Laboratory of Cell Biology, Center for Cancer Research, National Cancer Institute, NIH, Bethesda, Maryland, United States of America.
PLoS Pathog. 2010 Dec 23;6(12):e1001249. doi: 10.1371/journal.ppat.1001249.
The initial step in target cell infection by human, and the closely related simian immunodeficiency viruses (HIV and SIV, respectively) occurs with the binding of trimeric envelope glycoproteins (Env), composed of heterodimers of the viral transmembrane glycoprotein (gp41) and surface glycoprotein (gp120) to target T-cells. Knowledge of the molecular structure of trimeric Env on intact viruses is important both for understanding the molecular mechanisms underlying virus-cell interactions and for the design of effective immunogen-based vaccines to combat HIV/AIDS. Previous analyses of intact HIV-1 BaL virions have already resulted in structures of trimeric Env in unliganded and CD4-liganded states at ~20 Å resolution. Here, we show that the molecular architectures of trimeric Env from SIVmneE11S, SIVmac239 and HIV-1 R3A strains are closely comparable to that previously determined for HIV-1 BaL, with the V1 and V2 variable loops located at the apex of the spike, close to the contact zone between virus and cell. The location of the V1/V2 loops in trimeric Env was definitively confirmed by structural analysis of HIV-1 R3A virions engineered to express Env with deletion of these loops. Strikingly, in SIV CP-MAC, a CD4-independent strain, trimeric Env is in a constitutively "open" conformation with gp120 trimers splayed out in a conformation similar to that seen for HIV-1 BaL Env when it is complexed with sCD4 and the CD4i antibody 17b. Our findings suggest a structural explanation for the molecular mechanism of CD4-independent viral entry and further establish that cryo-electron tomography can be used to discover distinct, functionally relevant quaternary structures of Env displayed on intact viruses.
人类和密切相关的猿猴免疫缺陷病毒（分别为 HIV 和 SIV）感染靶细胞的初始步骤是通过三聚体包膜糖蛋白（Env）的结合来实现的，该糖蛋白由病毒跨膜糖蛋白（gp41）和表面糖蛋白（gp120）的异二聚体组成，与靶 T 细胞结合。了解完整病毒上三聚体 Env 的分子结构对于理解病毒-细胞相互作用的分子机制以及设计有效的基于免疫原的疫苗来对抗 HIV/AIDS 都非常重要。以前对完整 HIV-1 BaL 病毒粒子的分析已经导致了在未结合和 CD4 结合状态下约 20Å 分辨率的三聚体 Env 的结构。在这里，我们表明，SIVmneE11S、SIVmac239 和 HIV-1 R3A 株的三聚体 Env 的分子结构与之前确定的 HIV-1 BaL 非常相似，V1 和 V2 可变环位于刺突的顶点，靠近病毒和细胞的接触区。通过对工程表达缺失这些环的 HIV-1 R3A 病毒粒子的结构分析，明确证实了三聚体 Env 中的 V1/V2 环的位置。引人注目的是，在 CD4 非依赖性株 SIV CP-MAC 中，三聚体 Env 处于固有“开放”构象，gp120 三聚体展开，构象类似于与 sCD4 和 CD4i 抗体 17b 复合时 HIV-1 BaL Env 看到的构象。我们的发现为 CD4 非依赖性病毒进入的分子机制提供了结构解释，并进一步证实了低温电子断层摄影术可用于发现完整病毒上展示的不同、功能相关的 Env 四级结构。
