Collaboratory of AIDS Researchers for Eradication (CARE)

艾滋病根除研究人员合作实验室（CARE）

基本信息

批准号：
10313365
负责人：
DAVID M. MARGOLIS
金额：
$ 524.68万
依托单位：
UNIV OF NORTH CAROLINA CHAPEL HILL
依托单位国家：
美国
项目类别：
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/10313365
关键词：
Acquired Immunodeficiency Syndrome Address Affinity Animal Model Antibodies Area Back Biological Biological Assay Biological Models Biology Bispecific Antibodies CD4 Positive T Lymphocytes Cells Cellular biology Chromatin Clinical Clinical Trials Communities Complex Development Disease Disease remission Engineering Environment Funding Mechanisms Generations Genetic Transcription Genome Goals Government HIV HIV Entry Inhibitors HIV Infections HIV-1 Healthcare Human Industry Infection Infrastructure Interruption Intervention Laboratory Research Lead Lymphoid Macaca mulatta Measures Methods Mission Modality Monoclonal Antibodies Mus Myelogenous Myeloid Cells NF-kappa B Patients Peptides Pharmaceutical Preparations Prevention Process Proviruses Regulation Research Research Personnel Residual state SIV Science Scientist Signal Transduction Speed System T-Cell Receptor T-Lymphocyte Technology Testing Therapeutic Time Tissues Universities Validation Viral Viral Antigens Viral Proteins Viral reservoir Viremia Work antibody-dependent cell cytotoxicity antiretroviral therapy base chimeric antigen receptor T cells chromatin remodeling chronic infection clinical development collaboratory design experimental study humanized mouse improved in vivo industry partner insight latent infection mimetics mortality mouse model neonatal Fc receptor next generation nonhuman primate novel novel strategies peptidomimetics pre-clinical preclinical study prevent programs reconstitution response small molecule success sulfotransferase tool viral rebound

项目摘要

Abstract Since its inception in 2011, the Martin Delaney Collaboratory program has made important advances towards a cure for HIV. In response to the Martin Delaney Collaboratories (MDC) for HIV Cure Research RFA, we seek to continue to advance the field by discovery of successful modalities to cure HIV infection. We will expand our expertise and work toward a better understanding of persistent HIV infection, the discovery of novel approaches to disrupt latency, methods to clear the HIV reservoir, and identification of strategies to control viral rebound. By building on the significant advances that we have made to develop, implement, and execute a suite of pre-clinical experiments that represent the most advanced and novel concepts, we will continue to pursue our central unifying hypothesis that reversing HIV latency such that viral proteins are expressed, in parallel with interventions that speed the clearance of cells emerging from latent infection, will ultimately lead to eradication of persistent HIV infection. In parallel to the efforts to clear the infection, we will pursue interventions to prevent rebound of viremia after ART interruption. We will leverage a broad portfolio of tools from both academic and industry partners, and apply new discoveries, demonstrating proof-of-concept for clinical initiatives. We will engage academic scientists and clinicians, industry investigators, and the community to a) define novel targets to destabilize proviral genomes that persist despite antiretroviral therapy (ART) b) define novel approaches to block proviral establishment c) develop and deploy novel effectors to clear viral reservoirs, d) delineate effective strategies to prevent rebound viremia that might emanate from such reservoirs after ART is discontinued and e) create bridges to the community to improve the understanding of and access to HIV cure research and clinical trials. Our initial efforts will focus on biology discovery to illuminate new host targets for latency reversal, and the validation of the novel biological concept of latency prevention. Universal strategies for proviral control or clearance will be developed and tested, including those based on HLA-E targeting, eCD4, and CD4 mimetics. Our major recent advance in latency reversal via NF-kB signaling will be further developed in both non-human primate and humanize mice models, in combination with candidates to clear infected cells. We envision an iterative process with insights gained in ex vivo and pre-clinical studies, carried forward to enhance the next step in clinical development and, importantly, fed back to scientists to validate assays or hypotheses, and explore new directions. As we have done in the past, we will develop human clinical trials to address questions and test concepts developed in our work through funding mechanisms distinct from CARE. We are dedicated to working together in a nimble program, with our research direction following our discoveries. Together we will catalyze advances that will ultimately lead to the eradication of HIV infection.

抽象的自 2011 年启动以来，Martin Delaney 合作实验室项目在以下方面取得了重要进展：治愈艾滋病毒。为了回应 Martin Delaney Collaboratories (MDC) 的 HIV 治疗研究 RFA，我们寻求通过发现治愈艾滋病毒感染的成功方法，继续推进该领域的发展。我们将扩大我们的专业知识并致力于更好地了解持续性艾滋病毒感染、发现新方法破坏潜伏期的方法、清除艾滋病毒储存库的方法以及控制病毒反弹的策略的确定。经过以我们在开发、实施和执行一系列临床前研究方面取得的重大进展为基础代表最先进和新颖概念的实验，我们将继续追求我们的中心统一假设：在干预的同时逆转艾滋病毒潜伏期，使病毒蛋白得以表达加速清除潜伏感染中出现的细胞，最终将导致根除持久性感染艾滋病毒感染。在努力清除感染的同时，我们将采取干预措施，防止疫情反弹。 ART 中断后病毒血症。我们将利用学术和行业的广泛工具组合合作伙伴，并应用新发现，展示临床计划的概念验证。我们将让学术科学家和临床医生、行业研究人员和社区参与进来：破坏原病毒基因组稳定的新靶标，尽管经过抗逆转录病毒治疗 (ART)，但原病毒基因组仍然存在 b) 定义了新靶标阻止原病毒建立的方法 c) 开发和部署新型效应器以清除病毒储存库，d) 制定有效的策略，以防止在 ART 治疗后可能出现的病毒血症反弹 e) 与社区建立桥梁，以提高对艾滋病毒治疗的理解和获得研究和临床试验。我们最初的努力将集中于生物学发现，以阐明新的宿主目标潜伏期逆转，以及潜伏期预防的新生物学概念的验证。通用策略将开发和测试前病毒控制或清除，包括基于 HLA-E 靶向、eCD4 和 CD4 模拟物。我们最近在通过 NF-kB 信号传导实现延迟逆转方面取得的重大进展将在非人类灵长类动物和人源化小鼠模型，与清除受感染细胞的候选物相结合。我们设想一个迭代过程，将在离体和临床前研究中获得的见解发扬光大加强临床开发的下一步，重要的是，反馈给科学家以验证分析或提出假设，探索新的方向。正如我们过去所做的那样，我们将开展人体临床试验通过与 CARE 不同的资助机制解决我们工作中提出的问题和测试概念。我们致力于在灵活的计划中合作，我们的研究方向遵循我们的发现。我们将共同推动各项进展，最终消除艾滋病毒感染。