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.

总结 目前的艾滋病毒治疗策略已被证明不足以根除病毒储存库或防止病毒反弹后， 抗逆转录病毒治疗（ART）停止。BEAT-HIV合作实验室的统一假设是， 通过更好地了解HIV潜伏库和控制病毒的宿主因素， 控制和重新激活，长期病毒缓解或根除艾滋病毒将实现联合 免疫疗法包括bNAb、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验证这一假设。第一个目标是 了解完整前病毒的表观遗传状态，影响前病毒再激活的外在/内在因素， 表达，和新的宿主机制治疗后控制艾滋病毒。第二个目标是发展 在没有ART的情况下，通过使用DNA递送的抗HIV bNAb和eCD 4 Ig进行长期控制的策略， 结合优化的基于组织的CD 8 T细胞和NK细胞介导的应答。第三个目标将 开发纳米疗法和免疫疗法的组合策略，以根除病毒储存库。所有的目标都将是 由临床生物储存库（血液和组织）支持，CD 34+或患者来源的异种移植人源化小鼠， 非人灵长类动物（NHP）模型，以及作为ACTG链接的临床试验开发组。社区 参与将促进教育和社会行为科学和道德的重点，利用一个>25年 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 资源将确保实现高影响里程碑、研究团队沟通和年度目标- 根据实地的进展情况，以资源分配和（或）重新分配为导向。作为一项既定 合作实验室，我们汇集了不同的专业知识，创新和行业合作伙伴，以开发和测试新的 在没有ART的情况下，在单一共同的 多研究者多行业团队三个相互关联的目标中的研究与一个强大的 社区参与计划将为未来的临床试验奠定基础， 由BEAT HIV-1合作实验室获得，用于根除或功能性治愈HIV感染。