Collaboratory of AIDS Researchers for Eradication (CARE)

摘要 自2011年启动以来，马丁·德莱尼合作实验室方案在以下方面取得了重要进展 一种治疗艾滋病毒的方法。作为对马丁·德莱尼艾滋病毒治疗研究RFA合作者(MDC)的回应，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。我们将扩大我们的 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 中断潜伏期，清除艾滋病毒蓄积物的方法，以及确定控制病毒反弹的战略。通过 基于我们在开发、实施和执行临床前套件方面取得的重大进展 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 统一的假设，逆转艾滋病毒潜伏期，使病毒蛋白表达，与干预措施并行 这种清除潜伏感染的细胞的速度，最终将导致根除持久性 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，防止病毒反弹。 艺术中断后的病毒血症。我们将利用来自学术界和产业界的广泛工具组合 合作伙伴，并应用新的发现，展示临床倡议的概念验证。 我们将邀请学术科学家和临床医生、行业调查人员和社区来定义 尽管抗逆转录病毒治疗(ART)持续存在的破坏前病毒基因组稳定的新靶点定义了新的 阻断前病毒建立的方法c)开发和部署新的效应器以清除病毒库，d) 勾勒出有效的策略，以防止在抗逆转录病毒治疗后可能产生的反跳病毒血症。 停止和e)建立与社区的桥梁，以增进对艾滋病毒治疗的了解和获得治疗 研究和临床试验。我们最初的努力将集中在生物学发现上，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。通用战略，以 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。我们最近在通过核因子-kB信号逆转潜伏期方面的主要进展将在 非人灵长类动物和人源化小鼠模型，结合候选清除受感染的细胞。 我们设想了一个迭代过程，结合在体外和临床前研究中获得的见解，继续进行 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，我们将开发人体临床试验来 通过有别于CARE的资助机制解决我们工作中形成的问题和测试概念。 我们致力于在一个灵活的计划中合作，我们的研究方向遵循我们的发现。 我们将共同推动最终根除艾滋病毒感染的进展。

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.