Martin Delaney Collaboratory to Eradicate HIV-1 Infection

Martin Delaney 合作根除 HIV-1 感染

• 批准号: 8185798
• 负责人: DAVID M. MARGOLIS
• 金额: $ 638.02万
• 依托单位: UNIV OF NORTH CAROLINA CHAPEL HILL
• 依托单位国家: 美国
• 财政年份: 2011
• 资助国家: 美国
• 起止时间: 2011-07-08 至 2016-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8185798
• 关键词: Martin; Delaney; Collaboratory; Eradicate; HIV

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. PUBLIC HEALTH RELEVANCE: Despite the success of antiretroviral therapy (ART) in decreasing mortality for HlV-1-infected patients, ART has not cured the disease. A persistent viral reservoir in the T cells of HIV patients receiving potent ART is a significant barrier preventing an HIV cure. Including scientists from eight universities and Merck Research Laboratories, the Martin Delaney Collaboratory will seek to eradicate HIV infection by developing and testing therapies, capable of eventually being tested clinically, that will permanently destroy the viral reservoir. Project 1.1 - Identification Novel Host Factors Regulating HIV Latency Project Leader (PL): Warner Greene (Description as provided by applicant) Quiescent memory CD4 T cells harboring integrated, actively repressed HIV proviruses currently form a formidable barrier to viral eradication. This latent reservoir could be attacked by activating proviral gene expression thereby sensitizing the virus to antiretroviral therapy. For success, this strategy must both prevent viral spread and result in the death of all latently infected cells without producing a toxic state of generalized cellular activation. Currently, no effective therapies for HIV latency exist. We hypothesize that a more complete understanding of the molecular underpinnings of HIV latency - notably, the full range of the host's regulatory factors that promote and antagonize latency - will facilitate the development of effective therapies. In Aim 1, we will examine five novel candidate HIV repressors identified by genome wide siRNA screening of HIV-infected HeLa cells. These candidates have biological properties consistent with a role in latency and are expressed in lymphoid tissues. Expression of these candidate genes will be analyzed in biologically relevant cells and their function assessed by lentiviral shRNA knockdown. In Aim 2, we will screen a CD4 T-cell model of HIV latency for microRNAs (miRs) that promotes viral latency by impairing the expression of cellular activators. We will validate miR action using antagomirs in latently infected primary CD4 T-cells. In Aim 3, we will use bioinformatic and transcriptional profiling approaches to identify the host gene products that are suppressed by these miRs. Using this dual experimental approach, we will identify cellular factors that naturally promote and antagonize HIV latency. Where appropriate, mechanism-of-action studies will be performed. Identified targets will be prioritized, based on the robustness of their activity and overall "drugability," for entry into small-molecule high-throughput screening assays and primary and secondary screening assays will be developed. These proposed studies could identify small molecules that either inhibit the most interesting cellular repressors or activate the most compelling mRNA-regulated HIV activators. These studies fully support the goal of the Collaboratory - to identify combinations of nontoxic small molecules that can eradicate the virus or produce a functional cure (drug-free remission). PUBLIC HEALTH RELEVANCE: These studies promise to deepen our understanding of the cellular factors that both promote and antagonize HIV latency and ultimately to provide new approaches for purging HIV from the latent reservoir. Ultimately, we seek to translate these basic insights into HIV latency into combinations of small molecule inducers that effectively purge the latent reservoir. Success in these studies could radically change the landscape of clinical care for HIV-infected patients throughout the world.

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ART的人多。终身ART的困难-特别是在发展中国家-使得根除HIV势在必行。但是，清除接受抗逆转录病毒治疗的患者的逆转录病毒感染是一项艰巨的任务。尽管人们对艾滋病毒在ART治疗后的持续性了解很多，但仍然存在许多困惑。解决潜伏感染的新工具必须取代用于开发ART的范例和模型。代表体内HIV潜伏期的现有细胞和动物模型需要进一步开发，虽然潜伏前病毒可以在实验室中清除，但可测试的全面治疗策略还没有。 因此，我们提议成立马丁·德莱尼合作实验室，以根除HIV-1感染，这是一个由21名杰出研究人员组成的密切合作，他们在过去10年中共同领导了HIV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，并为动物模型中基于小分子的根除策略提供概念验证。目标1将确定病毒持续存在和潜伏的分子机制;目标2将确定候选药物和治疗策略，以减少潜伏病毒库;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将在人类中进行研究，以描述病毒持续存在的基础。三个核心将协助药理学，分子测定，序列和表达分析的研究项目。一个行政核心将确保协调，并保持这个经验丰富和强大的团队对翻译产品开发的关注。作为一个团体，我们致力于汇集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的承诺对于提供治疗进展至关重要。我们相信，我们将共同推动取得进展，最终导致根除艾滋病毒感染。 公共卫生相关性：尽管抗逆转录病毒疗法（ART）在降低HIV-1感染患者的死亡率方面取得了成功，但ART尚未治愈该疾病。接受有效ART的HIV患者的T细胞中的持续病毒库是阻止HIV治愈的重要障碍。包括来自八所大学和默克研究实验室的科学家在内，马丁·德莱尼合作实验室将寻求通过开发和测试疗法来根除艾滋病毒感染，最终能够进行临床测试，这将永久摧毁病毒储存库。 项目1.1 -鉴定调节HIV潜伏期的新宿主因子 项目负责人（PL）：Warner格林 （如申请人提供的描述）携带整合的、主动抑制的HIV前病毒的静止记忆CD 4 T细胞目前形成了病毒根除的强大屏障。这种潜伏的储库可以通过激活前病毒基因表达来攻击，从而使病毒对抗逆转录病毒疗法敏感。为了成功，这种策略必须既防止病毒传播，又导致所有潜伏感染的细胞死亡，而不产生全身细胞活化的毒性状态。目前，还没有针对HIV潜伏期的有效疗法。我们假设，更全面地了解HIV潜伏期的分子基础-特别是促进和拮抗潜伏期的宿主调节因子的全部范围-将有助于开发有效的治疗方法。在目标1中，我们将研究五种新的候选HIV抑制子，这些抑制子是通过对HIV感染的HeLa细胞进行全基因组siRNA筛选而鉴定的。这些候选物具有与潜伏期中的作用一致的生物学特性，并且在淋巴组织中表达。将在生物学相关细胞中分析这些候选基因的表达，并通过慢病毒shRNA敲低评估其功能。在目标2中，我们将筛选HIV潜伏期的CD 4 T细胞模型中的微小RNA（miR），其通过损害细胞活化剂的表达来促进病毒潜伏期。我们将在潜伏感染的原代CD 4 T细胞中使用miR验证miR作用。在目标3中，我们将使用生物信息学和转录谱分析方法来鉴定被这些miR抑制的宿主基因产物。使用这种双重实验方法，我们将确定自然促进和拮抗HIV潜伏期的细胞因子。适当时，将进行作用机制研究。将根据其活性的稳健性和总体“可药性”，对已确定的靶标进行优先排序，以进入小分子高通量筛选试验，并将开发初级和二级筛选试验。这些拟议中的研究可以识别出抑制最有趣的细胞阻遏物或激活最引人注目的mRNA调节的HIV激活剂的小分子。这些研究完全支持合作实验室的目标-确定可以根除病毒或产生功能性治愈（无药物缓解）的无毒小分子组合。 公共卫生相关性：这些研究有望加深我们对促进和拮抗HIV潜伏的细胞因子的理解，并最终提供从潜伏库中清除HIV的新方法。最终，我们寻求将这些对HIV潜伏期的基本见解转化为有效清除潜伏水库的小分子诱导剂的组合。这些研究的成功可能会从根本上改变全世界艾滋病毒感染者的临床护理状况。