A team of international researchers, including from Brown University, made new discoveries about the molecular mechanisms of an infection usually fatal in people with severely compromised immune systems.
PROVIDENCE, R.I. [Brown University] - In people with severely compromised immune systems, JC polyomavirus can trigger an untreatable, often fatal brain disease. An international research team has identified how virus mutations can strategically interfere with how human antibodies recognize the virus, allowing it to evade an immune response. The new insights into the interactions between the JC polyomavirus and the human immune system, published in PNAS, could lay the foundation for the development of treatments and vaccines.
The research was led by scientists at the University of Tübingen in Germany, in collaboration with researchers from Brown University and the University Hospital of Zürich in Switzerland.
"This work is the culmination of a 10-year international project between our institutions," said Walter Atwood, a professor of biology and medicine at the Warren Alpert Medical School and the lead researcher from Brown University. "There's now the possibility of therapeutic antibodies to be able to block an infection in patients who develop the disease. That's been the thought and the goal, but getting to this point has been a significant challenge for a very long time."
Polyomaviruses are a family of small DNA viruses that establish persistent, lifelong infections in a wide range of vertebrate hosts. Human polyomavirus 2, commonly referred to as the JC polyomavirus (after the initials from a patient from whom it was first isolated and identified) is widespread, infecting more than 60% to 70% of the population worldwide.
The virus usually remains dormant, but in some people - especially patients with AIDS and people whose immune systems have been modulated by strong medications designed to treat autoimmune conditions - it can reactivate and spread to the brain. There, it infects and destroys specialized glial cells in the central nervous system that produce the myelin sheath. The resulting disease, called progressive multifocal leukoencephalopathy (PML), is severely debilitating and often fatal, and there are no effective treatments.
Neutralizing antibodies
For the study, the research team drew on the observation that some patients are able to survive PML.
"Their bodies manage to neutralize the attacking JC polyomaviruses so that they can no longer penetrate the body's cells; the infection is stopped," said study author Thilo Stehle, a professor of biochemistry at the Interfaculty Institute of Biochemistry at the University of Tübingen.
The immune system achieves this neutralization by producing precisely tailored antibodies, Stehle explained. The antibodies attach like a lock to binding sites on the viral capsid, which prevents the virus from binding to cells.
At the University Hospital of Zürich, researchers isolated specialized antibodies against the protective protein shell of JC polyomavirus from PML patients. In Atwood's lab at Brown, a team of researchers tested the antibodies for their binding and neutralization properties. Stehle's team in Tubingen then analyzed the binding mechanism of the most promising antibodies to the virus using high-resolution structural analysis with atomic precision.
By studying the genetic mutations that can occur at the binding sites that antibodies use to defend themselves against the virus, the researchers developed insights into the structure and mechanisms of action between JC polyomaviruses and the human immune system that can be used to develop therapeutics and vaccines.
Atwood's team showed that one of the antibodies protected cells against infection by both the JC polyomavirus as well as the related BK polyomavirus. BK polyomavirus is also common in humans, and while it does not cause brain disease, it leads to nephropathy and hemorrhagic cystitis in kidney and bone marrow transplant patients, respectively.
"A potential vaccine could protect high-risk patients from infection with both polyomaviruses," Atwood said.
The research was funded by the National Institutes of Health (P01NS065719) and the German Research Foundation, DFG (FOR2327 ViroCarb).
