BEAT-HIV: Delaney Collaboratory to Cure HIV-1 Infection by Combination Immunotherapy

摘要 目前的艾滋病毒治疗策略已被证明不足以根除病毒库或防止病毒在感染后反弹 停止抗逆转录病毒治疗(ART)。BEAT-HIV合作实验室的统一假设是 通过更好地从机制上了解艾滋病毒潜伏宿主和控制病毒的宿主因素 艾滋病毒的控制和重新激活、长期病毒缓解或根除将通过组合实现。 免疫疗法，包括bNAbs、过继转移的免疫细胞和纳米颗粒疗法。 我们将通过追求三个高度相互关联的研究重点领域来检验这一假设。第一个目标是寻求 为了了解完整前病毒的表观遗传状态，影响前病毒重新激活的外在/内在因素和 表达，以及用于艾滋病毒治疗后控制的新宿主机制。第二个目标将会发展 在缺乏ART的情况下利用DNA传递的抗HIV bNAbs和eCD4Ig进行长期控制的策略 与优化的基于组织的CD8 T细胞和NK细胞介导的反应相结合。第三个目标将是 制定纳米疗法和免疫疗法相结合的战略，以根除病毒库。所有的目标都将是 由临床生物库(血液和组织)、CD34或患者来源的异种移植人源化小鼠支持， 非人灵长类(NHP)模型，以及一个临床试验开发小组作为ACTG的链接。社区 通过利用25年的参与，将促进教育以及社会行为科学和伦理的关注 与当地艾滋病毒社区的关系，从而确保与利益攸关方的伙伴关系。中央行政管理 将确保实现具有重大影响的里程碑、研究团队沟通和年度目标- 根据实地进展情况，以定向资源分配和/或再分配为导向。作为一个老牌的 协作，我们将不同的专业知识、创新和行业合作伙伴聚集在一起，以开发和测试小说 在缺乏抗逆转录病毒疗法的情况下推进艾滋病毒治愈和/或持久病毒控制的战略 多名调查员，多行业团队。三个相互关联的目标内的研究与强大的 社区参与计划将为未来的临床试验奠定基础，这些试验将整合新的知识 由Beat HIV-1合作实验室获得，用于根除或从功能上治愈艾滋病毒感染。

Summary Current HIV curative strategies have proven insufficient to eradicate viral reservoirs or prevent viral rebound after antiretroviral therapy (ART) cessation. The unifying hypothesis for the BEAT-HIV Collaboratory is that through a better mechanistic understanding of HIV latent reservoirs and host factors governing viral control and reactivation, long-term viral remission or eradication of HIV will be achieved by combination immunotherapy inclusive of bNAbs, adoptively transferred immune cells, and nanoparticle therapies. We will test this hypothesis by pursuing three highly interconnected research focus areas. The first aim will seek to understand epigenetic status of intact proviruses, extrinsic/intrinsic factors affecting proviral reactivation and expression, and novel host mechanisms for post-treatment control of HIV. The second aim will develop strategies for long-term control in the absence of ART by use of DNA-delivered anti-HIV bNAbs and eCD4Ig in combination with optimized tissue-based CD8 T-cell- and NK cell-mediated responses. The third aim will develop a combination nanotherapy and immunotherapy strategy to eradicate viral reservoirs. All aims will be supported by a clinical biorepository (blood and tissue), CD34+ or patient-derived xenograft humanized mice, non-human primate (NHP) models, and a clinical trial development group as a link to the ACTG. Community engagement will advance education and a socio-behavioral sciences and ethics focus by leveraging a >25-year relationship with the local HIV community thereby ensuring partnership with stakeholders. Central administration of resources will ensure achievement of high impact milestones, study team communications, and yearly goal- oriented resource allocation and/or redistribution as informed by advances in the field. As an established Collaboratory, we bring together diverse expertise, innovation, and industry partners to develop and test novel strategies to advance an HIV cure and/or durable viral control in the absence of ART under a single common multi-investigator, multi-industry team. Studies within the three interconnected aims together with a strong community engagement plan will lay the groundwork for future clinical trials that will integrate new knowledge gained by the BEAT HIV-1 Collaboratory to eradicate or functionally cure HIV infection.