UPTON, NY -- In what could be a first step toward finding a cure for the common cold, scientists at the U.S. Department of Energy's Brookhaven National Laboratory have discovered how one form of cold virus binds to human cells. The discovery, appearing in this week's issue of Science, could lead to the development of drugs that block infection.
"Viruses have to bind to cells in order to infect them,"says biologist Paul Freimuth. "If you could interrupt that binding, the virus would be dead in the water."
"That, in essence, is what the body's immune system does when it produces antibodies,"says Freimuth. "The antibodies bind to the virus so the virus can't bind to the cell."But it takes time for the immune system to stage its attack, he adds. With a molecular understanding of the virus-cell interaction, scientists could potentially tailor-make drugs that disable the virus.
Freimuth, John Flanagan, and other collaborators at Brookhaven had previously isolated proteins that initiate infection by adenovirus, one type of common cold virus, as well as the protein that the virus binds to on the surface of human cells. They then manufactured biologically active forms of the viral and cellular proteins in E. coli bacteria. "These small purified protein fragments bind tightly to each other in the test tube, and provided the raw material to initiate structural studies,"Freimuth says.
To determine the molecular structure of the virus/receptor complex, the scientists grew crystals of the complex and bombarded them with high-intensity X-rays from Brookhaven's National Synchrotron Light Source (NSLS). With this technique, called X-ray crystallography, scientists examine how the crystals diffract, or scatter, the X-ray beam. "From that you can work backward to deduce the structure of the proteins in the crystal,"Flanagan says. "The NSLS greatly facilitates the study of crystal structures because of the high intensity of the X-ray beam produced there,"he adds.
Previously, other scientists used this technique (also at Brookhaven's NSLS) to characterize how the human immunodeficiency virus (HIV, the virus that causes AIDS) binds to its cell-surface receptor. Adenovirus is the second virus to have its binding mechanism characterized at atomic resolution.
"Surprisingly, though adenovirus and HIV are very different, their mechanisms of entry into cells show some similarities,"Flanagan says. This may help scientists better understand how viruses evolve -- for example, how they change to evade the immune system while retaining their ability to bind to specific cell-surface receptors.
The findings could also have implications for using modified, non-symptom-causing viruses to deliver healthy genes to cells in the technique known as gene therapy. "If you understand the way a virus attaches to a specific cell, you might be able to modify the virus to precisely target specific cells, such as those that make up a tumor,"Freimuth says.
Understanding the molecular characteristics of viral binding sites might also lead to more effective vaccines. Viral binding proteins are often ornamented or decorated with bits of protein that have nothing to do directly with the virus's ability to bind to cells, but rather serve to "run interference"and distract the immune system, Freimuth says. "If you could eliminate those factors and make a vaccine that just had the receptor binding site, you might have a better chance of focusing the immune response on the binding site itself."
"This is an excellent example of how interconnected scientific research has become,"said Energy Secretary Bill Richardson. "The physics and engineering that helped build the National Synchrotron Light Source are now making possible insights in other areas of science such as biomedical research.²
The U.S. Department of Energy's Brookhaven National Laboratory creates and operates major facilities available to university, industrial and government personnel for basic and applied research in the physical, biomedical and environmental sciences and in selected energy technologies. The Laboratory is operated by Brookhaven Science Associates, a not-for-profit research management company, under contract with the U.S. Department of Energy.
Journal
Science