Share:
Medicines Hepatitis B viruses are a ticking time bomb
Infections with hepatitis B virus are a kind of ticking time bombs, which affects about 440,000 people in Germany alone, according to the joint press release of the German Cancer Research Center (DKFZ) and the University Hospital Heidelberg. In a recent study, researchers identified a previously unknown mechanism of infection.
Researchers from the DKFZ and the Center for Infectious Diseases at the University Hospital Heidelberg have discovered in a joint study a completely new maturation mechanism, with which the hepatitis B virus increases the efficiency of its infection. "Most of the time, the virus hides in the liver cells for a long time, which often leads to cirrhosis and liver cancer," according to the DKFZ. Worldwide, around 230 million people are affected by an infection with the hepatitis B virus (HBV).
Hepatitis B viruses are particularly effective in infecting cells dnk of a special mechanism. (Picture: University Hospital Heidelberg / S.Seitz) High efficiency of hepatitis B viruses
For infection of cells, viruses must first bind to specific receptor proteins on the cell surface, with the hepatitis B virus binding to heparin cells with a portion of its "L protein" in the viral envelope of heparan sulfate proteoglycans (HSPG) the explorers. Then it is taken into the cell and begins to multiply there. "The efficiency with which the hepatitis B virus infects cells is several orders of magnitude higher than that of most other viruses," emphasizes Stefan Seitz, first author of the current study, active at the Center for Infectious Diseases, Molecular Virology, Heidelberg University Hospital, and DKFZ.
Liver cells are specifically infected
According to the researchers, the hepatitis B viruses infect "highly specific liver cells", which is relatively surprising since the HSPG molecule, which serves as the receptor for the virus, occurs virtually on all cell types in the human body. Actually, the HSPG seems to be an extremely unfavorable receptor "for a virus that has to reach an organ that is far away from the portal of entry into the body," says first author Seitz. This contradiction was investigated by the scientists in their current study.
In their investigations, the researchers helped "two recently discovered secrets of the virus," reports the DKFZ. First, it had become clear on new electron micrographs of the hepatitis B virus, "that the pathogen occurs in two different variants that look different." And secondly, the L protein in the virus envelope can also take two different forms. Here, the portion that binds to the receptor on the liver cell, in one case directed into the interior of the virus particle and in the other case to the outside. But only the outward form allows the virus to infect liver cells.
Different forms of hepatitis B virus
In his research, the research team led by Stefan Seitz explored the question of how a connection between the two new observations exists. Their hypothesis: Hepatitis B viruses change shape while changing the orientation of the L protein. To test the theory, the researchers said they "established a biochemical test that could distinguish the mature, HSPG-binding variant B from the immature variant N, which does not bind to HSPG." In the subsequent analysis, it had become clear "That almost all viruses leave the cells in the immature state (N) and then spontaneously transform into the mature, binding (B) form by putting the receptor-binding portion of the L protein inside out."
Slow conversion of viruses
The researchers also found that the maturation of N-type viruses into infectious B-type is a slow process. This has a decisive influence on the course of infection. In mice, the scientists were able to show that after injecting a small number of viruses, B-type viruses were largely trapped on other tissues, while large numbers of N-type viruses reached their target organ, the liver, and there - after they had converted to the B-form - infected the liver cells. The "slow change process seems to increase the effectiveness of hepatitis infection," reports the DKFZ. He also explains why even small amounts of virus infect liver cells in a highly specific manner, although HSPG receptors are widely distributed in the body.
Elegant mechanism of a viral maturation process
In the immature form, the hepatitis B viruses are inactive and therefore can constantly swim along with the bloodstream until they reach the liver, according to the DKFZ. Here they are finally stopped and as soon as a change to the mature B-form, they begin to infect the liver cells. "This is a previously unknown and very elegant mechanism for a viral maturation process, which differs fundamentally from all those described so far," says Ralf Bartenschlager, Head of Research Departments at the Center for Infectious Diseases, Molecular Virology at the University Hospital Heidelberg and the DKFZ.
Small ticking time bombs
According to Ralf Bartenschlager, the current study also made clear that the hepatitis B viruses are not rigid immovable objects, but highly mobile miniature machines with a precisely running clockwork. "Actually, these are small ticking time bombs that suddenly eject molecular grappling hooks to infect their target cells," he warns. The researchers conclude that the discovered mechanism also provides a new target for drugs. "You could develop substances that block the viruses in the immature, non-infectious state," said Seitz. Such inhibitors may, according to the study author, "support the treatment of chronic hepatitis B, which is still incurable and a common cause of liver cancer."
Cancer risk significantly reducible?
In a next step, researchers plan to decipher the molecular mechanism underlying the maturation process and identify ways to inhibit it. "If we manage to interrupt the chronic hepatitis B virus infection and eliminate the virus, we could drastically reduce the cancer risk of those infected", emphasizes Ralf Bartenschlager in the joint press release of the DKFZ and the University Hospital Heidelberg. (Fp)