UNMC and University of Iowa researchers collaborate on major breakthrough that could lead to better HIV drugs; article published in June 10 issue of Nature
Researchers at the University of Nebraska Medical Center and the University of Iowa Carver College of Medicine have created a three-dimensional picture of an important protein that is involved in how HIV — the virus responsible for AIDS — is produced inside human cells. The picture may help researchers design drugs that can prevent HIV from reproducing.
The research team was led by Tahir Tahirov, Ph.D., professor of structural biology at the Eppley Institute at UNMC, and David Price, Ph.D., UI professor of biochemistry. Their combined expertise in protein chemistry and X-ray crystallography — a technique for observing protein structures – allowed them to produce the first crystal structure of the HIV protein called Tat.
The structure shows Tat attached to the human protein (P-TEFb) that the virus hijacks during infection.
“In the past two decades, numerous laboratories around the world have been pursuing the structural studies of the HIV Tat protein,” Dr. Tahirov said. “Our progress in the structure determination of the
Tat/P-TEFb complex is a significant breakthrough in the field of HIV research.”
The structure shows how Tat latches on to this particular human protein and how the interaction alters the shape of the human protein. The study is published in the June 10 issue of the journal Nature.
The high interest in the Tat/P-TEFb complex structure is due to the potential it has for the structure-based design of a novel class of HIV inhibitors, Dr. Tahirov said.
Such inhibitors are expected to be less toxic than existing HIV drugs, he said, and would be capable of reducing the number of viruses to undetectable levels. In addition, they are expected to fight viruses which are resistant to the currently available HIV drugs on the market.
Dr. Tahirov said the research findings were made possible due to the collaboration and expertise at the two universities. UNMC has an outstanding crystallography program, which allowed Dr. Tahirov’s lab to do the work on the crystals of the complex. Dr. Price’s lab provided expertise in biochemistry and function of Tat/P-TEFb complex, and the purified complex samples.
“We have solved the long sought-after structure of an important HIV protein,” Dr. Price said. “Now that we know the details of the interaction between Tat and P-TEFb, it may be possible to design inhibitors that target P-TEFb only when it is interacting with Tat.”
This distinction is important because although inhibiting P-TEFb blocks replication of the HIV virus, P-TEFb is a vital protein in human cells and inhibiting it kills cells. If an inhibitor could be designed that distinguishes between the P-TEFb attached to Tat and the form that is normal in human cells, that drug might target HIV replication without harming normal cell function.
In addition to Drs. Tahirov and Price, the research team included Nigar Babayeva at UNMC and UI researchers Katayoun Varzavand, Jeffrey Cooper and Stanley Sedore. The study was funded by grants from the National Institutes of Health and from the Nebraska Department of Health and Human Services.
As the state’s only academic health science center, UNMC is on the leading edge of health care. Breakthroughs are possible because hard-working researchers, educators and clinicians are resolved to work together to fuel discovery. UNMC’s extramural research support now exceeds $100 million, resulting in the creation of 3,600 jobs in Nebraska. UNMC’s academic excellence is shown through its award-winning programs, and its educational programs are responsible for training more health professionals practicing in Nebraska than any other institution. Through its commitment to education, research, patient care and outreach, UNMC and its hospital partner, The Nebraska Medical Center, have established themselves as one of the country’s leading health care centers. UNMC’s physician practice group, UNMC Physicians, includes 550 physicians in 50 specialties and subspecialties who practice primarily in The Nebraska Medical Center. For more information, go to UNMC’s Web site at www.unmc.edu.