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Chronic viral infections of the liver

Hepatitis B and hepatitis C are two of the most common infectious diseases in the world. They often take a chronic course and carry a high risk of progressing to cirrhosis and hepatocellular carcinoma. A new transregional collaborative research centre involving scientists from Heidelberg and Freiburg is looking into how hepatitis B and hepatitis C viruses, which have different symptoms and treatments, are able to evade the immune system and allow an infection to become chronic. Knowledge of the molecular relationships is expected to lead to new therapies for effectively treating or even preventing chronic hepatitis infections.

HCV particles under the electron microscope. © Heidelberg University Hospital

Although an effective vaccine against hepatitis B virus (HBV) infections has been available for around 30 years, around 440,000 people in Germany alone (the German Liver Foundation claims that this figure is even higher at around 650,000 people) carry the virus. Several thousand new HBV infections are recorded every year. People with chronic hepatitis B run a very high risk of developing cirrhosis of the liver and eventually even liver cancer. It is estimated that at least 230 million people around the world are chronically infected with hepatitis B and that more than half a million die due to complications arising from the infection. Interferons and antiviral therapeutics have the potential to delay complications, but a complete cure is highly unlikely. The situation is completely different with hepatitis C virus (HCV) infections. Although no vaccine is available, drugs that have been developed in recent years do provide a cure. Nevertheless, between 400,000 and 500,000 people in Germany and around 130 million people worldwide are chronically infected with hepatitis C.

How do hepatitis viruses evade the immune defence?

Prof. Dr. Ralf Bartenschlager, spokesperson of the CRC/TRR 179 © Heidelberg University Hospital

“The reproductive strategies of the two species of virus differ fundamentally and have been studied in great detail. However, we do not yet know how the two viruses manage to outsmart the host immune defence,” says Prof. Dr. Ralf Bartenschlager, director of the Department of Molecular Virology at the Centre of Infectious Diseases at Heidelberg University Hospital and head of the "Infection and Cancer" research programme at the German Cancer Research Center (DKFZ). Bartenschlager is the spokesperson of the new transregional cooperative research centre (CRC/TRR 179) entitled “Determinants and Dynamics of Elimination versus Persistence of Hepatitis Virus Infection”.

The research consortium brings together experts from different disciplines (immunology, virology, liver metabolism and liver diseases, pathology, cell biology, imaging and bioinformatics) to study the complex interactions between virus and host from different perspectives. The researchers from Heidelberg, Freiburg and Munich hope that their integrative approach will give them a better understanding of the mechanisms that determine whether a viral infection spontaneously heals or becomes chronic. Bartenschlager explains that, amongst other things, the project will focus on the question as to why the HBV genome in infected cells is left alone for a long time and why immune system killer cells either do not recognise infected cells or, in the case of chronic hepatitis C, only when the propagation of the virus has been substantially impeded with drugs.

A new hepatitis B infection model

”Smiling HBV“- hepatitis B viruses will soon have nothing to laugh about: electron microscope image of hepatitis B viruses (large oval structures with a dark nucleus) and non-infectious viral envelopes (small round and elongated structures). © Heidelberg University Hospital / S. Seitz

In their recent publication, Bartenschlager and his colleagues from the DKFZ and the University Hospital of Heidelberg reported on a previously unknown mechanism that governs the maturation of HBV, and which could explain the highly efficient way that HBV viruses infect liver cells to the exclusion of others. HBV binds to receptors (heparan sulphate proteoglycans, HSPG) on the liver cells by way of a specific region of the viral L protein. However, this does not explain the high specificity of the virus for liver cells as HSPG receptors are present on almost all human cell types.

The researchers from Heidelberg have now demonstrated that the viruses are initially present in the blood as immature, non-infectious N-type viruses. When they encounter liver cells, they turn into mature, infectious B-type viruses that are able to infect cells. N- and B-type viruses can also be morphologically differentiated under the electron microscope. The researchers carried out experiments in which they released B-type viruses into the bloodstream where they attached to a variety of other tissues and were thus unable to reach liver cells. The receptor-binding region of the L protein was found to be located inside the virus and was unable to recognise HSPG. Immature viruses convert into mature B-type viruses by turning the receptor-binding determinant inside out across the viral membrane. They then exclusively recognise HSPG receptors on liver cells, but not those on other cells. The investigation shows that hepatitis B viruses are not rigid, immobile objects, but rather highly mobile miniature machines with a precise clock mechanism,” says Bartenschlager. “They are small ticking time bombs that suddenly throw out molecular grappling hooks in order to infect their target cells.”

Reducing cancer risk

Immunohistochemical identification of hepatitis B virus in the liver. Only inactive N-type HBV (green, left) is able to enter the liver in the bloodstream. In the liver, N-type viruses become B-type viruses and are then able to infect liver cells. B-type viruses do not reach the liver. © Heidelberg University Hospital/ S. Seitz

This new elegant mechanism differs fundamentally from all others that have been described so far and offers new drug targets. If the maturation process could be impaired and viruses in the non-infectious N-type stage arrested, it would be possible to interfere with chronic hepatitis B infections, potentially also eliminate the virus and thus drastically reduce the cancer risk for people suffering from this incurable disease.

According to information from the American Center of Disease Control and Prevention, fifteen percent of all people who are chronically infected with HBV will develop hepatocellular cancer within ten years when the infection is not adequately treated. Chronic hepatitis C is also associated with a high risk of developing cirrhosis of the liver and hepatocellular carcinoma. The long-term objective of CRC/TRR 179 is therefore to develop new therapies that will cure chronic hepatitis B and C infections or prevent them from developing. However, the mechanisms that lead to chronic infections are not yet understood in detail. One of the major and as yet insufficiently understood questions concerns the role of the immune system in the chronification of liver infections. The project team led by Prof. Dr. Robert Thimme, medical director of the Department of Internal Medicine II at Freiburg University Medical Centre is investigating immune escape strategies that infected liver cells use to evade host immune system attacks in a subproject entitled "Mechanisms of antiviral therapy-induced virus-specific CD8+ T cell restoration in chronic viral hepatitis". The strengthening or activation of the host immune defence that enables virus-infected liver cells to be recognised is a promising therapeutic approach to stop chronic inflammation of the liver and prevent it from progressing into liver cirrhosis and subsequently into liver cancer.

Original publication:
Seitz S, Iancu C, Volz T, Mier W, Dandri M, Urban S, Bartenschlager R: A slow maturation process renders hepatitis B virus infectious. In: Cell Host & Microbe, 16.6.2016. DOI: 10.1016/j.chom.2016.05.013

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