Architecture and dynamics of immature HIV lattice

项目概要： 我们的长期目标是从分子水平上了解调节蛋白质组装、释放 和感染性HIV病毒粒子的成熟。新释放的艾滋病毒粒子是不成熟的，有一个蛋白质晶格 （主要是Gag多聚蛋白），支撑着它们的病毒膜。通过蛋白水解，HIV酶帮助 将这个晶格转变成一个圆锥形的成熟核心，之后病毒就具有了传染性。成熟抑制剂， 一种新型的抗病毒药物，被设计成与未成熟的晶格结合并干扰这种转化。 在前一个奖项期间，我们表明，不成熟晶格的稳定性取决于其他艾滋病毒 除了Gag多聚蛋白外，HIV病毒粒子的小尺寸使得研究它们的晶格动力学成为可能 具有挑战性，因此，我们开发了生物物理，成像和计算方法，使这些 测量.我们在这个颁奖期间有两个主要目标。我们的首要目标是研究 不同的非Gag组分对未成熟晶格的稳定性的影响，并确定生物分子的性质。 我们的第二个目标是确定晶格内的动力学如何驱动HIV的激活 酶和启动成熟过程。通过加深我们对生物力学原理的理解 控制艾滋病毒的不成熟晶格及其成熟，我们的研究将为下一代的设计提供信息， 新一代抗病毒药物以及未来的慢病毒系统。

Project Summary: Our long-term goal is to gain a molecular understanding of the machinery that regulates the assembly, release, and maturation of infectious HIV virions. Newly released HIV virions are immature and have a lattice of proteins (mainly the Gag polyprotein) that underpins their viral membrane. Through proteolysis, HIV enzymes help transform this lattice into a conical mature core, after which the virus becomes infectious. Maturation Inhibitors, a new class of antiviral drugs, are designed to bind to the immature lattice and interfere with this transformation. During the previous award period, we showed that the stability of the immature lattice is dependent on other HIV components aside from the Gag polyprotein. The small size of HIV virions makes studying their lattice dynamics challenging, therefore, we developed biophysical, imaging, and computational methods to enable these measurements. We have two main aims for this award period. Our first aim is to investigate the specific effects of different non-Gag components on the stability of the immature lattice and determine the nature of biomolecular forces stabilizing it. Our second aim is to determine how dynamics within the lattice drive the activation of HIV enzymes and kick start the maturation process. By advancing our understanding of the biomechanical principles governing the immature lattice of HIV and its maturation, our studies will inform both the design of next- generation antivirals as well as future lentiviral systems.