Mystery of How Hepatitis C Hides From the Immune System Solved

Each year, 300,000 people die from the hepatitis C virus. And it is estimated that more than 50 million people worldwide are infected with the virus which may cause liver inflammation and, in the worst case, liver cancer.

The hepatitis C virus was discovered in 1989 and is one of the most widely studied viruses on the planet. Yet, for decades it has been something of a mystery how this virus manages to hide from the human immune system and spread in the body. But now, researchers have become the first in the world to solve part of the puzzle.

It is very exciting that research into the hepatitis C virus has now resulted in a discovery that is so groundbreaking for the understanding of virus and RNA biology

A new method for examining virus samples has led the research team from the University of Copenhagen and Hvidovre Hospital to the answer, as follows: The virus simply puts on a 'mask'.

By doing this, the virus manages to remain hidden while making copies of itself so that it can infect new cells. The virus 'steals' the mask from us in the form of a molecule that is already present in our cells. When wearing the molecule as a disguise, our body’s defence systems mistake the virus for something harmless to which they do not need to react. 

“It has always been a bit of a mystery how the hepatitis C virus is able to hide in our liver cells without being detected by the immune system. Our uncovering of the virus's masking strategy is important as it may pave the way for new ways to treat viral infections, and it is likely that other types of viruses use the same trick,” says Associate Professor Jeppe Vinther from the Department of Biology, who – together with Associate Professor Troels Scheel and Professor Jens Bukh from the Copenhagen Hepatitis C Program (CO-HEP), Department of Immunology and Microbiology (ISIM) – has been at the forefront of the research.

“It is very exciting that research into the hepatitis C virus has now resulted in a discovery that is so groundbreaking for the understanding of virus and RNA biology,” says Professor Jens Bukh.

The study has just been published in the scientific journal Nature.

Camouflage for a malicious virus

The mask that the hepatitis virus is using to hide in our cells is called FAD and is a molecule made up of Vitamin B2 and the energy molecule ATP. FAD is vital for our cells when they need to transform energy. Because the FAD molecule is both important and familiar to our cells, it is also a perfect camouflage for a malicious virus.

For several years, the research team has had a strong idea that it was by means of FAD that the virus was able to stay hidden in the infected cells, but they lacked a precise way to prove it. To solve that challenge, they looked to the plant kingdom and the Arabidopsis Thaliana plant which is a well-known experimental plant among researchers.

“We were getting desperate to find a way to prove our hypothesis, but then we had an enzyme from the Arabidopsis Thaliana plant purified that is able to split the FAD molecule into two,” explains Anna Sherwood from the Department of Biology, who – together with Lizandro Rivera-Rangel from Troels Scheel's group in CO-HEP – are the lead authors on the study.

Using that enzyme, the researchers were able to divide FAD and thus prove that the Hepatitis C virus used the molecule as a mask.

Other viruses are probably using the same dirty trick

Like the corona virus and the common influenza virus, the Hepatitis C virus is an RNA virus, meaning that the genetic material of the virus consists of RNA that needs to be copied when the virus has infected its host organism. The new RNA copies are used to create new virus particles that can take over new cells, and this is the beginning of the RNA genetic material that is masked by FAD.

According to Troels Scheel, it is very realistic that other RNA viruses wear similar masks in order to spread without being detected by the cell's control systems. In fact, the researchers have already found a related virus that uses the same strategy and, probably, there are more.

“All RNA viruses have the same need to hide from the immune system, and there is a high probability that this is only the beginning. Now that we know about this trick, it opens the door to discovery of similar ways to evade the immune system in other viruses and maybe even new treatments for viral infections in the future,” says Troels Scheel.

Reference: Sherwood AV, Rivera-Rangel LR, Ryberg LA, et al. Hepatitis C virus RNA is 5′-capped with flavin adenine dinucleotide. Nature. 2023;619(7971):811-818. doi: 10.1038/s41586-023-06301-3

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