Unraveling the mystery of a rare, virus-mediated neurological disease

August 16, 2012 at 10:00 am Leave a comment

From bench to bedside

Dr. Aron Lukacher portrait

Aron Lukacher, M.D., Ph.D.

Most adults in the United States are asymptomatic carriers of persistent viral infections, such as herpes simplex (cold sores) or varicella zoster (chicken pox). Exposed to such viruses at some point during childhood, our immune systems produced effective antibodies against the virus, which decreased viral titers and eliminated clinical signs of illness. Although persistent viruses remain in some tissues of our bodies, our immune systems keep the viruses in check, and we remain illness-free. For a small subset of people, however, their immune systems fail to control these latent viruses and they fall victim to disease.

Identifying people who are most vulnerable to viral re-activation is one of the major challenges facing physicians who treat patients with compromised immune systems.

Such patients include those with acquired immune deficiency syndrome (AIDS), those treated with cancer chemotherapy, and those receiving agents to prevent rejection of transplanted organs and to control autoimmune and inflammatory diseases. According to Aron Lukacher, M.D., Ph.D., professor and new chair of the Department of Microbiology and Immunology at Penn State College of Medicine, in recent years, major strides have been made in researchers’ understanding of immune responses to persistent viruses and the diverse strategies viruses use to evade immune detection. Ongoing research by many groups seeks to understand and overcome such strategies, so that patients who are often the most desperately ill can avoid falling victim to these viruses. Lukacher’s research focuses on the immunological mechanisms that control persistent viral infections and defining the pathways by which a certain class of viruses called polyomaviruses escape immune control to cause serious disease.

A large component of Lukacher’s work revolves around a recently funded effort to develop a mouse model of the JC virus, a polyomavirus only found in humans, and the only known cause of progressive multifocal leukoencephalopathy (PML). PML is a rare but often fatal central nervous system disease that occurs in a fraction of immunocompromised individuals. More than 70 percent of all adults are carriers of the JC virus, with latent virus harmlessly residing in kidney and bone marrow. However, in some people, JC virus begins to replicate and infect the brain. Neurologic changes associated with PML include diminished cognitive abilities, loss of coordination, and deficits in motor function. PML is a life-threatening complication that affects 3-5 percent of patients with AIDS. Only 50 percent of HIV/AIDS patients with PML show a positive clinical response to currently available antiretroviral therapy. Lukacher says, “Because the JC virus only replicates in humans, until now there has been no animal model; we still don’t know the major cellular pathways and mechanisms that control replication or re-activation, and there are no effective anti-viral therapies to treat it. With the development of a mouse model, scientists will have a way to study what is happening.”

Lukacher’s work on the JC virus mouse model is likely to be crucial in the coming years, as the number of people at risk for PML is expected to grow. Those at the highest risk are patients with weakened immune systems, such as those with AIDS, but also bone and tissue transplant recipients, and anyone receiving long-term immunosuppressive therapy.

“The increasingly widespread use of biological agents to suppress the immune system for treatment of multiple sclerosis (MS), rheumatoid arthritis, psoriasis, and inflammatory bowel disease may place large numbers of patients at risk for PML. We’ve already seen that about 1 in 1,000 patients treated with drugs like natalizumab (Tysabri) develop PML.”

A similar drug, Raptiva™ was removed from the market in 2009 because of its link to PML.  Even so, for disabling and deadly diseases like MS, the benefits of immunosuppressive treatment often far outweigh risk for PML.

For patients with MS, the newer biological treatments offer hope for better disease management. But the problem of PML is real, Lukacher says, and patients with MS understand that drugs approved for MS for the first time may have a downside and could cause serious side effects, such as PML. “Rather than abandoning use of these disease-modifying therapies, the key is to figure out which patient factors and virus features predict PML and then tailor therapy to minimize risk,” Lukacher says.

Entry filed under: Profiles, Research. Tags: , , , , , .

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