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: 10609926
• 负责人: Luis J Montaner
• 金额: $ 578.07万
• 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/10609926
• 关键词: AIDS clinical trial group; Achievement; Address; Adoptive Transfer; Affect; Aftercare; Area; Basic Science; Behavioral Sciences; Binding; Blood; CCR5 gene; CD34 gene; CD8-Positive T-Lymphocytes; COVID-19; Cells; Clinical; Clinical Data; Clinical Trials; Collaborations; 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; Learning; Link; Maintenance; Mediating; Mission; Modeling; Natural Killer Cells; Persons; Proviruses; Reproducibility; Research; Research Personnel; Resource Allocation; Resources; Scientist; Series; Social Behavior; Testing; Therapeutic; Tissues; Viral; Viral reservoir; Viremia; Virus Integration; antiretroviral therapy; biobank; cancer therapy; chimeric antigen receptor; collaboratory; community engagement; delivery vehicle; design; humanized mouse; in vivo; industry partner; innovation; insight; interest; knowledge base; latent HIV reservoir; nanotherapy; nonhuman primate; novel; novel strategies; patient derived xenograft model; pressure; prevent; reactivation from latency; response; simian human immunodeficiency virus; therapeutic nanoparticles; therapy development; 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，目前的艾滋病毒治疗策略不足以根除病毒库或防止感染后病毒反弹。 停止抗逆转录病毒治疗（ART）。 BEAT-HIV 合作实验室的统一假设是 通过更好地了解 HIV 潜伏病毒库和控制病毒的宿主因素 通过联合控制和重新激活，将实现长期病毒缓解或根除艾滋病毒 免疫疗法包括 bNAb、过继转移免疫细胞和纳米颗粒疗法。 我们将通过三个高度关联的研究重点领域来检验这一假设。第一个目标将寻求 了解完整原病毒的表观遗传状态、影响原病毒再激活的外在/内在因素以及 HIV 治疗后控制的表达和新的宿主机制。第二个目标将发展 在没有 ART 的情况下使用 DNA 递送的抗 HIV bNAb 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 开发纳米疗法和免疫疗法相结合的策略来根除病毒库。所有的目标都将是 由临床生物储存库（血液和组织）、CD34+或患者来源的异种移植人源化小鼠支持， 非人类灵长类动物 (NHP) 模型，以及作为 ACTG 链接的临床试验开发小组。社区 参与将通过利用超过 25 年的经验来促进教育和社会行为科学和道德重点 与当地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 资源将确保实现高影响力的里程碑、研究团队的沟通和年度目标 根据该领域的进展进行定向资源分配和/或再分配。作为一个既定的 通过合作，我们汇集了不同的专业知识、创新和行业合作伙伴来开发和测试新颖的产品 在缺乏抗逆转录病毒治疗的情况下，在单一共同目标下推进艾滋病毒治愈和/或持久病毒控制的策略 多研究者、多行业团队。三个相互关联的目标内的研究以及强有力的研究 社区参与计划将为未来整合新知识的临床试验奠定基础 BEAT HIV-1 合作实验室获得的用于根除或功能性治愈 HIV 感染的药物。

项目成果

To prescreen or not to prescreen for broadly neutralizing antibody sensitivity in HIV cure-related trials.

• DOI: 10.1016/j.jve.2023.100339
• 发表时间: 2023-09
• 期刊: JOURNAL OF VIRUS ERADICATION
• 影响因子: 5.5
• 作者: Patel, Hursch;Dube, Karine
• 通讯作者: Dube, Karine

Impact of HIV-1 Vpu-mediated downregulation of CD48 on NK-cell-mediated antibody-dependent cellular cytotoxicity.

• DOI: 10.1128/mbio.00789-23
• 发表时间: 2023-08-31
• 期刊: mBio
• 影响因子: 6.4

Holding back: HLA-associated inhibition of NK cells gives HIV a leg up.

阻碍：HLA 相关的 NK 细胞抑制使 HIV 占据优势。

• DOI: 10.1016/j.chom.2022.07.009
• 发表时间: 2022
• 期刊: Cell host & microbe
• 影响因子: 30.3
• 作者: Jost,Stephanie

Single-cell transcriptomics identifies prothymosin α restriction of HIV-1 in vivo.

单细胞转录组学鉴定了体内 HIV-1 的胸腺肽α限制。

• DOI: 10.1126/scitranslmed.adg0873
• 发表时间: 2023
• 期刊: Science translational medicine
• 影响因子: 17.1
• 作者: Geretz,Aviva;Ehrenberg,PhilipK;Clifford,RobertJ;Laliberté,Alexandre;PrelliBozzo,Caterina;Eiser,Daina;Kundu,Gautam;Yum,LaurenK;Apps,Richard;Creegan,Matthew;Gunady,Mohamed;Shangguan,Shida;Sanders-Buell,Eric;Sacdalan,Carlo;Pha
• 通讯作者: Pha