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Researchers from Tübingen set out to thwart viral survival strategies

Around two thirds of people carry the JC polyomavirus, a normally harmless virus that, in immunocompromised patients, can evade the body’s defences and cause a fatal brain infection. An international research network has now found a way to activate the immune system and attack the virus.

Beautiful but dangerous: microscope image of a polyomavirus and its envelope proteins. © IFIB, University of Tübingen

"The brain virtually dissolves," says Prof. Dr. Thilo Stehle describing how the JC polyomavirus destroys the body. JC are the initials of a patient called John Cunningham from whom the virus was first isolated in the early 1970s. The JC polyomavirus is usually harmless. Most people infected with the virus are unaware of its presence. In one in three people, the virus disseminates to the kidneys where it remains for the life of the individual. However, with immunodeficient hosts, the virus can be reactivated by an as yet unknown mechanism and cause a fatal brain infection, known as progressive multifocal leukoencephalopathy (PML). Stehle is head of the Interfaculty Institute of Biochemistry (IFIB) at the University of Tübingen and has been focusing on the life of JC and similar polyomaviruses for many years in an effort to identify new strategies to combat them.

The virus is often reactivated in HIV infected people and cancer or multiple sclerosis (MS) sufferers who are on medication to suppress their immune system. "A clear link has been established between natalizumab, an antibody used for the treatment of MS, and PML," says Stehle. He and his team are part of a consortium that has been funded by the American National Institutes of Health (NIH) for the past seven years. Together with their colleagues from the Universities of Yale and Brown, Stehle's team have collected many new findings about the virus and have come up with a promising therapeutic approach. Stehle and his team made their first decisive contribution to the development of this approach back in 2010 when they deciphered the atomic structure of the virus. "We were able to show that the virus recognises and binds to a specific sugar molecule, sialic acid, on the host cells. That was the starting point for the work that is now being carried out in cooperation with scientists from Zurich University Hospital and a company called Neurimmune," says Stehle.

Mutations trigger the reactivation of the virus and turn it into a highly dangerous pathogen

The researchers from Tübingen were able to decipher in detail the site where the JC polyomavirus binds to the host cell. The yellow molecule structure shows the sugar residues on the surface of the host cell encased in the binding pocket of the viral protein. © IFIB, University of Tübingen

The virus establishes contact with the host cell via the protein VP1, which is the main component of the polyomavirus capsid. The virus remains bound to the host cell for as long as it has normal viral proteins and the host cell is not destroyed. However, like the HI virus, the JC polyomavirus has the ability to mutate and alter its proteins. These mutations occur predominantly at the sialic acid binding sites, which is presumably what enables the virus to detach from renal cells and migrate through the body. This would normally alert the immune system and lead to the destruction of the virus. However, in immunocompromised patients the immune system is unable to fight off the disease-causing mutated viruses. "We do not yet know how the virus functions on the molecular level and what tricks it uses to escape the human immune defence," says Stehle.

What is known for sure is that if the virus is able to enter the brain, it can bind to as yet unknown receptors, resulting in the destruction of the cells that form the myelin sheaths of the nerve cells. As a result, a large number of brain cells die in a relatively short space of time. "Most patients die within a year of diagnosis," says Stehle.

The researchers came up with the idea of trying to develop an innovative PLM therapy when they analysed the blood of PML survivors. They all have specific antibodies in their blood. The antibodies are well characterised and will now be used to develop a therapeutic vaccine. "The antibody probably binds to a critical site in the vicinity of the sialic acid binding pocket. We are now planning to design an antibody that can recognise the wild-type virus and the mutated versions. The antibody will therefore be particularly efficient. We expect to have an optimised antibody for treating PLM available within the next few years," says Stehle.

Wanted: a broad-spectrum antibody against the entire virus family

After completing his PhD in chemistry, Prof. Dr. Thilo Stehle spent more than ten years at Harvard University. He came to Tübingen in 2005 where he heads up the Interfaculty Institute of Biochemistry (IFIB). © IFIB, University og Tübingen

Stehle is already thinking ahead because his group is also studying other viruses in the polyomavirus family that can unfold a similarly destructive effect. The BK polyomavirus, for example, is responsible for kidney diseases that are associated with large lesions. "If we get really lucky, we will find antibodies that recognise and destroy both viruses," says Stehle. The foundations for future success have in any case already been laid through the successful cooperation with the international, NIH-funded consortium. While the virologists at Brown University in Providence, USA, are mainly focused on assay development and the geneticists at Yale University on the viruses' replication machinery, Stehle and his group have the know-how and equipment to produce the viruses and elucidate virus structure and the virus's binding partners. Stehle is able to produce relatively large quantities of virus crystals and carry out X-ray structure analyses. Moreover, cooperation with the Max Planck Institute for Developmental Biology in Tübingen gives Stehle access to spectroscopic methods to study the binding of the virus to ligands.

A real challenge is the development of glycan test systems that enable the researchers to analyse virus-host cell binding. Sugar residue is a decisive factor because sialic acids may differ considerably from one another. The monosaccharide with a nine-carbon backbone needs to be bent correctly in order for the viral binding site to be recognised. "It is difficult to synthesise the sugar, and there are only a handful of research groups in the world who can do this. One of these groups is in England and is working with us on this issue," says Stehle.

Stehle's research partners at the University of Zurich are also contributing to the work that is being done. "Cooperation with Zurich is a relatively new thing; it has put our data in a new light and we have been able to show that not all viruses are activated in people with weakened immune systems. However, it is not yet clear why this is so," says Stehle. "When all is said and done, what we structural biologists dream of is being part of the entire development process from identifying a drug target to developing a therapy." And this is exactly what is happening: Stehle and his team are living their dream with polyomaviruses.

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