科学家阐明HIV拦截宿主细胞实现病毒不断增殖的分子机理
日前，一项刊登在国际杂志Proceedings of the National Academy of Sciences上的研究报告中，来自芝加哥大学的研究人员利用计算机模拟技术成功揭示了此前关于HIV的一种未知细节，即HIV是如何强迫宿主细胞扩散病毒从而进入到其它细胞中的，相关研究发现有望帮助研究人员开发治疗HIV感染的新型疗法。http://cache1.bioon.com/webeditor/uploadfile/201711/20171110231102667_s.jpg图片来源：Voth et. al / University of ChicagoHIV能够成功感染宿主的一个关键技巧就是其能在宿主细胞内部不断进行病毒繁殖，一旦病毒感染细胞后，其就会驱动细胞利用自身的膜来制造胶囊结构，而胶囊结构中充满着HIV病毒，这种胶囊能够进行修剪（即芽殖过程），同时不断漂流感染更多宿主机体细胞，一旦进入到另一个值得信任的细胞中，胶囊就会破裂从中释放出HIV的RNA结构。科学家们都知道，芽殖过程主要涉及了HIV中名为Gag的蛋白复合体，但其中所涉及的具体分子过程研究人员并不清楚；如今研究人员已经知道了最终的组装结构，但所有的细节信息他们不得而知。研究者Gregory Voth表示，利用成像技术我们很难获取该蛋白复合体在分子层面上的图像，而这项研究中，我们构建了一种计算机模型技术来模拟Gag蛋白复合体的作用方式，模拟技术能够让研究者对模型进行调节以使其更清楚地观测到分子过程的构建过程，随后研究人员在实验室中进行实验对观察到的结构进行了证实。研究者构建了缺少Gag蛋白复合体关键部分的模型，随后他们对其进行调节以便能够清楚观察到蛋白质如何利用宿主细胞的基础结构来开启芽殖过程，进而组装关键蛋白的产生。这项研究阐明了利用现代计算机技术来模拟病毒活动的强大力量。研究者希望一旦他们掌握了HIV的致命弱点，或许就有望开发出新型药物来阻断Gag蛋白复合体的积累，从而有效遏制HIV的增殖。下一步研究人员计划在HIV开启芽殖过程后对其Gag蛋白的结构进行深入研究。（生物谷Bioon.com）
Immature HIV-1 lattice assembly dynamics are regulated by scaffolding from nucleic acid and the plasma membrane
Alexander J. Paka,b,c, John M. A. Grimea,b,c, Prabuddha Senguptad,e, Antony K. Chene,f, Aleksander E. P. Durumerica,b,c, Anand Srivastavag, Mark Yeagerh,i, John A. G. Briggsj,k, Jennifer Lippincott-Schwartzd,e, and Gregory A. Votha,b,c,1
The packaging and budding of Gag polyprotein and viral RNA is a critical step in the HIV-1 life cycle. High-resolution structures of the Gag polyprotein have revealed that the capsid (CA) and spacer peptide 1 (SP1) domains contain important interfaces for Gag self-assembly. However, the molecular details of the multimerization process, especially in the presence of RNA and the cell membrane, have remained unclear. In this work, we investigate the mechanisms that work in concert between the polyproteins, RNA, and membrane to promote immature lattice growth. We develop a coarse-grained (CG) computational model that is derived from subnanometer resolution structural data. Our simulations recapitulate contiguous and hexameric lattice assembly driven only by weak anisotropic attractions at the helical CA–SP1 junction. Importantly, analysis from CG and single-particle tracking photoactivated localization (spt-PALM) trajectories indicates that viral RNA and the membrane are critical constituents that actively promote Gag multimerization through scaffolding, while overexpression of short competitor RNA can suppress assembly. We also find that the CA amino-terminal domain imparts intrinsic curvature to the Gag lattice. As a consequence, immature lattice growth appears to be coupled to the dynamics of spontaneous membrane deformation. Our findings elucidate a simple network of interactions that regulate the early stages of HIV-1 assembly and budding.
http://www.pnas.org/content/early/2017/10/31/1706600114
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