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Researchers at the Medical Center - University of Freiburg demonstrate that specific fish viruses are evolutionarily related to hepatitis B viruses / 400-million-year-old relationship provides insights into virus biology and new therapeutic approaches

Hepatitis B viruses replicate their genetic material using a complex and unique strategy, the evolutionary origin of which was previously unknown. Now, scientists at the Medical Center - University of Freiburg, in collaboration with the University of Heidelberg, have shown that distantly related viruses from fish replicate their genetic material using a very similar mechanism. These findings could be used in the future for new therapeutic approaches in the fight against chronic hepatitis B. The research results were published on March 22, 2021 in the online edition of the renowned journal Proceedings of the National Academy of Sciences of the United States of America - PNAS.

"Hepatitis B viruses exhibit a very unusual replication mechanism that we have never seen before in any other virus. How hepatitis B viruses evolved was therefore a great mystery for a long time," explains the initiator of the study, Dr. Jürgen Beck from Prof. Dr. Michael Nassal 's Molecular Virology research group at the Department of Medicine II at the Medical Center - University of Freiburg. The research group has been investigating the molecular biology of hepatitis B viruses for more than 30 years. The Freiburg researchers have now been able to unravel a large part of this mystery.

Naked viruses provide decisive clue

They compared the genetic information of hepatitis B viruses with that of a family of fish viruses that was only discovered in 2017. These have no outer envelope and were therefore referred to as "naked" DNA viruses by their discoverers Dr. Stefan Seitz (University of Heidelberg) and Dr. Chris Lauber (DKFZ, Heidelberg) and named "Nackednaviren" in allusion to the Swabian dialect.

According to calculations by Beck and his colleagues, the evolutionary development of the two virus families separated around 400 million years ago. The decisive step was the emergence of a new gene that gave the hepatitis B viruses their envelope and thus a pronounced specificity for the liver. "This relationship constellation offered us a unique opportunity to study the development of the replication mechanism of hepatitis B viruses over an extremely long period of time," explains Nassal.

Ancient lock-and-key principle

The scientists have now discovered that hepatitis B viruses and naked viruses use the same mechanism to bring together the virus's own genetic material and viral proteins in human cells. "There are thousands of different cellular transcripts in a liver cell. That's why finding the right transcript is as difficult as finding your own chicks in a seabird colony. Nature has solved this problem by equipping the viral genome with a highly specific signal, a kind of barcode," explains Beck. This three-dimensional structure on the genome, known as the "epsilon signal", is recognized by the processing virus proteins according to the lock-and-key principle.

It is particularly remarkable that "epsilon" has changed very little over 400 million years. This extreme conservation suggests that this complex mechanism was optimized very early on in evolutionary terms and that further genetic changes are only possible to a limited extent without losing the ability to reproduce. This makes it an interesting target for the development of novel therapeutics against the human hepatitis B virus (HBV): due to its high degree of adaptation, it cannot be assumed that HBV will change its lock-and-key principle in order to circumvent the blockade. The development of resistance to corresponding active substances is therefore rather unlikely.

Around 250 million people chronically infected with hepatitis B

HBV is one of the most important human pathogens. According to estimates by the World Health Organization (WHO), around 40 percent of the world's population has already been infected with HBV. In many cases, the immune system eliminates the invader quickly and without lasting damage. However, in more than 250 million infected people, this is not successful and a chronic, often lifelong infection of the liver occurs, which can be severely damaged by the recurring attacks of the immune system. Every year, almost one million deaths from liver cirrhosis and liver cancer are the sad result. Current therapies with modified basic DNA building blocks can greatly suppress the multiplication of the virus, but are usually unable to eliminate it completely. To make matters worse, virus mutants that are resistant to the effect of the drugs can easily emerge during the course of treatment. The development of new therapeutic strategies, ideally with low resistance potential, is therefore of great medical importance.

Original title of the publication: Conservation of the HBV RNA element epsilon in nackednaviruses reveals ancient origin of protein-primed reverse transcription

DOI: 10.1073/pnas.2022373118.

Link to the study: www.pnas.org/content/118/13/e2022373118

Contact:
Dr. Jürgen Beck
Department of Medicine II (Gastroenterology, Hepatology, Endocrinology, Infectiology)
Uniklinik Freiburg
juergen.beck@uniklinik-freiburg.de