Martin Delaney Collaboratory to Eradicate HIV-1 Infection

描述(由申请人提供)：尽管抗逆转录病毒疗法(ART)在临床上取得了成功，但每天感染人类免疫缺陷病毒(HIV)的人比开始抗逆转录病毒治疗的人更多。终身抗逆转录病毒治疗的困难--特别是在发展中国家--使根除艾滋病毒成为当务之急。但对于接受抗逆转录病毒治疗的患者来说，清除逆转录病毒感染是一项艰巨的任务。尽管人们对艾滋病的持续存在有很多了解，但仍有许多谜团。应对潜伏感染的新工具必须取代用于发展抗逆转录病毒治疗的范例和模式。现有的代表体内艾滋病毒潜伏期的细胞和动物模型需要进一步开发，虽然潜伏期前病毒可以在实验室中清除，但可测试的全面治疗策略尚不存在。因此，我们建议成立马丁·德莱尼合作实验室来根除艾滋病毒-1感染，这是21名杰出的研究人员的密切合作，他们在过去10年里共同领导了艾滋病毒潜伏期领域。为了最大限度地取得成功，我们将在四个研究领域开展工作，以开发定义根除疗法所需的基础设施和系统，识别具有治疗潜力的新分子，并在动物模型中为基于小分子的根除策略提供概念验证。目标1将确定病毒持续和潜伏的分子机制；目标2将确定减少潜伏病毒库的候选药物和治疗策略；目标3将建立信息丰富的动物模型系统以评估潜伏期和测试治疗策略；最后。目标4将在人类身上进行研究，以描绘病毒持续存在的基础。三个核心将在药理学、分子分析以及序列和表达分析方面协助研究项目。管理核心将确保协调，并保持这一经验丰富和强有力的团队对翻译产品开发的关注。作为一个团队，我们致力于集中我们的资源和专业知识，以超越学术研究的正常限制。值得注意的是，默克研究实验室的专业知识和持久承诺将是提供治疗进展的关键。我们相信，我们将共同推动取得进展，最终根除艾滋病毒感染。

DESCRIPTION (provided by applicant): Despite the clinical success of antiretroviral therapy (ART), more people contract human immunodeficiency virus (HIV) infection daily than initiate ART. The difficulties of lifelong ART - particularly in the developing world - make the eradication of HIV imperative. But clearance of a retroviral infection for patients on ART is a herculean task. While much is known about HIV persistence despite ART, many puzzles remain. New tools to address latent infection must replace the paradigms and models used to develop ART. Existing cellular and animal models that represent HIV latency in vivo require further development, and while latent provirus can be purged in the laboratory, a testable, comprehensive therapeutic strategy is not at hand. Therefore we propose the Martin Delaney Collaboratory to Eradicate HIV-1 Infection, a close collaboration of 21 exceptional investigators who have collectively led the field of HIV latency over the last 10 years. To maximize success, we will work across four areas of research to develop the infrastructure and systems needed to define eradication therapies, identify new molecules with therapeutic potential and provide a proof-of-concept for a small molecule based eradication strategy in animal models. Objective 1 will identify the molecular mechanisms underlying viral persistence and latency; Objective 2 will identify drug candidates and therapeutic strategies to reduce the latent viral pool; Objective 3 will establish informative animal model systems to evaluate latency and test therapeutic strategies; and finally. Objective 4 will perform studies in humans to delineate the basis for viral persistence. Three cores will assist research projects with pharmacology, molecular assays, and sequence and expression analysis. An administrative core will assure coordination, and maintain the focus of this experienced and potent group towards translational product development. As a group, we are committed to pooling our resources and expertise to transcend the normal constraints of academic research. Of note, the expertise and durable commitment of Merck Research Laboratories will be critical to delivering therapeutic advances. We are convinced that together we will catalyze advances that will ultimately lead to the eradication of HIV infection.