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

BEAT-HIV：Delaney 合作实验室通过联合免疫疗法治愈 HIV-1 感染

• 批准号: 10313067
• 负责人: Luis J Montaner
• 金额: $ 610万
• 依托单位: WISTAR INSTITUTE
• 依托单位国家: 美国
• 财政年份: 2021
• 资助国家: 美国
• 起止时间: 2021-08-16 至 2026-04-30
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10313067
• 关键词: AIDS clinical trial group; Achievement; Address; Adoptive Transfer; Affect; Aftercare; Area; Basic Science; Blood; CCR5 gene; CD34 gene; CD8-Positive T-Lymphocytes; COVID-19; Cells; Clinical; Clinical Data; Clinical Trials; Combination immunotherapy; Communication; Communities; DNA; Development; Disease remission; Education; Ensure; Epigenetic Process; Ethics; Foundations; Future; Goals; HIV; HIV Infections; HIV-1; Immune; Immunotherapeutic agent; Immunotherapy; Industry; Infection; Institution; Integration Host Factors; Interruption; Intervention; Intrinsic factor; Knowledge; Lead; Link; Maintenance; Malignant Neoplasms; Mediating; Mission; Modeling; Natural Killer Cells; Persons; Proviruses; Reproducibility; Research; Research Personnel; Resource Allocation; Resources; Science; Scientist; Series; Social Behavior; Testing; Therapeutic; Tissues; Viral; Viral reservoir; Viremia; Virus; antiretroviral therapy; base; biobank; chimeric antigen receptor; collaboratory; community engagement; design; humanized mouse; in vivo; industry partner; innovation; insight; interest; knowledge base; latent HIV reservoir; nanoparticle; nanotherapy; nonhuman primate; novel; novel strategies; patient derived xenograft model; pressure; prevent; reactivation from latency; response; simian human immunodeficiency virus; vector; viral rebound

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.

概括 事实证明，当前的HIV治疗策略不足以消除病毒库或防止病毒反弹 抗逆转录病毒疗法（ART）停止。 Beat-HIV合作的统一假设是 通过对艾滋病毒潜在储层和控制病毒的宿主因素的更好理解 控制和重新激活，长期的病毒缓解或消除HIV将通过组合实现 免疫疗法包括BNAB，采用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联系的研究重点领域来检验这一假设。第一个目标将寻求 了解完整的原病毒的表观遗传状况，影响病毒重新激活和的外在/内在因素 表达和新型宿主机制用于HIV后治疗后控制。第二个目标将发展 在没有ART的情况下，通过使用DNA分配的抗HIV BNAB和ECD4IG的策略 结合优化的基于组织的CD8 T细胞和NK细胞介导的反应。第三个目标 制定组合纳米疗法和免疫疗法策略，以消除病毒库。所有目标都是 在临床生物疗法（血液和组织）的支持下，CD34+或患者衍生的异种移植物人源化小鼠 非人类灵长类动物（NHP）模型和临床试验开发小组作为ACTG的联系。社区 参与将通过利用> 25年来提高教育以及社会行为科学和道德的重点 与当地的艾滋病毒社区的关系，从而确保与利益相关者的伙伴关系。中央管理 资源的资源将确保实现高影响力的里程碑，研究团队沟通以及年度目标 - 该领域进步所告知的定向资源分配和/或重新分配。作为一个既定 合作，我们将各种专业知识，创新和行业合作伙伴汇集在一起​​，以开发和测试小说 在没有单一共同的情况下没有艺术的情况下，可以提高艾滋病毒治愈和/或持久病毒控制的策略 多投资者，多工业团队。在三个相互联系的目标中的研究与强大 社区参与计划将为将来的临床试验奠定基础，以整合新知识 由BET HIV-1协作获得的，以根除或在功能上治愈HIV感染。