Innovative therapies to elimate persistent HIV Infection

消除持续性艾滋病毒感染的创新疗法

• 批准号: 7660987
• 负责人: DAVID M. MARGOLIS
• 金额: $ 135.45万
• 依托单位: UNIV OF NORTH CAROLINA CHAPEL HILL
• 依托单位国家: 美国
• 财政年份: 2009
• 资助国家: 美国
• 起止时间: 2009-09-02 至 2011-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7660987
• 关键词: Innovative; therapies; elimate; persistent; HIV

DESCRIPTION (provided by applicant): No one with HIV infection has been cured, despite the development of effective antiretroviral therapy. Nevertheless, stable remission or cure of infection is the ultimate goal of HIV therapy. The difficulties of lifelong therapy make it imperative to understand the obstacles to eradication of HIV infection. Several molecular mechanisms restrict proviral expression and can contribute to proviral persistence. Targeted therapeutics directed at these mechanisms may therefore be developed, designed to augment HIV promoter and viral expression without global T cell activation or increased de novo HIV infection. Such agents that induce expression of latent HIV but do not enhance de novo infection would be a major advance towards the eradication of HIV infection. Three collaborative projects will allow iterative evaluation and development of reagents to interrupt HIV latency. Project 1 will identify novel drug candidates to target persistent HIV infection, evaluate the effects of these agents on human gene expression, and perform preclinical assessment of PK/PD in pilot studies. Project 2 will establish the fully suppressive antiviral therapies in the BLT murine model of HIV infection, and test the ability of reagents to delay or prevent viral rebound after the interruption of antiviral therapy. Project 3 will establish tissue culture testing platforms, perform ex vivo studies in resting CD4 T cells obtained from HIV-infected volunteers, and implement a human study to deplete HIV infection in resting T cells. This IPCP collaborative will evaluate new anti-latency therapeutics in a continuum of cell culture models, a novel murine model, and primary human cells, leading ultimately to the rational implementation of human trials to target HIV latency and move towards eradication of HIV infection. RELEVANCE (See instructions): Anti-retroviral therapy has not lead to the eradication of virus from HIV-infected individuals. This is due in part to the ability of HIV to establish latency in resting CD4+ T-lymphocytes. Our approach to overcome HIV latency is to develop agents capable of inducing expression of quiescent HIV without enhancing new infection, so that persistent viral infection may be cleared. We will study novel candidate anti-latency drugs in a novel mouse model system, in cells from HIV infected patients, and ultimately in patients. PROJECT 1: [TITLE (Hazuda, D)] PROJECT 1 DESCRIPTION (provided by applicant): The long term goal of therapy for HIV-1 infection should be to develop treament regimens which can provide durable control of viral replication and/or eradicate the infection. Included among the limitations of current therapy is the incomplete suppression of viral replication in many patients and the inability to targent persistent, replication-competent proviral genomes. While new agents in development may enhance the overall potency and long term durability of antretroviral treatments, these will not address the long term problem of latency. The current program application proposes to evalaute the hypothesis that therapeutics can be developed that can disrupt proviral quiescence in vivo. This hypothesis is based on in vitro observations that have provided compelling evidence that HIV-1 latency is maintained by cellular mechanisms which affect chromatin and regulate cofactor availability to the provirus. These studies demonstrate that derepression of HIV-1 transcription can be induced without activating T-cells. In Project 1 of this Program, we will identify novel molecules that induce the expression of latent provirus, and provide these reagents for studies in the BLT mouse model (Project 2), and in primary human cell systems and clinical experiments (Project 3). The objectives of Project 1 include providing potent integrase inhibitors for a novel combination regimen (ART) that will be effective in fully suppressing HIV replication in the BLT mouse model, to identify novel inducers of latent proviral expression, and to use biomarker assays to prioritize these molecules for further study in Projects 2 and 3. The overall objective is to identify mechanisms for therapeutic targeting to disrupt HIV latency, and assess the susceptibility of proviral genomes to therapeutic intervention, with the ultimate goal of establishing treatment paradigms suitable for clinical testing. RELEVANCE: Despite antiviral therapy, eradication of HIV infection is unachievable as the virus can establish latency in CD4+ cells. This Project will seek to develop agents capable of inducing expression of quiescent HIV without enhancing new infection, so that persistent viral infection may be cleared. Within the Integrated Program, we will facilitate the study of "anti-latency therapy" on cells from HIV infected patients, and in model systems to move towards reagents might be used in future efforts to clear HIV infection.

描述（由申请人提供）： 尽管有有效的抗逆转录病毒疗法发展，但没有人治愈HIV感染的人。然而，稳定的缓解或治愈感染是艾滋病毒治疗的最终目标。终身治疗的困难使得必须了解根除HIV感染的障碍。几种分子机制限制了病毒的表达，并可能导致病毒持久性。因此，可以开发针对这些机制的靶向治疗剂，旨在增强HIV启动子和病毒表达，而无需全局T细胞激活或增加从头艾滋病毒感染。这种诱导潜在艾滋病毒但不增强从头感染的药物将是消除HIV感染的重大进步。三个协作项目将允许迭代评估和开发试剂中断艾滋病毒潜伏期。项目1将确定靶向持续性艾滋病毒感染的新型药物候选物，评估这些药物对人基因表达的影响，并在试点研究中对PK/PD进行临床前评估。项目2将在HIV感染的BLT鼠模型中建立完全抑制性的抗病毒疗法，并测试试剂在抗病毒疗法中断后延迟或预防病毒反弹的能力。项目3将建立组织培养测试平台，对从HIV感染的志愿者获得的静息CD4 T细胞进行离体研究，并实施人类研究以耗尽静息T细胞中的HIV感染。该IPCP协作将在细胞培养模型，一种新型的鼠模型和原代人类细胞的连续性中评估新的抗延迟治疗剂，最终导致人类试验的合理实施，以靶向HIV潜伏期，并朝着消除HIV感染迈向艾滋病毒。相关性（请参阅说明）：抗逆转录病毒疗法并未导致艾滋病毒感染者根除病毒。这部分是由于HIV在静止的CD4+ T淋巴细胞中建立潜伏期的能力。我们克服艾滋病毒潜伏期的方法是开发能够诱导静态艾滋病毒表达的药物而不会增强新感染，以便可以清除持续的病毒感染。我们将在新型的小鼠模型系统，HIV感染患者的细胞以及最终在患者中研究新型候选抗延迟药物。 项目1：[标题（Hazuda，d）] 项目1描述（申请人提供）： HIV-1感染治疗的长期目标应该是开发疾病方案，该方案可以提供对病毒复制和/或消除感染的持久控制。包括当前疗法的局限性包括许多患者对病毒复制的不完全抑制，以及无焦油持续性，具有复制能力的前病毒基因组。尽管开发中的新代理可以提高腹膜病毒治疗的总体效力和长期耐用性，但这些方法将无法解决长期的延迟问题。当前的计划申请提出了评估可以开发可以破坏体内前病毒静止的治疗剂的假设。该假设是基于体外观察结果，这些观察结果提供了令人信服的证据，表明HIV-1潜伏期是通过影响染色质并调节辅助因子的细胞机制维持的。这些研究表明，可以在不激活T细胞的情况下诱导HIV-1转录的压抑。在该程序的项目1中，我们将确定诱导潜在病毒表达的新分子，并为BLT小鼠模型（项目2）以及原代人细胞系统和临床实验提供这些试剂（项目3）。项目1的目标包括为一种新型组合方案（ART）提供有效的整合酶抑制剂，该抑制剂将有效地完全抑制BLT鼠标模型中的HIV复制，以识别潜在的预炎性表达的新型诱导者，并使用生物标志物测定法，并使用这些分子来确定整体目标和3个项目。前病毒基因组对治疗干预的敏感性，其最终目的是建立适合临床测试的治疗范例。相关性：尽管抗病毒疗法，但根除HIV感染是无法实现的，因为该病毒可以在CD4+细胞中建立潜伏期。该项目将寻求开发能够在不增强新感染的情况下诱导静态HIV表达的药物，从而可以清除持续的病毒感染。在综合计划中，我们将促进对来自HIV感染患者的细胞的“抗延迟治疗”的研究，在模型系统中朝向试剂的模型系统中，可能会用于清除HIV感染的未来努力。