Targeting regulators of cellular gene transcription to impact HIV latency

靶向细胞基因转录调节因子以影响 HIV 潜伏期

• 批准号: 7860484
• 负责人: DOUGLAS D RICHMAN
• 金额: $ 87.1万
• 依托单位: VETERANS MEDICAL RESEARCH FDN/SAN DIEGO
• 依托单位国家: 美国
• 财政年份: 2009
• 资助国家: 美国
• 起止时间: 2009-06-05 至 2011-12-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7860484
• 关键词: Targeting; regulators; cellular; gene; transcription

DESCRIPTION (provided by applicant): The impact of antiretroviral therapy represents a major demonstration of the capability and success of modern drug discovery, development, and implementation. Nevertheless, in infected individuals this success lasts only as long as adherence to the regimen is maintained. Discontinuation of treatment results in viral rebound, necessitating the chronic, lifelong administration of antiretroviral therapy. The requirement for lifelong therapy results from the inability to deplete the persistent reservoir of latently infected cells. The admittedly ambitious ultimate goal of this application is to purge the latently infected reservoir with the objective of eradicating the infection or minimizing the HIV reservoir sufficiently to attain durable immunologic control. This Program Project has been designed with three Projects and two Scientific Cores. Project 1 will identify and characterize potent histone deacetylase inhibitors for the initial studies, while using a human genome siRNA library to identify additional targets for small molecule intervention. These treatment strategies will be systematically evaluated in the following models: (1) the in vitro model of latently infected primary human CD4 lymphocytes developed in our laboratory (Project 2), (2) CD4 lymphocytes obtained ex vivo from chronically infected, HAART-suppressed patients (project 2), and (3) an SIV/Rhesus macaque model (Project 1). Latent infection will be quantified by the two scientific cores. The Molecular Virology Core will measure infectivity, HIV (SIV) nucleic acid species including integrated DNA, and ability of CD4 lymphocytes to express p24 (p27) upon activation. The Molecular Imaging Core (Haase lab) will quantify and characterize infection in antiretroviral drug-suppressed cells from the in vitro HIV model and from macaque tissues. While assessing treatment efficacy and minimizing toxicity, potential collateral immunological consequences of these interventions targeted to host functions will be systematically characterized in Project 3. This highly coordinated, collaboration which ranges from target and drug discovery through animal model proof-of-concept will reveal new insights regarding the pathogenetic mechanisms of HIV latency; however, the goal of the Program Project is to cure AIDS.

描述（由申请人提供）：抗逆转录病毒疗法的影响代表了现代药物发现、开发和实施的能力和成功的重要证明。然而，对于感染者来说，只有坚持坚持治疗方案，这种成功才能持续。停止治疗会导致病毒反弹，需要长期、终生服用抗逆转录病毒治疗。终生治疗的要求是由于无法耗尽潜伏感染细胞的持久储存库。诚然，该应用雄心勃勃的最终目标是清除潜伏感染的病毒库，以消除感染或充分减少艾滋病毒病毒库，以获得持久的免疫控制。该计划项目设计有三个项目和两个科学核心。项目 1 将鉴定和表征用于初步研究的有效组蛋白脱乙酰酶抑制剂，同时使用人类基因组 siRNA 库来鉴定小分子干预的其他靶点。这些治疗策略将在以下模型中进行系统评估：（1）我们实验室开发的潜伏感染原代人 CD4 淋巴细胞体外模型（项目 2），（2）从慢性感染、HAART 抑制患者离体获得的 CD4 淋巴细胞（项目 2），以及（3）SIV/恒河猴模型（项目 1）。潜伏感染将通过两个科学核心进行量化。分子病毒学核心将测量感染性、HIV (SIV) 核酸种类（包括整合 DNA）以及 CD4 淋巴细胞激活后表达 p24 (p27) 的能力。分子成像核心（Haase 实验室）将量化和表征来自体外 HIV 模型和猕猴组织的抗逆转录病毒药物抑制细胞的感染。在评估治疗效果和最大限度地减少毒性的同时，项目 3 将系统地描述这些针对宿主功能的干预措施的潜在附带免疫后果。这种高度协调的合作范围从靶点和药物发现到动物模型概念验证，将揭示有关 HIV 潜伏期发病机制的新见解；然而，该计划项目的目标是治愈艾滋病。