Analysis of HIV-1 core assembly and inhibition

HIV-1核心组装和抑制分析

• 批准号: 8546425
• 负责人: ERIC W BARKLIS
• 金额: $ 28.24万
• 依托单位: OREGON HEALTH & SCIENCE UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2012
• 资助国家: 美国
• 起止时间: 2012-09-30 至 2016-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8546425
• 关键词: Acquired Immunodeficiency Syndrome; Address; Affect; Alternative Therapies; Antiviral Agents; Antiviral Therapy; Biological Assay; Capsid; Capsid Proteins; Clinical; Complex; Core Assembly; Development; Drug resistance; Environment; Enzymes; Epidemic; Factor Analysis; Failure; Fostering; Growth; HIV; HIV Infections; HIV-1; Highly Active Antiretroviral Therapy; Individual; Investigation; Lead; Morphogenesis; Nature; Pathway interactions; Peptide Hydrolases; Pharmaceutical Preparations; Process; RNA-Directed DNA Polymerase; Resources; Ribonucleoproteins; Structure; Therapeutic; Viral; Virion; Virus; Virus Replication; Work; gag Gene Products; inhibitor/antagonist; mutant; novel; novel strategies; particle; public health relevance; virus core

DESCRIPTION (provided by applicant): The AIDS epidemic has claimed millions of lives, and millions more are currently infected with HIV. HAART (highly active antiretroviral therapy), which is directed against the viral reverse transcriptase (RT) and protease (PR) enzymes, is the preferred present treatment for HIV infections, and has extended the lives of many infected individuals. However, because of the capacity of HIV to acquire drug-resistance, the continued development of alternative therapies is imperative. The critical process of forming a mature virus core represents an attractive new target for antiviral therapies. Mature HIV-1 cores are conical or cylindrical structures composed of the viral capsid (CA) protein that surrounds the ribonucleoprotein complexes in virions. The morphogenesis of an infectious virus core appears to be exquisitely sensitive, and failure to form such a core is fatal to virus replication. However the mechanisms that regulate the many steps of core assembly nucleation and growth require characterization in order to understand how potential inhibitors work, and to identify how new inhibitors might block specific bottlenecks in the process. The investigations we propose address this need, and take advantage of our lab's expertise, our unique resources, and the novel approaches that we have devised and invented. Through these efforts the specific steps of HIV-1 core formation will be elucidated, and mechanisms by which these steps can be blocked will be discovered. Our aims are as follows: 1. Characterization of the mechanism of HIV-1 core assembly nucleation and its inhibition. 2. Elucidation of mature HIV core oligomerization and morphogenesis assembly steps. 3. Analysis of factors controlling mature HIV-1 core stabilities. Our investigations on the nucleation, growth and stability of HIV-1 cores will foster the development of antiviral therapeutics against new viral processes.

说明（由申请人提供）：艾滋病流行病夺去了数百万人的生命，目前还有数百万人感染了艾滋病毒。针对病毒逆转录酶（RT）和蛋白酶（PR）酶的高效抗逆转录病毒疗法（HAART）是目前治疗艾滋病毒感染的首选方法，并延长了许多感染者的生命。然而，由于艾滋病毒获得耐药性的能力，继续发展替代疗法是必要的。形成成熟病毒核心的关键过程代表了抗病毒治疗的一个有吸引力的新靶点。成熟的HIV-1核是由病毒衣壳（CA）蛋白组成的圆锥形或圆柱形结构，它包围着病毒粒子中的核糖核蛋白复合物。传染性病毒核心的形态发生似乎非常敏感，不能形成这样的核心对病毒复制是致命的。然而，调节核心组装成核和生长的许多步骤的机制需要表征，以了解潜在的抑制剂如何起作用，并确定新的抑制剂如何阻断过程中的特定瓶颈。我们提出的研究解决了这一需求，并利用了我们实验室的专业知识，我们独特的资源，以及我们设计和发明的新方法。通过这些努力，HIV-1核心形成的具体步骤将被阐明，这些步骤可以被阻断的机制将被发现。我们的目标如下：HIV-1核心组装成核机制的表征及其抑制作用。2. 成熟HIV核心寡聚化和形态发生组装步骤的阐明。3. 控制成熟HIV-1核心稳定性的因素分析。我们对HIV-1核的成核、生长和稳定性的研究将促进针对新病毒过程的抗病毒治疗的发展。