里程碑式的发现－科学家扫描出了艾滋病病毒图片
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佛罗里达州立大学扫描出了艾滋病病毒图片，图片可能指导相应疫苗的研制。《自然》杂志网络版发表了这一里程碑式的发现。
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【DavidShi译文】【美国佛罗里达州首府塔拉哈西报道】在确诊首例艾滋病的25周年的时候，佛罗里达州立大学的科学家们获得了重大的研究进展：他们扫描出了该病毒以及病毒表面的用于吸附与融合人类免疫细胞的蛋白刺突的三维图像。
该发现可能加速研制出相应疫苗，从而通过靶向定位和削弱1型艾滋病病毒蛋白刺突的黏性来阻断该病毒的感染。
这些结果发表于《自然》杂志网络版。
人们首次得到该病毒和病毒刺突如此精细的超级图像。由此，研究人员第一次仔细地看到了该病原体用于感染的复杂的分子表面结构。
“尽管很多实验室作了一些深入的研究，人们至今对刺突的详细结构和它们在病毒表面的分布方式所知甚少，这限制了我们对病毒究竟如何发生感染的认识，影响了疫苗的研制，”鲁（音译）说。
为了扫描出这些图片，研究助理鲁平朱（音译）和同事们使用了一种称作冷冻电镜断层摄影术（cryoelectron microscopy tomography）的神奇技术。此项技术产生的三维图像和计算机化轴向X线断层摄影扫描类似，但冷冻电镜断层摄影术应用于病毒和分子水平，而不是组织和器官水平。
他们扫描了艾滋病病毒样品和一种非灵长类的病毒突变株。国立癌症研究所的合作者设计出该突变株，它表达约74种刺突，加上艾滋病病毒的14种刺突，这样更多的刺突有利于开展研究。他们先将病毒样品悬浮于微型铜网薄液膜上，而后快速冷冻，形成比小方冰块内的水晶还要清澈透明的冰粒。
样品被置入电镜后，电子束开始从多角度轰击样品，形成了放大43,000倍以上的图像，从而显示出令人惊讶的结构－没有更为典型的需要烘干和染色样品的成像方法所产生的扭曲效果。
由此研究人员开始能够研究该病毒的被膜－包裹病毒的脂膜。他们扫描了伸出被膜的刺突，刺突含有艾滋病病毒表面唯一的病毒蛋白分子。这些科学家们因而也获得了刺突的头部和柄部的超级图像。刺突头部负责将病毒吸附到靶细胞上。刺突柄部负责融合作用，在融合过程中，艾滋病病毒将自身基因注入具有天然亲和力的宿主细胞－T淋巴细胞和巨噬细胞。
“能有效结合这些刺突结构的抗体会中和病毒，从而阻止感染，”鲁说。自1978年以来，鲁一直是佛罗里达州立大学生物学专业的一名教职员。
最让他吃惊的是：柄部有分支。
“人们曾经认为刺突柄部由三股紧密结合成，刺突顶部向上突出。但我们的图像揭示，柄部分成三个分支，像三角架一样撑着，这加强了它们和病毒表面间的结合能力，”鲁说。“三角架式柄部提示，1型艾滋病病毒存在一种有效融合人体细胞的新机制。”
佛罗里达州立大学艺术和科学院院长约瑟夫·特拉维斯声称这项工作是“应用坚实可靠的基础科学解决了大难题的绝好例子。”
国家卫生研究院资助了此项为期2年的研究。佛罗里达州立大学生物系和分子生物物理学研究所的人员开展了这项研究。
艾滋病是迄今最恶劣的世界流行病之一。全球约2千5百万人死于此病，4千万人受感染－其中1百万在美国。
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1型艾滋病病毒表面的被膜刺突
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（作者：利比·费尔赫斯特）
【英文原文】
FSU research published in Nature produces images of AIDS virus that may shape vaccine
by Libby Fairhurst
As the world marks the 25th year since the first diagnosed case of AIDS, groundbreaking research by scientists at Florida State University has produced remarkable three-dimensional images of the virus and the protein spikes on its surface that allow it to bind and fuse with human immune cells.
Envelope spikes on surface of HIV-1 virusFindings from this AIDS research could boost the development of vaccines that will thwart infection by targeting and crippling the sticky HIV-1 spike proteins. In fact, said principal investigator and FSU Professor Kenneth H. Roux, at least two laboratories already are crafting vaccine candidates based on preliminary results uncovered by his team of structural biologists.
Those results are described in the May 24 online edition of the journal Nature.
Never before generated in such intricate detail, the super-sized images of the virus and its viral spikes have given researchers their first good look at the pathogen's complex molecular surface architecture that facilitates the infection process.
"Until now, despite intensive study by many laboratories, the design details of the spikes and their distribution pattern on the surface of the virus membrane have been poorly understood, which has limited our understanding of how the virus infection actually occurs and frustrated efforts to create vaccines," Roux said.
To produce the images, research associate Ping Zhu, Roux and their colleagues used a state-of-the art technique called cryoelectron microscopy tomography. It generates three-dimensional images similar to those from a CAT scan, but at the level of viruses and molecules rather than tissues and organs.
They imaged HIV samples as well as a mutant SIV (non-human primate) strain, genetically engineered for the study by collaborators at the National Cancer Institute to express about 74 spikes as opposed to the 14 found on the HIV virus—more spikes make it easier to work with. The virus samples were suspended in a thin liquid film stretched across the holes of a small copper grid and then flash-frozen, creating a solid form of ice that is more like clear glass than the typical crystalline form in ice cubes.
Once inside the electron microscope, electrons bombarded the samples from myriad angles, magnifying it more than 43,000 times to reveal its surprising structure—without the degree of distortion caused by the more typical imaging methods involving drying and staining of specimens.
As a result, the researchers were able to hone in on the envelope—the lipid membrane covering the virus itself. They imaged the spikes protruding from the envelope, which contain the only viral protein molecules on the HIV surface.
The FSU scientists also were able to capture super-sized images of both the head of the spike and its supporting stalk. The spike head is responsible for binding the virus to the target cell. Its stalk is responsible for the fusion event in which HIV injects its genes into the human host cells for which the virus has a natural affinity—T lymphocytes and macrophages.
"Antibodies that effectively bind to either of these spike parts will neutralize the virus to prevent infection," said Roux, a member of FSU's biological science faculty since 1978.
His biggest surprise: the stalk has legs.
"Researchers thought the spike stalk was comprised of a tight collection of three rods bound together with the head of the spike perched on top. But our images reveal that the stalk is split into three legs, spread more like a tripod, which increases their contact with the viral membrane," Roux said. "Seeing the tripod stalk suggests a novel mechanism by which HIV-1 is able to so effectively fuse with our cells. That essential knowledge should help us design better weapons to fight the virus."
FSU Arts and Sciences Dean Joseph Travis has declared the work "a beautiful example of what happens when strong, sound basic science is applied to a very difficult problem."
The National Institutes of Health funded the two-year study, conducted by members of the department of biological science and the Institute of Molecular Biophysics at FSU.
AIDS has produced one of the worst pandemics ever known. About 25 million people have died and 40 million are infected worldwide—including 1 million in the United States.
