Targeting regulators of cellular gene transcription to impact HIV latency

描述（由申请人提供）：抗逆转录病毒治疗的影响是现代药物发现、开发和实施的能力和成功的主要证明。然而，在受感染的个体中，这种成功仅持续到坚持该方案。停止治疗会导致病毒反弹，需要长期、终身给予抗逆转录病毒治疗。终身治疗的要求是由于无法耗尽潜伏感染细胞的持久储存库。无可否认，该应用雄心勃勃的最终目标是清除潜伏感染的宿主，目的是根除感染或充分减少艾滋病毒宿主，以实现持久的免疫控制。该计划项目设计了三个项目和两个科学核心。项目1将为初步研究鉴定和表征有效的组蛋白去乙酰化酶抑制剂，同时使用人类基因组siRNA文库鉴定小分子干预的其他靶点。将在以下模型中系统评价这些治疗策略：（1）我们实验室开发的潜伏感染原代人CD 4淋巴细胞体外模型（项目2），（2）从慢性感染、HAART抑制患者中离体获得的CD 4淋巴细胞（项目2），和（3）SIV/恒河猴模型（项目1）。潜在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（包括整合的DNA）和CD 4淋巴细胞在活化后表达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中的感染。在评估治疗疗效和最大限度地减少毒性的同时，这些针对宿主功能的干预措施的潜在附带免疫学后果将在项目3中进行系统表征。这种高度协调的合作，从目标和药物发现到动物模型概念验证，将揭示有关艾滋病毒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。

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.