Feb. 4, 1999 Viruses employ all the techniques of seasoned spies to infiltrate cells. They change identities frequently and find secret gateways, known as receptors, through cell walls. Now, Chetankumar Tailor, Ph.D., postdoctoral fellow and David Kabat, Ph.D, professor, both of Oregon Health Sciences University's Department of Biochemistry and Molecular Biology, have uncloaked a mechanism used by certain leukemia viruses to attach themselves to a cell surface and then sneak into the cell's interior.
The same researchers have also devised a way to rapidly clone human genes that encode receptors for selected viruses. Their study results, being published in the February issue of the Proceedings of the National Academy of Sciences, could help uncover clues to the diagnosis and treatment of not only leukemia, but HIV and other viral infections. The research was funded by the National Institutes of Health and The Wellcome Trust.
"Using DNA from human cells, we developed an improved method for cloning a human gene that encodes the receptor for two kinds of leukemia viruses called xenotropic and polytropic murine leukemia," said Kabat, in whose laboratory the experiments took place. "Receptors are proteins that serve as gatekeepers for the cell. For over a decade, many labs have been searching for receptors that viruses attach themselves to, with limited success. We have found new methods and now can reliably clone the gatekeeping system that welcomes the leukemia virus and guides it into the cell."
What's more, this research proves that diverse viruses can get into cells using the same receptor. The xenotropic leukemia viruses are part of a class of "retroviruses" that infect humans, other mammals and some wild strains of mice. The polytropic retroviruses cannot infect humans and are especially infectious to mice. But both forms of the virus use the same receptor to invade the cell. In other words, the receptor mechanism is the same in mice as in people.
The discovery itself was made possible by a method, refined by Tailor, for cloning the receptors relatively quickly. "The basic technique we are using is to isolate a gene from a cell which is susceptible to the virus and express that gene in cells that are resistant to the virus. If the resistant cell becomes susceptible, we know we've found the gene," said Tailor. While the process sounds simple, successfully isolating receptor genes has, until recently, taken many years of painstaking work. But the method used by Tailor employs a retrovirus as a kind of Trojan horse. A retrovirus containing the susceptibility gene is used to infiltrate the resistant cell and deliver its genetic cargo. The process can be complete in as little as six weeks. "To be able to reliably clone the gene we want in such a short time is a major breakthrough," said Kabat.
The OHSU study lays the groundwork for finding other receptors that help viruses, such as HIV, invade cells and could open up new areas of research into drugs to combat the viruses. Viruses and cells are constantly involved in an elaborate arms race. Cells develop resistance to certain viruses, then the viruses mutate and find a way to enter the cells, then the cells develop resistance again, and so on. The leukemia viruses studied in the Kabat laboratory are mutations of earlier forms of the virus. In the case of leukemia, as with AIDS, mutant forms of the virus are often far more damaging than the original virus they sprang from. So finding the receptor the mutant viruses attach themselves to could be used as a clinical tool.
"By identifying the receptor there is a potential to design drugs that block the virus," said Tailor. "The virus first has to attach to the receptor before it can invade the cell. If we can block that part of the process we could potentially prevent entry of the virus."
Efforts to isolate viral receptors continue in the Kabat laboratory. Tailor has recently identified receptors for one of three forms (subgroup C) of the feline leukemia virus that causes fatal anemia in domestic cats, and for type D primate retroviruses, a family of viruses that cause severe immunodeficiencies in primates and that have been found in numerous AIDS patients, particularly in Africa. Results of those studies are awaiting publication.
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