Structure and function of the assembled protein network of HIV-1 and its changes upon maturation

感染性HIV-1和其他逆转录病毒的形态发生涉及Gag多聚蛋白晶格的组装、主要由未裂解的Gag多聚蛋白组成的未成熟的非感染性病毒从质膜的颗粒释放以及Gag蛋白水解后成熟为具有其特征性锥形形态的感染性病毒。在我们与John Briggs（现为LMB剑桥）的联合项目中，我们确定了未成熟Gag晶格中CA（衣壳）结构域的高分辨率结构，确定了控制衣壳结构成熟的中心开关，并确定了HIV-1和MLV成熟衣壳中的CA晶格结构。基于这些结果，我们现在计划继续与John Briggs合作，以识别和结构表征HIV-1成熟中间体，确定MA（基质）晶格的结构和组织及其在成熟过程中的变化以及其与病毒糖蛋白的潜在关联，并表征基因组逆转录过程中和/或宿主因子结合时衣壳结构的变化。该项目继续我们正在进行的合作，沿着病毒复制步骤的过程中，并将这项工作扩展到其他必要的病毒体成分的结构分析和它们的变化过程中成熟的感染性病毒体。

Morphogenesis of infectious HIV-1 and other retroviruses involves assembly of the Gag polyprotein lattice, particle release of the immature, non-infectious virus consisting largely of uncleaved Gag polyproteins from the plasma membrane and maturation to the infectious virus with its characteristic cone-shaped morphology following Gag proteolysis. In our joint project with John Briggs (now LMB Cambridge), we have determined the high resolution structure of the CA (capsid) domain in the immature Gag lattice, have identified the central switch controlling architectural maturation of the capsid and have determined the CA lattice structure in the mature capsid for both HIV-1 and MLV. Based on these results, we now plan in our continued collaboration with John Briggs to identify and structurally characterize HIV-1 maturation intermediates, to determine the structure and organization of the MA (matrix) lattice and its changes during maturation as well as its potential association with the viral glycoproteins and to characterize changes in capsid architecture during reverse transcription of the genome and/or upon host factor binding. This project continues our ongoing collaboration along the course of viral replication steps and extends this work to structural analysis of other essential virion components and their changes during the course of maturation to the infectious virion.