Collaboratory of AIDS Researchers for Eradication (CARE)

艾滋病根除研究人员合作实验室（CARE）

• 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
• 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

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.

摘要 自2011年成立以来，马丁·德莱尼合作实验室计划取得了重要进展， 艾滋病的治疗方法为了响应马丁德莱尼合作实验室（MDC）的艾滋病毒治疗研究RFA，我们寻求 通过发现治愈艾滋病毒感染的成功方法，继续推进这一领域。我们将扩大我们 专业知识和工作，以更好地了解持续的艾滋病毒感染，发现新的方法， 破坏潜伏期，清除HIV储存库的方法，以及确定控制病毒反弹的策略。通过 在我们已经取得的重大进展的基础上，开发，实施和执行一套临床前 实验，代表了最先进和新颖的概念，我们将继续追求我们的中心 统一的假设，逆转艾滋病毒潜伏期，使病毒蛋白质的表达，同时进行干预， 加速清除从潜伏感染中出现的细胞，最终将导致根除持续性感染。 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，防止艾滋病毒/艾滋病反弹。 抗逆转录病毒治疗中断后的病毒血症。我们将利用来自学术界和工业界的广泛工具组合 合作伙伴，并应用新的发现，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、行业调查人员和社区参与a）定义 使尽管抗逆转录病毒治疗（ART）仍持续存在的前病毒基因组不稳定的新靶点B）定义了新的 阻断前病毒建立的方法c）开发和部署新的效应物以清除病毒储库，d） 描述有效的策略，以防止反弹病毒血症，可能源于这样的水库后，艺术是 e）建立与社区的桥梁，以提高对艾滋病毒治疗的理解和获得艾滋病毒治疗的机会 研究和临床试验。我们最初的努力将集中在生物学发现，以阐明新的宿主靶点， 潜伏期逆转，以及潜伏期预防的新生物学概念的验证。普遍战略， 将开发和测试前病毒控制或清除，包括基于HLA-E靶向、eCD 4和 CD 4模拟物。我们最近在通过NF-kB信号传导的潜伏期逆转方面的主要进展将在2015年进一步发展。 非人灵长类动物和人源化小鼠模型，与清除感染细胞的候选物组合。 我们设想了一个迭代过程，其中包含在体外和临床前研究中获得的见解，并将其应用于 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 假设，并探索新的方向。正如我们过去所做的那样，我们将开展人体临床试验， 通过不同于CARE的资助机制解决我们工作中提出的问题和测试概念。 我们致力于在一个灵活的计划中共同努力，我们的研究方向遵循我们的发现。 我们将共同推动取得进展，最终导致根除艾滋病毒感染。