Researchers have discovered a new way in which the hepatitis C virus tricks the immune system to avoid detection. The research shows that the virus protects its genome with a cap comprising flavin adenine dinucleotide (FAD).
Viruses are constantly battling the human immune system. They try to use our cells to make more and more viruses, while the immune system tries to destroy them.
Part of the immune system’s strategy involves recognising RNA that differs from human RNA. If the RNA does not have the same characteristics as human RNA, the immune system activates the cellular defence systems to combat the virus.
A new study shows how the hepatitis C virus tricks the immune system by hiding its RNA under a FAD cap, which is one of our own metabolites derived from riboflavin (vitamin B2) and ATP.
When the immune system cannot easily recognise the hepatitis C virus, it takes longer to destroy an infection, and this provides the virus better opportunities to infect new liver cells and cause chronic infections.
The discovery of the virus’s tactics to evade the immune response provides new insight into the battle between the body and the virus. In the long term, this knowledge could be harnessed to improve treatments.
“Knowing the viral evasion strategy presents new opportunities of how to target the RNA from virus particles and potentially treat hepatitis C virus infections and other viruses that may use the same trick. However, treatments based on this discovery will require more research and development,” explains Jeppe Vinther, Department of Biology, University of Copenhagen, who headed the study together with Jens Bukh and Troels Scheel, Copenhagen Hepatitis C Program, Amager and Hvidovre Hospital, Copenhagen.
The research, which has been published in Nature, was carried out in a collaboration between 28 researchers, including first authors Anna Sherwood and Lizandro Rene Rivera Rangel.
Never-ending battle between viruses and the immune system
When viruses infect human cells, the virus sends its RNA into the cells and use its resources to copy the virus RNA for making new viruses.
One strand of virus RNA can thus create thousands of new virus RNA strands, which can infect new cells in the surroundings.
However, the immune system does not simply surrender and let the virus take over our cells. To distinguish between human RNA and foreign RNA, the human body attaches a molecular cap to one end of human RNA. In addition, the immune system contains proteins that recognise RNA that do not have this cap, including RNA from viruses, and initiates the cellular defence mechanisms.
“Our immune response recognises RNA that has no molecular cap attached to it. All viruses have to evade this system somehow, because being recognised effectively prevents further infection,” says Jeppe Vinther.
Thorough examination of disseminated viruses
Hepatitis C virus can evade the immune system and cause chronic infection of the liver, resulting in about 300,000 deaths annually, but how it avoids having its RNA recognised by the immune system was unknown – until now.
The researchers hypothesised that this virus, like other types, masks its RNA with a molecular cap but with a new type of capping.
“The problem is that the cap is not visible under a microscope, and we therefore have to examine the viral RNA in other ways, such as using special enzymes in combination with sequencing methods to recognise the cap,” explains Jeppe Vinther.
Capping RNA with specific molecules
The results showed that the hepatitis C virus did indeed protect its RNA in a previously unreported way, using FAD, which comprises riboflavin and ATP, as a cap. In fact, the virus begins its entire replication of RNA with FAD, so that the end of the RNA is automatically capped when it is produced.
When the hepatitis C virus caps its RNA with FAD, the immune system’s proteins no longer recognise it as foreign and therefore leave it alone, enabling the virus to spread.
FAD is present in human cells and is used to transfer electrons between molecules, but our own cells do not cap our RNA with this molecule.
“Studies had previously shown that the hepatitis C virus needs FAD to make new copies in human cells, but the reason was unknown. Now we have solved this mystery and shown that the virus uses FAD to protect its RNA and thus avoid recognition by the immune system’s cellular proteins,” says Jeppe Vinther.
Difficult to target with drugs
This is the first time researchers have found this type of RNA capping in viruses, and the researchers’ next step is to discover whether this method of protecting viral RNA is widespread and, if so, which viruses use it.
According to the researchers, the new knowledge provides opportunities to improve the targeting and detection of viruses.
In this context, it is reasonable to think that drugs could be designed that split FAD, thereby exposing the virus to the immune system’s proteins.
However, the solution is not that simple.
“You cannot just target FAD, since FAD is also an important molecule for human cells. So we cannot just cleave it in the process of attacking viruses. If we want to attack viruses this way, we need to develop something that only targets FAD when it caps viral RNA. We have some ideas how this may be achieved, but this will require further research,” concludes Jeppe Vinther.
