PITTSBURGH, Nov. 12 – Structural biologists at the University of Pittsburgh School of Medicine have described the architecture of the complex of protein units that make up the coat surrounding the HIV genome and identified in it a "seam" of functional importance that previously went unrecognized. Those findings, reported today in Cell, could point the way to new treatments for blocking HIV infection.
The researchers used a combination of nuclear magnetic resonance and cryoEM, which are standard structural biology tools, to see both the overall shape and the atomic details of capsid protein (CA) assembly. It takes about 1,500 copies of CA to make the coat, or capsid, that surrounds the genome of the AIDS virus.
"This strategy allowed us to see both the forest and the trees," explained study co-author Peijung Zhang, Ph.D., assistant professor in the Department of Structural Biology, Pitt School of Medicine. "Knowing what the CA protein looks like and how the capsid is built will allow scientists to rationally design therapeutic compounds that interfere with assembly of the protein and affect its function."
Capsid proteins, and particularly the interfaces or seams where one connects to another, are very important for assembling and disassembling the HIV coat, said senior author Angela Gronenborn, Ph.D., chair, Department of Structural Biology, and director, University of Pittsburgh Center for HIV Protein Interactions. The study indicates that these seams provide the flexibility to dismantle the coat efficiently after viral entry into the host and to put it back together when new viruses emerge from the cell.
"Our lab experiments show that if we replace a few of the pivotal stitches in the seam by mutation, the resulting viruses are less infectious or even non-infectious," Dr. Gronenborn said. "The capsid, and therefore the virus, can no longer function properly."
Study co-authors include In-Ja L. Byeon, Ph.D., Xin Meng, Ph.D., Jinwon Jung, Ph.D., Gongpu Zhao, Ph.D., Jinwoo Ahn, Ph.D., and Jason Concel, all of the Department of Structural Biology, Pitt School of Medicine; and Ruifeng Yang, Ph.D., Jiong Shi, and Christopher Aiken, Ph.D., all of the Department of Microbiology and Immunology, Vanderbilt University School of Medicine.
The research was funded by the National Institutes of Health.
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 1997 and now ranks fifth in the nation, according to preliminary data for fiscal year 2008. 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 www.medschool.pitt.edu.
Journal
Cell