On October 5, 2020, at about 17:30 Beijing time, American virologist Harvey James alter, British virologist Michael Houghton and American virologist Charles M. Rice won the 2020 Nobel Prize in physiology or medicine for discovering hepatitis C virus.
Nobel Prize winners in physiology or medicine 2020: Harvey James alter, Michael Houghton and Charles M. Riceuff09
Harvey James alter, born in New York on September 12, 1935, received his Bachelor of Arts degree from the University of Rochester in 1956 and a medical degree in 1960. Alter is currently Deputy Director of the Department of transfusion medicine at the Warren grant Magnuson clinical center at the National Institutes of Health (NIH) and head of infectious diseases. Arter and his team demonstrated in the mid-1970s that most post transfusion hepatitis is not caused by hepatitis A virus and hepatitis B virus. Alte and Edward Tabor, a scientist from the U.S. Food and Drug Administration (FDA), conducted independent studies on the transmission of chimpanzees to prove that a new type of hepatitis originally known as non-A, non-B hepatitis caused the post transfusion infection, and the pathogen may be a virus. This work eventually led to the discovery of hepatitis C virus.
Michael Houghton was born in England and received his doctorate from Kings College London in 1977. He first joined G. Du3002 Searle & Company (now a Pfizer subsidiary) joined Chiron Corporation in 1982. He joined the University of Alberta in 2010. He is currently a virologist at CERC, Professor of Virology at the University of Alberta, and director of the Li Ka Shing applied virology Institute at the University of Alberta.
Charles M. Rice was born in Sacramento in 1952. He received his doctorate from California Institute of technology in 1981 and received postdoctoral training from 1981 to 1985. In 1986, rice set up her own research group at Washington University School of medicine in St. Louis, and became an official professor in 1995. He has been a professor at Rockefeller University in New York since 2001. From 2001 to 2018, he was the scientific and executive director of the center for hepatitis C research at Rockefeller University, where he has been engaged in research.
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This years Nobel Prize is awarded to three scientists who have made a decisive contribution in the field of blood borne hepatitis. Blood borne hepatitis is a major global health problem leading to liver cirrhosis and liver cancer.
Harvey J. Alter, Michael Houghton and Charles M. Rice) and identified a new type of virus, hepatitis C virus. Before this, the discovery of hepatitis A and hepatitis B virus has been a major achievement in the struggle between human beings and viral hepatitis. But even so, most cases of blood borne hepatitis still cannot be explained. The discovery of hepatitis C virus has revealed the cause of the remaining cases of chronic hepatitis and made it possible for blood tests and the development of new drugs, thus saving millions of lives.
Figure 1: there are two main forms of hepatitis. The first is an acute disease caused by hepatitis A virus, which is transmitted by contaminated water or food. The other is caused by hepatitis B virus (HBV) or hepatitis C virus (contribution of this years Nobel Prize). This form of blood borne hepatitis is usually a chronic disease that may develop into cirrhosis and hepatocellular carcinoma.
Figure 2: Harvey J. A methodological study of transfusion associated hepatitis (transfusion related hepatitis) conducted by alter showed that a virus unknown at the time was a common cause of chronic hepatitis. Michael Houghton used an untested strategy to isolate the genome of the new virus, which was later named hepatitis C virus. Charles M. Rice) provided final evidence that hepatitis C virus alone can cause hepatitis.
Figure 3: the discovery of three Nobel laureates allowed researchers to design highly sensitive blood tests to detect the virus, thereby eliminating the risk of transmission of transfusion related hepatitis in most parts of the world. This breakthrough also enables future generations to develop enough antiviral drugs to cure the disease. Hepatitis C is still a major global health problem, but now we have the opportunity to eliminate it.
The end of hepatitis C
According to the World Health Organization, in 2015, hepatitis C caused 400000 deaths, 150000 of whom died of liver cancer. The World Health Organization also said the actual number of deaths caused by hepatitis C exceeded the above figure due to the lack of data. Since 2012, hepatitis C has become the leading fatal infectious disease in the United States, many people died of liver cancer caused by hepatitis C or liver failure related to liver cirrhosis; the number of people who died of hepatitis C was more than that of 60 other infectious diseases including AIDS and tuberculosis combined. The mortality of hepatitis C is about to peak, because according to the World Health Organization, there are 71 million people suffering from chronic hepatitis C in the world. Hepatitis C and alcoholism are the main causes of liver transplantation worldwide.
The task of controlling hepatitis C is very difficult because most patients know nothing about their condition. We estimate that only 20% of people with chronic hepatitis C know they are infected. To make matters worse, not all hepatitis C patients have symptoms. Once the hepatitis C virus takes root in the human body, the chronic disease can be latent in the human body for decades before the symptoms of liver damage appear for the first time.
Catch the mysterious virus
However, now infected with hepatitis C does not mean that the prospects are bleak. This was totally unthinkable seven years ago, but now we can treat most of the hepatitis C patients in a few weeks, even in the late stage. This achievement is due to a series of breakthroughs in drug research: researchers have figured out the structure of hepatitis C virus, successfully reproduced their infection process in vitro, and found drugs targeting the enzymes needed for the virus to proliferate in the human body.
Peoples understanding of hepatitis C began in the late 1970s. At that time, some doctors discovered a new type of chronic hepatitis infected by blood transfusion. Neither hepatitis A virus nor hepatitis B virus is responsible for this hepatitis. For the next 10 years, biologists tried to isolate the hepatitis virus from patients without success. In 1989, a team led by Michael Houghton of Chiron pharmaceutical company in the United States finally identified hepatitis C virus with the help of a new molecular biological technology.
Unable to purify the hepatitis C virus particles from the blood and culture them in vitro, Horton and others tried to isolate the viral genome directly from the blood. They built a library of genetic material from the blood of an infected chimpanzee, whose blood cells had been cleared, and then inserted the fragments into one million phages, viruses that attack bacteria. Bacteria infected with these phages can synthesize protein fragments of the target virus.
In addition, they obtained a serum sample from a patient who had developed antibodies to the mysterious virus. After contact with the bacteria, the antibody in serum recognized the viral protein fragment expressed by the bacteria. Using this method, they finally traced the viral gene sequences that encode these proteins. Using these techniques, Hortons team was able to sort out almost all the sequences of the viruss genome.
be the most changeful
After the hepatitis C virus genome was decoded, scientists found that it was a small RNA virus belonging to Flaviviridae (Zika virus and dengue virus belong to this family), and they only encode 10 proteins. At this point, researchers can finally study these proteins, which is the first step to inactivate the virus. The researchers sequenced the genes of the virus produced in the course of infection, and found that hepatitis C virus also has a terrible unknown feature: Super variability. Like hepatitis C virus, another small RNA virus, HIV, has this property. The strong variability of hepatitis C virus enables hepatitis C virus to bypass the recognition mechanism of the immune system, which makes vaccine development more difficult.
Because viruses are very small, they can replicate quickly in liver cells. We estimate that 1 trillion new viruses are produced every day in an infected person, and there are subtle differences between these viruses. In the face of the large number and variability of viruses, the hosts defense mechanism quickly collapsed. In order for the immune system to regroup and clear infected liver cells, it is necessary to find a way to stop the virus from replicating endlessly. At first, researchers had no idea what to do with hepatitis C virus, because they couldnt grow the virus in vitro. In addition, the researchers reproduced the process of hepatitis C virus infection in only one model animal, chimpanzees.
However, in the process of studying virus replication, researchers have made two exciting findings. First of all, hepatitis C virus mainly infects the liver, and drugs can easily reach this organ by oral administration. Second, unlike hepatitis B virus and HIV, hepatitis C virus only exists in the cytoplasm, not in the nucleus or cell genome. Because of these two characteristics, it is possible to eliminate hepatitis C virus completely in human body. This was confirmed in 1997 by Patrick Marcelin, who treated some patients with hepatitis C for several months with a small antiviral protein, interferon alpha (IFN - u03b1).
In 1986, liver disease experts in the United States noted that some patients with hepatitis C were injected with IFN - u03b1 three times a week for a year. IFN - u03b1, a protein derived from the human body itself, can stimulate the immune system infected by the virus. Since then, scientists have been using genetic engineering to make this protein. Marcelins study in 1997 showed that after treatment with the protein, hepatitis C virus disappeared completely from the liver and blood of some patients.
In 1999, a great discovery finally opened up the prospect of hepatitis C virus research. Ralf bartenschlagers team at the University of Mainz in Germany announced that they had achieved stable replication of the hepatitis C virus genome in cells. The team found that if only part of the viral genome was introduced into human liver cancer cells, the virus would start replicating automatically.
The successful replication of the virus in vitro gives the pharmaceutical industry an opportunity to study hepatitis C virus carefully and test various blocking drugs. However, it was not until 2005, when a special type of hepatitis C virus was found in a Japanese patient, that the researchers reproduced the complete infection cycle of the virus in human liver cells in vitro. The virus can avoid the anti-virus mechanism inside the cell and has strong toxicity. However, long before the full model of the virus was available, researchers began to test different antiviral methods.
The first target they found was NS3, an important protein encoded by the virus genome. The genetic material of hepatitis C virus is a special RNA molecule, which can encode a long chain precursor protein, which is composed of 10 viral proteins. Among them, NS3 is a kind of protease, which can decompose some long chain precursor proteins and release some mature viral proteins. In 1996, virologists obtained the crystal of the protease, which enabled us to study its structure in more detail. NS3 seemed to be a perfect target at the time, and researchers can refer to previous HIV research experience.
HIV can also produce a protease, and the drug that inhibits it, saquinavir, is quite effective. The drug was developed in 1995 thanks to advances in computer modeling. Because of its excellent effect on AIDS, the number of people who died of AIDS in the United States dropped to one-third in 1997, the second year after its launch. The drug marks the golden age of AIDS cocktail therapy. Cocktail therapy combined with several oral drugs to inhibit viral replication, patients also had good tolerance to these drugs.
The first inhibitor of hepatitis C virus
However, research on hepatitis C virus has encountered an unexpected obstacle. The three-dimensional structure of NS3 protein was analyzed by bioinformatics technology, and it was found that this molecule had no pocket structure for inhibitor binding. Therefore, many researchers have turned to other viral proteins to serve as drug targets. However, the team led by montse llinas brunet, a chemist at Boehringer Ingelheim, Canada, decided to hold its ground. In 2003, the team synthesized a molecule that blocks NS3. This molecule is very stable and small, so it can be absorbed orally. The initial clinical test results were very good. After taking the drug, called biln2061, the viral load in the patients blood dropped to one thousandth of its original level and could hardly be detected. This is unheard of compared with other therapies of the time.
Other therapies of the same era mainly rely on once a week, 24 or 48 weeks of subcutaneous injection of IFN - u03b1, combined with an oral antiviral small molecule drug ribavirin (ribavirin, can enhance the efficacy of IFN - u03b1, the mechanism is unknown). However, such treatments are expensive and poorly tolerated. Six months after receiving this treatment, if the virus is not detected in the blood of the patient, it can be regarded as cured. Whether a patient can recover depends on the virus strain (the genotype of the virus) and the viral load in the blood. IFN - u03b1 therapy is more useful for hepatitis C virus genotypes 2 and 3, but not as good for genotype 1. Genotype 1 is the most common virus strain in the western world. Less than half of patients infected with genotype 1 virus can be cured with IFN - u03b1 therapy.
However, biln2061, an NS3 protease inhibitor, is quite effective against genotype 1 virus infection. As NS3 can be specifically blocked, biln2061 can not only block the replication of hepatitis C virus, but also prevent the destruction of cell defense mechanism by NS3 protease. In addition, compared with IFN - u03b1, biln2061 had fewer side effects. IFN - u03b1 often causes flu like symptoms, such as fatigue, depression, anxiety, insomnia, and sometimes anemia is caused by ribavirin, a drug used in combination.
Other laboratories have followed suit and produced a series of new NS3 inhibitors, two of which were launched in 2011, namely, telaprevir and boceprevir. In any case, these three oral new drugs alone are not enough to cure hepatitis C, because the virus is so variable that only one mutation can bypass the drug blocking. In addition, these three drugs and many drugs can not be shared, and there are some side effects. However, if these three drugs are combined with the old treatment (IFN - u03b1 and ribavirin), the cure rate of genotype 1 can be significantly increased, and even the patients who have failed in the old therapy can be saved.
This is the first time that hepatitis C has succumbed to a simple drug that targets one of its components. The powerful efficacy of these specific inhibitors shows that blocking viral proteins with multiple roles can achieve twice the result with half the effort. The era of direct acting antiviral drugs (DAA) has come. Drug developers have begun a competition to block other viral proteins, which has brought new surprises.
Antiviral weapons depot
Another well studied target is NS5B, a polymerase that helps viral genomes replicate. Like NS3, NS5B is the nonstructural protein of virus (this protein is not part of mature virus particles, but plays an important role in virus replication and assembly), and human cells do not contain similar proteins. In 1999, researchers isolated and purified NS5B, and made the crystal of NS5B protein. They found that there are many potential sites for inhibitor binding on NS5B. Because the previous research on the structure of HIV reverse transcriptase has greatly promoted the research and development of AIDS drugs, some pharmaceutical enterprises have started a scientific research competition after knowing the research results of NS5B, competing to find inhibitors that are not easy to make hepatitis C virus resistant. Their specific method is to test the emergence rate of drug-resistant virus strains in vitro.
In 2004, the first inhibitor appeared to prevent HCV from synthesizing RNA using NS5B polymerase. Because the binding target of this inhibitor is an active site on NS5B, it is effective on all virus strains. In addition, mutations that prevent the inhibitor from acting can seriously interfere with the function of NS5B polymerase, so that the virus can not replicate normally. In 2010, another similar inhibitor, sofosbuvir, was developed by the team of Michael Sofia, a U.S. start-up called pharmat. Pharasset was acquired by Gilead in 2011.
In 2012, the results of the first clinical trials of sofibuprovir were published. When combined with ribavirin, the inhibitor not only has a significant effect on genotype 2 and 3, but also has good tolerance for patients. Ideally, just one dose a day can work, and the inhibitor is compatible with other drugs, which greatly expands the number of patients that can be cured.
In 2013, the U.S. Food and Drug Administration (FDA) approved the use of sofibuprovir because of the gratifying clinical trial results. After 27 years of research, this is the first time we have been able to cure some hepatitis C patients without using IFN - u03b1.
At the same time, researchers began to look at another hepatitis C virus protein, NS5A, because they noticed that mutations in the protein could prevent the virus from infecting cells. However, it was very difficult to block NS5A, because at that time, researchers did not even know the specific function of this protein (we already know that it can regulate virus replication and assembly). In 2010, a team from Bristol Myers Squibb, an American pharmaceutical company, announced the development of a specific inhibitor for NS5A.
In vitro tests, the team screened one million molecules that could inhibit viral replication. The researchers then excluded from the selected molecules those that inhibit enzymes other than NS5A - the remaining molecules can only block NS5A, thereby inhibiting virus replication. The team then adjusted the structure of one of the molecules to improve its absorption and pharmacological properties. The result of their efforts is daclatasvir, the most effective drug for hepatitis C virus so far. In fact, the next years clinical trials confirmed that patients were well tolerated with dacetavir, and that it could reduce the virus concentration in the patients blood to less than one thousandth of its original level (compared with a quarter of biln2061). In 2012, this new type of weapon to accurately combat hepatitis C virus finally came on the stage, and its anti infection effect was unprecedented. Now its time to test it on more patients.
The emergence of direct acting antiviral drugs (DAA) has brought new hope for the fight against hepatitis C. human beings are expected to completely eradicate hepatitis C virus in all patients without using IFN - u03b1 and ribavirin. In 2012, the first clinical trial of patients with completely ineffective old therapies brought that hope closer to reality. After three months of treatment, four of the 11 patients were cured with a combination of dacetavir and another NS3 inhibitor. This is the first time that hepatitis C has been cured by oral treatment.
The next year, in a clinical trial of nearly 100 people, a combination of dacetavir and sofibvir cured more than 90% of patients within 24 weeks, some of whom were refractory patients who had failed all previous therapies, and had entered advanced cirrhosis. This treatment works not only for genotype 1, but also for genotypes 3 and 4, an unheard of result.
In 2013, sofibuprovir was approved to be used in combination with traditional therapy in the treatment of hepatitis C, becoming the third officially launched DAA drug. At the same time, a series of large-scale clinical trials have been carried out to determine the most effective DAA drugs and the best combination of drugs for different patients through in-depth cooperation between medical experts, drug research and development laboratories and drug regulatory agencies in Europe and the United States.
In 2014, a decisive step was taken in the field of hepatitis C treatment - the first treatment without IFN - u03b1 and ribavirin was approved in Europe and the United States. The treatment combines two DAA drugs: sofibvir and ledipasvir. Redipavir is another NS5A inhibitor. The treatment is well tolerated and is particularly effective for genotype 1, as long as it is administered orally for 12 weeks. The current treatment of hepatitis C is mainly used in this way.
At present, there are five treatments approved in the United States and Europe for the combined use of NS3, NS5A and NS5B inhibitors, and other therapies will appear in the next few years. The combination of sofibvir and other DAA therapies can treat all genotypes of hepatitis C virus worldwide. In addition, these drugs are effective even for advanced liver cirrhosis, thus helping to reduce the number of patients requiring liver transplantation. Also, they are useful for patients who have received liver transplants. Patients with liver transplantation need immunosuppressive therapy to reduce the rejection of the immune system to the transplanted liver, but this will cause the virus to infect the transplanted liver again, which is the main reason of liver transplantation failure, and the above drugs can prevent this problem. Cirrhosis caused by hepatitis C virus can seriously damage liver function. After the virus is removed by drugs, the liver function of patients will recover. Now, more than 95% of hepatitis C patients can be completely cured. The number will be refreshed when new therapies (combined with existing or new inhibitors) are launched, because the results of the first clinical trials show that these new therapies can deal with all virus strains, regardless of the genotype of the virus.
These new therapies will revolutionize the treatment of hepatitis C and its control at the level of public health. Patients can take medicine at home and only need to go to a special treatment center for monitoring. After 3 months of treatment, if the virus load is not detected in the blood, it will not recur. In the eyes of experts, with these advances, it is possible to eliminate hepatitis C throughout the country. Those at risk of hepatitis C, such as injecting drug users, prisoners and people living with HIV, will have more access to treatment. For example, in 2011, 193000 people in France were infected with hepatitis C virus, according to estimates by the Institut deveillesanitaire, of whom 65% were injecting drug users, 5% were prisoners and 18% were HIV carriers.
Elimination of hepatitis C
Is our war with hepatitis C over? Dont be too happy. In fact, there are still several problems to be solved. The first is to screen out a large number of chronic hepatitis C patients who are not aware of their own infection. DAA is their good news, because drugs can cure the fatigue, muscle and joint pain caused by hepatitis C, and greatly improve their quality of life. In addition, studies on patients with chronic hepatitis C have shown that hepatitis C virus often causes insulin resistance and diabetes, and increases the risk of cardiovascular and cerebrovascular diseases. Hepatitis C can also induce some cancers, such as cholangiocarcinoma and diffuse large B-cell lymphoma. In late 2016, a cheaper portable diagnostic method was certified by the World Health Organization, marking the first step in large-scale hepatitis C screening.
The second problem is the large-scale financial support needed to implement these therapies. At present, these therapies are too expensive, especially for developing countries that suffer from hepatitis C. However, several countries, including France, Germany, Portugal, Scotland, Australia and Ireland, have shown their determination to eliminate hepatitis C virus within 10 years, in anticipation of a drop in drug prices and a reduction of treatment courses to eight weeks or less.
Worldwide, 194 member states of the World Health Organization collectively announced on May 28, 2016 that they would eliminate hepatitis B and hepatitis C by 2030. For those countries where hepatitis B and hepatitis C virus are rampant (such as China, Pakistan), this is a very difficult target. Both China and Pakistan have more than 10 million hepatitis C patients, while Russia, Ukraine, Brazil and Argentina have not so many, but also many.
In order to help nearly 100 underdeveloped countries fight hepatitis C, Bristol Myers Squibb approved a series of generic drug licensing agreements for dakatavir in 2015. Gilead Sciences sold the drugs to these countries at 1% of the original price, and allowed more than a dozen Indian pharmaceutical companies to produce generic drugs. Gilead has also worked with countries with severe hepatitis C outbreaks, such as Egypt, where 12% of the population has hepatitis C. In 2014, Egypt launched a campaign to provide free hepatitis C treatment to its citizens, with about 1 million patients receiving treatment by 2016. Georgia has the third highest rate of hepatitis C infection, accounting for 5% of the total population. With the support of the U.S. government, the government of Georgia launched a nationwide free treatment program for hepatitis C in 2015, using drugs provided by Gilead science. More than 24000 patients have been treated in the country. However, in other countries, such as Brazil and China, the patent application was rejected because of the high price of sofibvir produced by Gilead science. Some organizations, such as doctors of the world and doctors without borders, even protested to the European Patent Office about the rationality of their patents, hoping to promote the emergence of generic hepatitis C drugs through this means.
Other problems that need to be solved in order to eliminate hepatitis C include: the means to make treatment available to all patients quickly, and the method to confirm the disappearance of the virus three months after the end of treatment (which is a sign of cure). Finally, a unique problem in developing countries is the iatrogenic infection caused by the cross use of medical equipment. According to the World Health Organization, 5% of the worlds medical injections are not safe; if drug injections are included, they caused 1.75 million new cases of hepatitis C infection in 2015.
In less than 10 years, the discovery of DAA has completely changed our fight against hepatitis C. Will health departments and government agencies around the world firmly grasp this historic opportunity to rid the general public of this deadly virus infection?