Kiss and Tell: Virus Helps Scientists Find Cellular Control Switch By Michael Purdy Johns Hopkins investigators have caught the virus that causes mononucleosis in the act, developing a detailed "snapshot" of the virus as it begins to make mischief in a human immune cell. The new details, published in the April 28 issue of Science, may help scientists stop the virus' meddling, which increases a patient's risk of developing serious cancers. The snapshot also appears to show the virus with its "hands" on a key cellular control switch that may be important to the human body's ability to fight off invaders. If so, scientists may soon owe new understanding of the human immune system to the virus that causes kissing disease. Almost 90 percent of all U.S. adults carry this virus, known as Epstein-Barr virus. Initially, the virus causes severe coldlike symptoms. After a few skirmishes with the body's defenders, it goes underground, hiding from the defenders in their own ranks--in a human immune cell known as a B-cell. The virus then forces the B-cell to make new copies of itself and the virus. Scientists suspect that these new cells may develop into malignant cancers in some patients, although details of how the infected B-cells become cancerous are not clear yet. Most viruses take over cells by binding to the cells' control panels, their DNA. Binding to DNA in the right way flips the switches on this control panel, turning the cell's production of various proteins on and off and altering a cell's characteristics and behaviors. EBNA-2, the first protein produced by Epstein-Barr when it enters a cell, cannot bind to DNA. Hopkins researchers learned two years ago that EBNA-2 reaches DNA indirectly, attaching itself to a protein, CBF-1, that naturally binds to DNA. Hopkins researcher Diane Hayward, a professor of pharmacology and molecular sciences, mapped the switches or genes present at the sites where CBF-1 binds to DNA, and looked up their function in a gene bank--a computer database of genes known to have a specific function. She found that CBF-1 binds to a very powerful master control switch. Turning this switch on or off triggers a cascade of reactions that turns other control switches on or off. "We found that, instead of making a simple alteration, the virus was massively reprogramming the B-cell," she said. CBF-1 is designed to keep this master control switch turned off. EBNA-2 binds with the portion of CBF-1 that performs this function, defeating it. This turns the switch on. The results_B-cells reproducing themselves--are similar to the first stage of a B-cell's response to invading microorganisms. When a normal B-cell encounters an invader it recognizes, it first begins reproducing itself. The new copies spew out deadly antibodies but are preprogrammed to self-destruct. Copies from an infected B-cell do not self-destruct. Under the right circumstances, this extra group of cells appears to be able to evolve into malignant tumors. Drug experts trying to stop this process can focus on the areas of EBNA-2 and CBF-1 mapped out in the new paper by Dr. Hayward and Hopkins graduate student James J.-D. Hsieh. "They can search for a drug that blocks the interactions without affecting CBF-1's normal functions," Dr. Hayward said. The findings also provide an important glimpse of the human immune system's innermost workings. If the switch fooled by EBNA-2 is the same switch that begins arming B-cells, then immunologists may be able to use it to find the biochemical signals and reactions that make the new B-cells release antibodies and self-destruct.
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