Hepatitis B virus infection: Degradation of viral DNA in the cell nucleus is opening up new treatment possibilities
Neuherberg, 21 February 2014. Scientists from the Helmholtz Zentrum München and the Technische Universität München have discovered how the viral DNA of the hepatitis B virus (HBV) can be degraded in the cell nucleus of liver cells, consequently allowing the virus to be eliminated. Viruses such as HBV can persist by depositing their genetic information (DNA) in the cell nucleus, where the DNA is normally not degraded. This prevents antiviral drugs from eliminating these viruses. But the newly discovered mechanism could make this possible without damaging the infected cell in the liver. In the current issue of the prestigious journal 'Science', the scientists report that now new therapeutic possibilities are consequently opening up.
Although preventive vaccination is possible, the World Health Organization (WHO) reports that more than 240 million people around the world are currently suffering from a chronic hepatitis B infection. They face a high risk of developing liver cirrhosis or even liver cancer. In Germany alone, more than half a million people are affected. Although available antiviral medicines can control the hepatitis B virus, they cannot completely eliminate it. As a result, the HBV in the patient's liver is reactivated as soon as the treatment is discontinued.
This is due to virus DNA (cccDNA: covalently closed circular DNA) "hidden" in the cell nucleus. This virus DNA stores multiple copies of the virus in the nucleus of infected liver cells (hepatocytes) and in this way protects itself from destructive influences. The cccDNA serves as a template for the virus' own proteins and new viral genomes. An international team of scientists headed by Prof. Ulrike Protzer and Prof. Mathias Heikenwälder, Institute of Virology at the Helmholtz Zentrum München and the Technische Universität München, has now found a way to selectively attack and eliminate the viral genetic information in the cell nucleus of the liver cells without damaging the host cell in the process.
"The degradation of viral DNA in the cell nucleus that we describe represents an important mechanism in the defence against the virus", Protzer reports. "Moreover, for the first time, the results offer the possibility to develop a treatment that can heal hepatitis B."
The scientists have discovered that in addition to interferons (the immune system's defence agents), activation of the lymphotoxin β receptor in the host cell promotes certain proteins and supports their function in such a way that they chemically modulate and degrade viral cccDNA. This keeps the virus from reactivating, and also prevents the disease from breaking out again, even after the treatment has ended. On the other hand, the proteins do not influence the genetic information of the host cell itself, which here is the liver cell. "With the activation of the lymphotoxin β receptor, also combined with substances that are already available, we have a very promising new therapy concept available", Heikenwälder explains.
In addition to the Helmholtz Zentrum München and the Technische Universität München (TUM), TUM's Klinikum rechts der Isar and the Düsseldorf, Hamburg, Mainz and Munich university hospitals also participated in the publication. International partners from Belgium, France, Switzerland and the USA also contributed.
The research was supported by the German Center for Infection Research (DZIF).
Lucifora, J., Yuchen X., et al. (2014), Specific and Non-Hepatotoxic Degradation of Nuclear Hepatitis B Virus cccDNA. Science, doi: 10.1126/science.1243462
Link to publication
As German Research Center for Environmental Health, Helmholtz Zentrum München pursues the goal of developing personalized medical approaches for the prevention and therapy of major common diseases such as diabetes mellitus and lung diseases. To achieve this, it investigates the interaction of genetics, environmental factors and lifestyle. The Helmholtz Zentrum München has about 2,200 staff members and is headquartered in Neuherberg in the north of Munich. Helmholtz Zentrum München is a member of the Helmholtz Association, a community of 18 scientific-technical and medical-biological research centers with a total of about 34,000 staff members.
The Institute of Virology (VIRO) investigates viruses that chronically infect humans and can cause life-threatening diseases. The research activities of the institute focus mainly on the HI virus which causes AIDS, on endogenous retroviruses, which are integrated into our germline, and hepatitis B and C viruses, which cause liver cirrhosis and hepatocellular carcinoma. Molecular studies identify new diagnostic and therapeutic concepts to prevent and treat these viral diseases or to prevent the formation of virus-induced tumors.
Technische Universität München (TUM) is one of Europe’s leading research universities, with around 500 professors, 10,000 academic and non-academic staff, and 36,000 students. Its focus areas are the engineering sciences, natural sciences, life sciences and medicine, reinforced by schools of management and education. TUM acts as an entrepreneurial university that promotes talents and creates value for society. In that it profits from having strong partners in science and industry. It is represented worldwide with a campus in Singapore as well as offices in Beijing, Brussels, Cairo, Mumbai, and São Paulo. Nobel Prize winners and inventors such as Rudolf Diesel and Carl von Linde have done research at TUM. In 2006 and 2012 it won recognition as a German "Excellence University." In international rankings, it regularly places among the best universities in Germany.
In the German Center for Infection Research (DZIF) more than 150 scientists from 32 institutions are working together all over Germany to develop new approaches for the prevention, diagnosis and treatment of infectious diseases. The goal is the so-called translation: the swift and effective implementation of research results in clinical practice. The DZIF is consequently paving the way for the development of new vaccines, diagnostic tools and medicines against infections.
Prof. Ulrike Protzer, Institute of Virology, Helmholtz Zentrum München - German Research Center for Environmental Health (GmbH) and TU München, Trogerstr. 30, 81735 München - Tel. +49 89 4140-6886 - E-Mail: protzer(at)helmholtz-muenchen.de; protzer(at)tum.de