The disorder, called progressive multifocal leukoencephalopathy or PML, affects hundreds of Americans with suppressed immune systems, including kidney transplant recipients, cancer patients undergoing chemotherapy and an estimated 4 percent of people with AIDS.
PML is caused by the JC virus, which destroys the cells that produce the fatty sheath that covers nerve cells. This causes dementia, vision loss, movement and speech impairment, paralysis and coma. The disorder is fast moving and fatal; Many patients die within four months after onset. PML is also on the rise. Due to the AIDS pandemic, incidence of the disorder rose 20-fold in the United States between 1979 and 1994, according to a study conducted by federal researchers.
But a team of scientists, led by Brown virologist Walter Atwood, has found that a handful of antipsychotic drugs can prevent brain cells from becoming infected by the JC virus. The drugs may prove to be an effective, ready-made therapy for PML prevention or treatment. Their results are published in the current issue of Science.
"This is very promising," Atwood said. "These are generic drugs we can take off the shelf that may help a lot of people."
"It is likely that there are many other drugs with none of the potential side effects of antipsychotic drugs that will also block infection," said co-author Bryan Roth, professor of biochemistry at the Case School of Medicine and director of the National Institute of Mental Health's Psychoactive Drug Screening Program.
Atwood, an associate professor of medical science in the Department of Molecular Microbiology and Immunology at Brown, has studied the JC virus for more than a decade. The virus is common ??“ anywhere from 70 to 80 percent of adults carry it in a latent form ??“ and it infects certain types of glial cells, which support and protect neurons. It travels to the brain in people with severely weakened immune systems. But scientists didn't know precisely how it infects those cells. Atwood knew that cellular entry depended on a particular protein, called clathrin, and began to test compounds that would block it.
Atwood tried chlorprozamine, a drug used to control psychotic symptoms such as hallucinations and delusions, and found that it worked. But chlorprozamine can cause serious side effects, such as lowered blood pressure, stiffness and tremors, so Atwood and his team tested seven similar drugs. They found that three others, most notably the antipsychotic clozapine, also prevented infection in human glial cells without troubling side effects.
By pinpointing drugs that block the JC virus, researchers uncovered how the virus operates in the body. The JC virus attaches itself to a receptor on the surface of glial cells, called 5HT2AR, which normally binds with serotonin, a compound that plays an important role in depression and anxiety. That receptor, or cellular "gate," opens and allows the virus to get inside cells.
To be sure that 5HT2AR was the cellular receptor for the virus, Atwood's team conducted a novel experiment. They took a line of cancer cells that lack 5HT2AR and inserted the receptor gene. They found that these re-engineered cells were now susceptible to infection from the JC virus. Then researchers used the antipsychotic drugs to see if they blocked the virus. They did.
By understanding that the JC virus can be stopped with clozapine and comparable serotonin receptor blocking drugs, Atwood and Roth said new avenues for PML therapy are now open. The antihistamine cyproheptadine, for example, could have the same effect on the virus.
"Cyproheptadine has very high affinity for 5-HT2A receptors and is not likely to have many of the side effects associated with drugs like clozapine and chlorpromazine," Roth said.
Atwood is establishing collaborations with several clinical neurology centers to determine whether compounds such as cyproheptadine will, in fact, help prevent or treat PML.
Atwood's team at Brown included Gwendolyn Elphick, a research associate in the Department of Molecular Microbiology and Immunology; William Querbes, Joslynn Jordan, Sylvia Eash and Aisling Dugan, students in the graduate program in pathobiology; and Gretchen Gee, Kate Manley and Megan Stanifer, students in the graduate program in molecular biology, cell biology and biochemistry. Bryan Roth, Anushree Bhatnagar, and Wesley Kroeze from Case Western Reserve University Medical School collaborated with Atwood on the project.
brown/