The Biophysics of Virus Capsid Assembly

描述（由申请人提供）：乙型肝炎病毒（HBV）是世界范围内发病率和死亡率的主要原因。每年约有3.5亿人患有慢性乙肝病毒，约60万人死于其后遗症。HBV是一种包膜病毒，具有二十面体核心，也具有代谢室的功能。事实上，核心蛋白在HBV复制的许多要素中起着多效性作用。为了实现多种功能，我们假设蛋白质和组装核心有复杂的变构调节。我们将研究空核的组装，并将其与核酸底物上的核组装联系起来。我们将研究核在核酸底物上的组装，并将其与逆转录联系起来。我们的初步数据表明，核心在逆转录中起积极作用；它不仅仅是一个被动容器。我们将把核心结构和逆转录之间的协同作用与核心的细胞内定位联系起来。通过强调这些相关性的结构基础，我们将定义与组装、病毒RNA的逆转录和细胞内核心运输相关的机制。在过去的几年中，HBV核心蛋白已成为抗病毒治疗的靶点。在我们的建议中描述的研究将作为确定这些抗病毒分子的分子机制的基础。

DESCRIPTION (provided by applicant): Hepatitis B virus (HBV) is a major cause of morbidity and mortality, worldwide. About 350 million people suffer from chronic HBV and about 600,000 die from its sequellae annually. HBV is an enveloped virus with an icosahedral core that also functions as a metabolic compartment. Indeed, the core protein plays pleiotropic roles in many elements of HBV replication. To accomplish multiple functions we hypothesize a complex allosteric regulation of the protein and the assembled core. We will study assembly of empty cores and correlate that with assembly of cores on nucleic acid substrates. We will examine assembly of cores on nucleic acid substrates and correlate that with reverse transcription. Our preliminary data indicates that the core plays an active role in reverse transcription; it is much more than a passive container. We will correlate the synergism between core structure and reverse transcription with intracellular localization of core. By emphasizing the structural basis f these correlations, we will define the mechanisms relating assembly, reverse transcription of viral RNA, and core trafficking within a cell. In the last few years, the HBV core protein has emerged as a target for antiviral therapeutics. The studies described in our proposal will serve as a basis for defining molecular mechanisms of such antiviral molecules.