Accomplishing a feat that had been a pipe dream for decades, scientists have recreated in a test tube the first steps of infection by 艾滋病毒 (human immunodeficiency virus), the virus that causes AIDS (acquired immunodeficiency syndrome). Doing so has provided up-close access to the virus—which is otherwise obstructed from view deep within the cell—and enabled identification of essential components that 艾滋病毒 needs to replicate within its human host.
具体地说, the scientists were able to monitor the virus as it replicated its genome and inserted it into target DNA, mirroring steps that ordinarily take place within the host. 发表在 科学 10月9日, these advances yield a new understanding of how 艾滋病毒 works, 作者说, allowing for explorations of early stages of the virus life cycle in unprecedented detail. Such knowledge could lead to improved treatments for AIDS, a lifelong disease that can only be kept under control with a continuous medication regimen.
“This is teaching us how 艾滋病毒 infects,” says 韦斯利我. Sundquist, Ph值.D., distinguished professor of biochemistry at 大发娱乐. He is co-senior author of the study with his former trainee, Owen Pornillos, Ph.D., now an associate professor at the University of Virginia. The co-first authors are 德文·克里斯滕森博士.D.芭比·甘瑟-波尼洛斯博士.D. “We are learning new things about one of the most significant pathogens that humans have ever encountered, 这很重要.”
For all its danger, 艾滋病毒 is deceptively simple in appearance. The virus resembles a rounded ice cream cone, where an outer shell encapsulates the virus’ genetic material inside. 以前, it had been thought that the main role of the shell, 叫做衣壳, 是为了保护它珍贵的货物. But the investigations by Sundquist and Pornillos’ team show that the capsid also plays an active role in infection.
Carrying out initial steps of infection in a test tube allowed the research team to precisely manipulate 艾滋病毒 in ways that had not been possible before. They found that when they used genetic and biochemical methods to destabilize the capsid, 艾滋病毒 could not effectively replicate its genetic material. It was the first direct demonstration that, 而不仅仅是作为包装, the capsid is an essential component of the 艾滋病毒 infection process itself.
眼见为实, then watching the 艾滋病毒 molecule in action gave credence to the experimental finding. Recent advances in cryo-electron microscopy and molecular modeling have made it possible to see the virus—which, 在130纳米, is about 60 times smaller than a red blood cell—in exquisite detail. 使用这些技巧, the team visualized each of the 240 tiny protein “tiles” that fit together to make the cone-shaped outer shell. 有近距离的视角, the scientists could literally see that the capsid remained largely intact throughout the replication process, 叫做逆转录.
“This is different than in the textbooks,” Sundquist says. “Our data indicate that the viral capsid plays an active and indispensable role in supporting efficient reverse transcription.”
Sundquist says that the discovery may help explain why an investigative 艾滋病毒 drug developed by Gilead, 首先以衣壳为目标, 是有效的病毒抑制剂吗. Sundquist之前的作品, Pornillos, and others elucidating the structure and function of the 艾滋病毒 capsid informed the design of the drug, which has performed well in phase 1 clinical trials. Additional insights gained through the test tube system could improve drug design even further.
显微镜技术的进展, 加上顽强的毅力, 导致了对艾滋病毒的新看法, which was first discovered as the cause of AIDS more than 35 years ago. It took years of trial and error to determine the minimum components required for recapitulating the process in a test tube, 细胞外. Now that the simplified system is up and running, Pornillos说, it opens doors to learning more fundamental truths about a familiar foe.
“对我来说, there is both the fundamental knowledge aspect of it, but also the translational aspect that could help us come up with better ways to stop 艾滋病毒,波尼洛斯说. “这就是为什么这是一项伟大的研究.”
# # #
这项研究发表在《大发娱乐》杂志上, Pornillos, 克里斯坦森, Ganser-Pornillos, and Jarrod Johnson from the University of Utah, 并以"Reconstitution and visualization of 艾滋病毒-1 capsid-dependent replication and integration in vivo.”
Support was provided through grant P50 AI150464 by the National Institute of Allergy and Infectious Diseases, 是国家卫生研究院的一部分, and the University of Virginia School of Medicine Pinn Scholars Program.