For release: Friday, January 14, 2005
Researchers funded in part by the National Institute of Neurological Disorders and Stroke (NINDS) have identified the cellular receptor for the JC virus, which causes the fatal neurological disease progressive multifocal leukoencephalopathy (PML). Generic medicines currently available may be useful in preventing the infection. Findings appeared in the November 19, 2004 issue of Science.
Walter Atwood, Ph.D., professor of biology and medicine at Brown University, and colleagues hoped to identify the way the JC virus enters the cell and learn how to prevent its transmission into the nervous system. They first tested the drug chlorpromazine and found it was able to effectively block viral transmission to glial cells—non-nerve cells in the brain that support and protect its function. This drug, however, which is used to treat psychosis, can cause severe side effects. The scientists then tested the related compound clozapine, which produces less adverse effects, and found that it also blocked viral transmission. Since both drugs belong to a class of drugs known as serotonin-dopamine inhibitors, the research team hypothesized that the JC virus may use either serotonin receptors or dopamine receptors to infect glial cells.
By testing similar compounds, the scientists learned that the JC virus enters the central nervous system by fastening itself to the 5HT2AR receptor for serotonin, which is found on the surface of glial cells. When this receptor for serotonin is triggered, it opens the pathway that allows the virus to enter the cell.
To verify this finding, the team tried but failed to transmit the JC virus to cancer cells that don’t contain the protein that signals 5HT2AR. The team then genetically modified the cancer cells to express 5HT2AR and found the altered cells could be infected by the virus.
“This is a very exciting finding because it increases our understanding of the basic biology of JC virus infection and at the same time opens the door to possible therapeutic intervention of PML using existing drugs that do not harm nervous system function,” said Dr. Atwood.
“This discovery of how the JC virus enters glial cells is very important to the study of brain infectivity and drug viability in the nervous system,” said Michael Nunn, Ph.D., NINDS program director for neuro-AIDS research. “Although these findings are preliminary, an avenue has been opened for developing new drugs that might prevent viral infection in the brain without causing harmful side effects.”
PML is a severe, rapidly progressive disease that destroys the myelin coating that protects nerve cells. The JC virus, which travels through the blood stream to the brain, attacks certain glial cells that support brain function and produce myelin. The resulting infection produces neurological symptoms including ataxia, loss of cognitive function, visual loss, changes in balance and coordination, and loss of sensation. Death commonly occurs within two years following diagnosis. Although the initial infection with the JC virus usually occurs in childhood and has little, if any, effect on persons with healthy immune systems, it establishes a lifelong persistent infection but generally remains dormant. Most persons with normal immune systems develop antibodies to the virus by early adulthood. PML occurs almost exclusively in severely immunosuppressive patients, with the majority of cases occurring in patients with AIDS. Approximately 4 to 5 percent of AIDS patients develop PML.
The NINDS, a component of the National Institutes of Health within the U.S. Department of Health and Human Services, in the primary federal funder of research on the brain and nervous system.
Reference: Elphick GF, Querbes W, Jordan JA, Gee GV, Eash S, Manley K, Dugan A, Stanifer M, Bhatnagar A, Kroeze W, Roth BL, Atwood WJ. “The Human Polyomavirus, JCV, Uses Serotonin Receptors to Infect Cells.” Science, November 19, 2004, Vol. 306, pp. 1380-1383.
-By Paul Girolami, NINDS Office of Communications and Public Liaison
Last Modified March 9, 2005