
• 资助国家: 美国
• 起止时间: 2020-04-15 至 2025-03-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/9891590
• 关键词: Antibodies; Biological Assay; Cells; Clinic Visits; Data; Dependovirus; Disease remission; Environment; Epitopes; Goals; HIV; HIV-1; Healthcare; Human; Immune response; Immunologics; Infection; Integrase Inhibitors; Laboratories; Logistics; Macaca; Macaca mulatta; Measurement; Mediating; Mus; Muscle; Pharmaceutical Preparations; Primates; Process; Property; RNA; Research; Resistance; SIV; Safety; Series; Tail; Technology; Testing; Therapeutic; Time; Transgenes; Universities; Variant; Viral Proteins; Viral Vector; Viral reservoir; Virion; Virus; Virus Replication; Wisconsin; Work; adeno-associated viral vector; antiretroviral therapy; base; experience; improved; inhibitor/antagonist; insight; neutralizing antibody; nonhuman primate; prevent; programs; rate of change; simian human immunodeficiency virus; therapeutic transgene; tool; transgene expression; vector; virology

PROGRAM SUMMARY In preliminary data we show the results of two studies demonstrating that a sustained state of ART-free virologic remission, a ‘functional cure’, is possible in non-human primates. First, the Desrosiers laboratory has shown that long-term expression of two broadly neutralizing antibodies (bNAbs) can suppress an untreated SHIV-AD8 infection in three rhesus macaques, in one case, to undetectable (<15 copies/ml) for over two years. Second, the Farzan laboratory has shown that long-term expression of the antibody-like entry inhibitor eCD4-Ig can also efficiently suppress viral replication in five of six SHIV-AD8-infected rhesus macaques for more than a year after cessation of anti-retroviral therapy (ART). We propose to build on these initial results by making these functional cures safer, more consistent, and more robust. In the process, we will establish a useful platform for evaluating latency-reversing agents (LRAs), a so-called ‘kick’, by providing an environment in which a potent ‘kill’ is always present, and develop a way to halt transgene expression, thereby enabling time-to-rebound measurements. We will determine how best to limit anti-drug antibodies (ADA) that emerge with AAV-expressed bNAbs. We will determine how to best use ART or the long-lasting integrase inhibitor cabotegravir to establish AAV-mediated functional cures. Finally, we will determine whether a sustained and potent kill can by itself change the decay rate of latently infected cells. To do so, we have assembled a team with deep experience in HIV and SIV studies, years of experience working together, and a long-term commitment to understanding and improving AAV-based functional cures. These effort are accomplished with four projects and three cores. Project 1 will establish robust functional cures in SHIV-AD8- and SIVmac239-infected macaques using AAV-expressed eCD4-Ig and evaluate the impact of sustained eCD4-Ig on the viral reservoir. Project 2 will develop and test multiple approaches for eliminating anti-drug antibodies that frequently emerge with AAV-expressed bNAbs. Project 3 will assess the impact of triple therapy and long-acting cabotegravir on the establishment of eCD4-Ig- mediated functional cures, and determine how cabotegravir might best be combined with eCD4-Ig. Project 4 will develop a permanent off- and on-switches for AAV transgenes, facilitating time-of-rebound studies after sustained bNAb expression and increasing the safety of AAV-mediated functional cures. These projects are organized around a uniform experimental pipeline of assays supporting a series of non-human primate studies, established and implemented by Core B. Core A will manage regulatory and logistical aspects of the Program, and Core C will provide produce high-quality AAV particles for these studies, and improve its capacity for doing so. Collectively these efforts will develop and improve a viable approach to functional cures in humans, and provide tools and insight useful for complete eradication of the virus.

项目概要 在初步数据中，我们展示了两项研究的结果，表明持续的无 ART 状态 病毒学缓解，即“功能性治愈”，在非人类灵长类动物中是可能的。首先，Desrosiers 实验室。 已经表明，两种广泛中和抗体（bNAb）的长期表达可以抑制 三只恒河猴中未经治疗的 SHIV-AD8 感染，其中一例感染无法检测到（<15 拷贝/毫升） 其次，Farzan 实验室已经证明了类似抗体的长期表达。 进入抑制剂 eCD4-Ig 还可以有效抑制六只感染 SHIV-AD8 的恒河猴中的五只的病毒复制 我们建议在停止抗逆转录病毒治疗（ART）后继续对猕猴进行一年多的治疗。 通过使这些功能性治疗更安全、更一致、更稳健来实现这些初步结果。 在此过程中，我们将建立一个有用的平台来评估延迟反转代理（LRAs），即所谓的 “踢”，通过提供一个始终存在有效“杀”的环境，并开发一种方法来阻止 转基因表达，从而实现反弹时间测量，我们将确定如何最好地进行。 限制 AAV 表达的 bNAb 出现的抗药物抗体 (ADA) 我们将确定如何最好地进行。 使用 ART 或长效整合酶抑制剂 cabotegravir 来建立 AAV 介导的功能性治疗。 最后，我们将确定持续有效的杀戮本身是否可以改变后期的腐烂率 为此，我们组建了一支在 HIV 和 SIV 研究方面拥有多年丰富经验的团队。 合作经验，以及对理解和改进基于 AAV 的长期承诺 这些努力将通过四个项目和三个核心项目 1 来完成。 使用 AAV 表达的 eCD4-Ig 对 SHIV-AD8 和 SIVmac239 感染的猕猴进行强有力的功能性治愈 并评估持续的 eCD4-Ig 对病毒库的影响 项目 2 将开发和测试多种病毒。 消除 AAV 表达的 bNAb 项目中经常出现的抗药物抗体的方法。 3 将评估三联疗法和长效卡博特韦对 eCD4-Ig- 建立的影响 介导的功能性治疗，并确定 cabotegravir 如何最好地与 eCD4-Ig 项目结合。 4 将开发 AAV 转基因的永久开关，促进反弹时间研究 持续 bNAb 表达并提高 AAV 介导的功能性治疗的安全性后。 项目是围绕支持一系列非人类的统一分析实验管道组织的 灵长类动物研究，由核心 B 建立和实施。核心 A 将管理监管和后勤 该计划的各个方面，Core C 将为这些研究提供高质量的 AAV 颗粒，以及 提高其这样做的能力，这些努力将共同制定和改进可行的方法。 对人类进行功能性治愈，并提供有助于彻底根除病毒的工具和见解。