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.