PITTSBURGH, May 29, 2013 – A team led by researchers at the University of Pittsburgh School of Medicine has described for the first time the 4-million-atom structure of the HIV's capsid, or protein shell. The findings, highlighted on the cover of the May 30 issue of Nature, could lead to new ways of fending off an often-changing virus that has been very hard to conquer.
Scientists have long struggled to decipher how the HIV capsid shell is chemically put together, said senior author Peijun Zhang, Ph.D., associate professor, Department of Structural Biology, University of Pittsburgh School of Medicine.
"The capsid is critically important for HIV replication, so knowing its structure in detail could lead us to new drugs that can treat or prevent the infection," she said. "This approach has the potential to be a powerful alternative to our current HIV therapies, which work by targeting certain enzymes, but drug resistance is an enormous challenge due to the virus' high mutation rate."
Previous research has shown that the cone-shaped shell is composed of identical capsid proteins linked together in a complex lattice of about 200 hexamers and 12 pentamers, Dr. Zhang said. But the shell is non-uniform and asymmetrical; uncertainty remained about the exact number of proteins involved and how the hexagons of six protein subunits and pentagons of five subunits are joined. Standard structural biology methods to decipher the molecular architecture were insufficient because they rely on averaged data, collected on samples of pieces of the highly variable capsid to identify how these pieces tend to go together.
Instead, the team used a hybrid approach, taking data from cryo-electron microscopy at an 8-angstrom resolution (a hydrogen atom measures 0.25 angstrom) to uncover how the hexamers are connected, and cryo-electron tomography of native HIV-1 cores, isolated from virions, to join the pieces of the puzzle. Collaborators at the University of Illinois then used their new Blue Waters supercomputer to run simulations at the petascale, involving 1 quadrillion operations per second, that positioned 1,300 proteins into a whole that reflected the capsid's known physical and structural characteristics.
The process revealed a three-helix bundle with critical molecular interactions at the seams of the capsid, areas that are necessary for the shell's assembly and stability, which represent vulnerabilities in the protective coat of the viral genome.
"The capsid is very sensitive to mutation, so if we can disrupt those interfaces, we could interfere with capsid function," Dr. Zhang said. "The capsid has to remain intact to protect the HIV genome and get it into the human cell, but once inside it has to come apart to release its content so that the virus can replicate. Developing drugs that cause capsid dysfunction by preventing its assembly or disassembly might stop the virus from reproducing."
The project was funded by National Institutes of Health grants GM082251, GM085043 and GM104601 and the National Science Foundation.
"By using a combination of experimental and computational approaches, this team of investigators has produced a clearer picture of the structure of HIV's protective covering," said the National Institutes of Health's Michael Sakalian, Ph.D., who oversees this and other grants funded through an AIDS-related structural biology program. "The new structural details may reveal vulnerabilities that could be exploited by future therapeutics."
Co-authors include Gongpu Zhao, Ph.D., Xin Meng, Ph.D., Jiying Ning, Ph.D., Jinwoo Ahn, Ph.D., and Angela M. Gronenborn, Ph.D., all of the University of Pittsburgh; Juan R. Perilla, Ph.D., and Klaus Schulten, Ph.D., of the University of Illinois at Urbana-Champaign; Ernest L. Yufenyuy, Ph.D., and Christopher Aiken, Ph.D., of Vanderbilt University School of Medicine; and Bo Chen, Ph.D., of the University of Central Florida, in Orlando.
About the University of Pittsburgh School of Medicine
As one of the nation's leading academic centers for biomedical research, the University of Pittsburgh School of Medicine integrates advanced technology with basic science across a broad range of disciplines in a continuous quest to harness the power of new knowledge and improve the human condition. Driven mainly by the School of Medicine and its affiliates, Pitt has ranked among the top 10 recipients of funding from the National Institutes of Health since 1998. In rankings recently released by the National Science Foundation, Pitt ranked fifth among all American universities in total federal science and engineering research and development support.
Likewise, the School of Medicine is equally committed to advancing the quality and strength of its medical and graduate education programs, for which it is recognized as an innovative leader, and to training highly skilled, compassionate clinicians and creative scientists well-equipped to engage in world-class research. The School of Medicine is the academic partner of UPMC, which has collaborated with the University to raise the standard of medical excellence in Pittsburgh and to position health care as a driving force behind the region's economy. For more information about the School of Medicine, see http://www.medschool.pitt.edu. http://www.upmc.com/media
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