AIDS patients live longer and better than ever before thanks to improved drug therapy, but an unlucky few still have their brains damaged by a devastating and fatal neurological disease called progressive multifocal leukoencephalopathy (PML). Now, researchers have traced the path by which the virus that causes PML invades brain cells. The findings indicate that widely used psychiatric drugs may prolong the lives of AIDS patients with the disease.
More than 70% of adults harbor JC virus, which causes PML. The virus is harmless in people with a healthy immune system, but in up to 5% of AIDS patients the virus destroys brain cells called oligodendrocytes that provide the myelin insulation that allows neurons to function. These patients develop tremors, partial blindness, and dementia and die within a year and a half.
To stop JC virus from destroying brain tissue, Walter Atwood of Brown University and colleagues first asked how it invaded oligodendrocytes. They knew from earlier work that JC virus sticks to the cell surface and then triggers the cell to engulf and swallow it. They also knew that Thorazine, a commonly prescribed antipsychotic drug, blocked that swallowing process in other types of cells, and that Thorazine bound receptors for the neurotransmitters dopamine and serotonin on the cell surface. So Atwood's team hypothesized that the JC virus latched onto one of those receptors as a prelude to invasion.
To test that hypothesis, the team added one of several drugs or chemicals that bound to either dopamine or serotonin receptors to cultured cells. Then they added virus. Only those drugs that bound to serotonin receptors blocked infection. To confirm that the JC virus targeted serotonin receptors, they took lab-grown cervical cancer cells that resisted JC virus infection and engineered them to produce a serotonin receptor from oligodendrocytes called 5HT[2A]R. JC virus infected the engineered cells, and antibodies to the 5HT[2A] receptor blocked that infection, the researchers report in the 19 November issue of Science. The results mean that U.S. Food and Drug Administration-approved serotonin-blocking drugs such as Thorazine and cyproheptadine could prevent JC virus infection in the brain. A clinical trial is not yet in the works, but it could be soon, Atwood says.
"It's a fantastic study," says cancer virologist Kamel Khalili of Temple University in Philadelphia, Pennsylvania. A serotonin-blocking drug wouldn't rid the body of virus already hiding in cells, he cautions, but the results nonetheless have "great potential to help with a therapeutic strategy for PML."