Analysis of HIV-1 core assembly and inhibition

描述（由申请人提供）：艾滋病流行已夺去了数百万人的生命，目前还有数百万人感染艾滋病毒。 HAART（高效抗逆转录病毒疗法）针对病毒逆转录酶（RT）和蛋白酶（PR），是目前治疗艾滋病毒感染的首选疗法，并延长了许多感染者的生命。然而，由于艾滋病毒具有获得耐药性的能力，因此必须继续开发替代疗法。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 核心是圆锥形或圆柱形结构，由病毒衣壳 (CA) 蛋白组成，围绕病毒颗粒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，无法形成这样的核心对于病毒复制来说是致命的。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，以便了解潜在的抑制剂如何工作，并确定新的抑制剂如何阻止该过程中的特定瓶颈。我们提出的研究旨在解决这一需求，并利用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颖方法。通过这些努力，HIV-1核心形成的具体步骤将被阐明，并且将发现阻止这些步骤的机制。我们的目标如下： 1. HIV-1核心组装成核及其抑制机制的表征。 2. 阐明成熟的HIV核心寡聚化和形态发生组装步骤。 3. 成熟HIV-1核心稳定性控制因素分析。我们对 HIV-1 核心的成核、生长和稳定性的研究将促进针对新病毒过程的抗病毒疗法的开发。 公共卫生相关性：我们的研究重点是成熟 HIV-1 病毒核心组装和形态发生的机制。我们建议描述 HIV-1 核心形成的步骤，阐明该过程的潜在抑制剂如何发挥作用，并确定新的抑制剂如何阻止该过程中的特定瓶颈。这些研究与公共卫生具有直接相关性，因为它们将导致新的抗病毒药物的开发并了解它们的作用原理。

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. PUBLIC HEALTH RELEVANCE: Narrative our investigations focus on the mechanism of mature HIV-1 virus core assembly and morphogenesis. We propose to characterize the steps by which HIV-1 cores are formed, to clarify how potential inhibitors of the process work, and to identify how new inhibitors might block specific bottlenecks in the process. These studies are of direct public health relevance in that they will lead to the development of new antivirals and an understanding of how they work.