Find out the hidden hepatitis C virus, Unfinished Journey

 Find out the hidden hepatitis C virus, Unfinished Journey

This afternoon, Beijing time, the Nobel Foundation announced that Harvey J will be awarded the 2020 Nobel Prize in physiology or medicine. Dr. alter, Dr. Michael Houghton and Charles M. Dr. rice, in recognition of their important discovery of hepatitis C virus.

This years Nobel Prize winner in physiology or medicine, Harvey J. Dr. alter, Dr. Michael Houghton and Charles M. Dr. rice

The root of Millennium virus in the battlefield

Hepatitis C virus confirmed by modern medicine can be traced back to the epidemic of icteric hepatitis in 3000 BC. In modern times, the outbreak and spread of hepatitis C is more like a cloud spreading on the battlefield of World War II. A study in the Journal of Virology, after analyzing the global data on hepatitis C cases, conjectured that the spread of hepatitis C virus was linked to the field hospitals in World War II, believing that the lack of medical conditions contributed to the spread of blood-borne hepatitis C virus. After the end of the war, the soldiers who carried or infected with the virus became the seeds of hepatitis C virus spread to all parts of the world.

The spread of hepatitis C may be related to World War II (image source: USMC [public domain])

At present, we can not really determine the direct correlation between World War II and the spread of hepatitis C, but we can be sure that World War II promoted the discovery and treatment of hepatitis C virus. In 1947, shortly after the end of World War II, some scientists constructively proposed the existence of hepatitis A virus and hepatitis B virus based on past experience and hepatitis cases of soldiers in World War II, which opened a window for the exploration of viral hepatitis in modern medicine, and indirectly promoted the development and treatment of hepatitis C virus.

Find out the hidden virus

At first, it was speculated that hepatitis A virus was transmitted by mouth feces, while hepatitis B virus was transmitted by blood. In the next decade or so, scientists tried to find out the culprits of these two kinds of hepatitis and develop better therapeutic drugs to combat the threat of viral hepatitis to human health.

After 1965, the presumed hepatitis B and hepatitis A viruses were discovered one after another, but one of the scientists at that time, Harvey arteruff08 HarveyJ.Alter uff09The professor soon discovered that they were not all hepatitis viruses. Because nearly 80% of the hepatitis samples found after blood transfusion are neither hepatitis B nor hepatitis A. This also means that there is a third type of hepatitis virus, like hepatitis B virus, which takes blood and other body fluids as the transmission route, conceals itself in the crowd, and becomes a potential risk affecting blood transfusion and even human health.

In the next 15 years, due to the limitations of medical research methods at that time, neither Professor art nor his team could see the true appearance of the third hepatitis virus. But they did what they could to build a security wall for the world - reducing post transfusion viral hepatitis infection from 33% to 4% by increasing blood transfusion test indicators, and leaving clues for the discovery of the virus - to cultivate the infection serum of the mysterious third hepatitis in chimpanzees and leave it to the successor who can crack the code.

Due to the discovery that hepatitis C virus can be transmitted through the blood and the accurate detection method, Professor art and Professor Horton won the Lasker prize for clinical medicine research in 2000 (photo source: screenshot of Lasker Award official website)

In 1989, Professor Michael Houghton and his team took over the baton. Using molecular biological cloning technology, they isolated the RNA fragment of hepatitis C virus (HCV-RNA), so that hepatitis C detection from the previous exclusion method to a new stage of accurate discovery.

Through this technology, scientists have been able to detect: 88% of cases that are neither hepatitis B nor hepatitis A are hepatitis C! By 1992, with the improvement of technology, hepatitis C virus almost disappeared from blood transfusion and blood products supply, and millions of patients were protected from hepatitis C infection every year.

Give hepatitis C virus life

After completing the crucial and difficult step of discovering hepatitis C virus, the story should have gone smoothly along the conventional route of from identifying the molecule, finding the target, and then finding the right medicine. However, the complacent scientists soon encountered a new problem: it is extremely difficult for hepatitis C virus to replicate in the laboratory environment. How can scientists who cant get experimental materials to study the composition and life cycle of hepatitis C virus? What should be used to develop targeted antiviral drugs?

Professor bartenschlag and Professor rice shared the 2016 Lasker clinical medicine research award with Dr. Michael Sofia, the team leader of the R & D team of the heavyweight new hepatitis C drug sofosbuvir for their contribution to the in vitro culture of hepatitis C virus (photo source: screenshot of Lasker Award official website)

The problem goes back to hepatitis C itself. Professor Charles rice from Washington University in St. Louis and Ralf bartenschlage from Germany have made breakthroughs in overcoming the problem of infecting living cells with hepatitis C virus.

Professor rice compared a large number of HCV RNA isolated from patients and found their consensus sequence.. After the standard RNA was injected into the orangutan, it successfully caused hepatitis C infection. Two years later, on the basis of Professor Rices research, Professor bartenschlag went further and found the first cell line that could efficiently replicate hepatitis C virus. Another year later, Professor rice also reported in the journal Science the new cell line independently developed by his team.

These two big news triggered the whole academic and industrial circles - people finally had tools to screen hepatitis C drugs, laying the foundation for the development of direct acting antiviral agents (DAAS).

The night is long, but the dawn has come

Before this foundation was established, hepatitis C was regarded as a kind of liver disease which was extremely difficult to treat. The only effective treatment was interferon combined with ribavirin (a broad-spectrum antiviral drug), but such a standard scheme of blind people and elephant would cause great side effects. Scientists have been exploring targeted antiviral drugs for hepatitis C treatment to avoid damage to other parts of the body caused by friendly fire. The successful cultivation of hepatitis C virus in the laboratory provides necessary conditions for scientists to study its composition and life cycle.

Through continuous experimental screening, scientists have found that NS3 / 4A protease, NS5A protease and NS5B polymerase have the potential to become targets for hepatitis C. Among them, NS5B polymerase is directly responsible for viral RNA replication; NS3 / 4A protease catalyzes the hydrolysis and maturation of HCV nonstructural protein, which is necessary for the life cycle of hepatitis C virus; and there is interferon sensitive determinant region in NS5A protein, and NS5A can regulate the replication of HCV. If we can develop drugs to effectively target these targets, we can greatly interfere with the replication of hepatitis C virus and let them die of offspring.

As the first direct anti HCV drug, trapivir showed higher antiviral activity and good safety and tolerance (photo source: Edgar 181 [public domain])

In 2011, the first batch of direct anti HCV drugs such as telaprevir were approved by FDA. The results showed that trapivir targeting NS3 / 4A protease had higher antiviral activity, better safety and tolerability than the previous standard regimen for the treatment of hepatitis C. After 12 weeks of treatment, the triple therapy of trapivir combined with interferon and ribavirin resulted in no detection of hepatitis C virus (svr89%) in 89% of the subjects, which was significantly better than that of the control group (svr44%) treated with interferon and ribavirin. Although there are still side effects of the related treatment, but also let hepatitis C patients see the hope of cure for the first time.

Molecular structure of sofosbuvir, a heavy hepatitis C drug (image source: yikrazuul [public domain])

In 2013, the birth of NS5B inhibitor sofosbuvir was a milestone in the history of hepatitis C. It is the first direct antiviral drug that can effectively cure hepatitis C without interferon, which completely changes the treatment of hepatitis C and makes patients no longer troubled by side effects of interferon. In clinical trials, sofibvir showed a 100% cure rate for patients with hepatitis C type 2 and type 3! The famous academic journal Cell magazine called it one of the most important achievements of this generation in the field of public health.

Unfinished Journey

In the history of medicine, only a few chronic diseases can be cured, hepatitis C is one of them. According to a new study published in the annals of internal medicine, based on the existing screening and treatment methods, by 2036, hepatitis C, which once ranked among the worlds top infectious diseases, will become a rare disease. The World Health Organization has set the goal of eliminating hepatitis C by 2030.

The existing hepatitis C therapy has been able to cure all major types of hepatitis C with a success rate of more than 90% in just 2-3 months! (source: who)

The fight against hepatitis C seems to be coming to an end, but scientists efforts are not over. At present, both hepatitis A and hepatitis B have vaccines, but there is no vaccine for hepatitis C. Compared with hepatitis A and hepatitis B virus, hepatitis C virus is more likely to mutate, which brings complex challenges to the development of hepatitis C vaccine. In addition, it is still a long way to go to promote direct antiviral therapy for hepatitis C worldwide. Facing the unmet medical needs of a small number of hepatitis C patients, we need to continue to invest in research and development, and at the same time, we need to further reduce the cost of research and development, so that good medicine can benefit patients around the world as soon as possible.

In the past 30 years, the joint efforts of scientists and industry people have made us see the miracle of hepatitis C cure, and also bring us the courage to explore the future.

Extended reading just now! Nobel Prize in physiology or medicine announced in 2020 Nobel Prize in physiology or medicine: why the discovery of hepatitis C virus is of great significance_ NT5054