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Editorial

Hepatitis c – three decades of the path from discovery to the Nobel prize

Maja Ćupić1
  • Institute of Microbiology and Immunology, Faculty of Medicine of the University of Belgrade

ABSTRACT


INTRODUCTION

This year, the Nobel Prize in Medicine was awarded to the three scientists who, 31 years ago, identified a new, blood-borne, primarily hepatotropic virus (BBV). This was the hepatitis C virus (HCV) that causes the infection with the same name, which is a global health problem linked to serious complications, such as liver cirrhosis and hepatocellular carcinoma (HCC). Because of this major discovery achieved by this year’s laureates of the Nobel Prize – Harvey Alter, Michael Houghton and Charles M. Rice, a discovery which the whole world has these scientists to thank, it is quite natural that, in the year when they are awarded this most prestigious prize, we should pay tribute to their work [1].

The hepatitis C virus is a new paradigm for the identification and control of viral infections, and its discovery has become a milestone in the fight against viral diseases in the 20th century. From the moment the HCV, as a new BB hepatotropic virus, had been identified, an era of rapid development of very sensitive laboratory tests for its detection started, which in turn, resulted in posttransfusion hepatitis C being eradicated in a large part of the developed world, with a tendency of decreasing the prevalence of posttransfusion HCV infection in the rest of the world to negligible percentages [2]. Also, this discovery has brought about advancements in the treatment of HCV infection, through the design of very efficient antiviral drugs, which completely put the HCV infection under control, providing a chance that can lead to a cure and, for the first time, offering hope that the HCV will be eradicated from the world population. However, this goal is global and requires international efforts in order to make HCV testing as well as up-todate antiviral therapy with new, direct-acting anti-HCV drugs, accessible all over the world. This is an imperative which has been set as a goal before new teams of researchers by Alter, Houghton and Rice [3].

THE NEW UNKNOWN VIRUS CAUSING HEPATITIS – HOW IT ALL BEGAN

As early as the first half of the 20th century it became clear that there were two types of hepatitis of viral etiology. The first viral hepatitis pathogen to be discovered was the hepatitis A virus (HAV), which is transmitted by contaminated food, water and unclean hands and it causes only an acute infection without serious long-term consequences to people’s health. In the 1960s, Baruch Blumberg identified a new hepatitis virus transmitted by blood and other bodily fluids. This was the hepatitis B virus (HBV), which, in addition to acute, can also cause chronic infection [4]. It was established that HBV usually develops chronic infection quietly and imperceptibly, which is what caused the infection to be often diagnosed only when serious clinical forms or complications occurred, such as liver cirrhosis and hepatocellular carcinoma. In 1976, Blumberg was awarded the Nobel Prize in Medicine, for identifying this new viral pathogen. The discovery of HBV very quickly initiated a series of further research, which necessitated the work on sensitive diagnostic tests for early HBV infection detection, and sparked research in the area of prevention and therapy. This research resulted in the discovery of very efficient antiviral drugs with a high genetic barrier for the development of viral resistance, which makes these drugs exceptionally effective therapy in patients with chronic hepatitis B. Also, an efficient anti-HBV vaccine was developed, and it is expected to bring about the eradication of HBV from the world population in the near future [5].

HOW THE PUZZLE OF THE NEW BB VIRUS, THE COUSE OF HEPATITIS C, WAS PIECED TOGETHER

In the period between the 1960s and the 1970s, Alter worked together with Blumberg on perfecting the methodology for detecting the HBsAg, a glycoprotein in the HBV capsule, which was later to become the main candidate for the development of an effective anti-HBV vaccine. In the early 1970s, Alter and his research team noticed a frequent incidence of hepatitis in patients who had received blood transfusions, although, at the time, there were serological tests for detecting HBV, which were able to eliminate HBV as a potential cause of posttransfusion hepatitis. The other known hepatotropic A virus was also not linked to the occurrence of the new posttransfusion hepatitis. It was clear that there was a new, blood-related pathogen, which was causing hepatitis [6]. At the time, the new BBV linked to hepatitis was named non-A, non-B (NANB). Alter and his associates had to prove their finding, which was the next step in their research, i.e. the goal was to demonstrate the link between NANB and hepatitis developing after blood transfusion [7]. During 1975, in the absence of other in vitro laboratory procedures for proving the existence of the new NANB virus, Alter and his associates continued their research on the animal model. On the experimental model of chimpanzees, they demonstrated that, after the inoculation of the serum taken from people with the clinical presentation of the new viral NANB hepatitis, in amounts equivalent to the blood transfusion performed in people, the animals got sick. They achieved success immediately after the first infecting procedure, since five out of the five chimps developed an increase in alanin-aminotransferase (ALT).

The initial success encouraged the research team to continue their studies, so the experiments were then continued with the titration of the inoculum obtained from the blood taken from patients which had serious clinical presentation of NANB hepatitis, which correlated with drastic increase in the level of ALT in the experimental animals. A new filtrated pathogen was isolated from the samples obtained from the sick animals [5],[8]. What they isolated were small viral particles, 30 - 70 nm in diameter, spherical in appearance, with a lipid envelope, which were sensitive to organic solvents [9]. The new virus causing hepatitis, which was linked to blood transfusions, was named NANB. As to its morphology, it was similar to the viruses belonging to the togavirus and/or flavivirus family, and was therefore, initially, treated as a toga/flavi-like particle. It was only later that it received its place in the taxonomy of the flavivirus family, genus Hepacivirus. Alter’s research resulted also in a very important finding, that during the infection, neutralizing anti-NANB antibodies developed, which were highly specific to the strain of the virus, but were not capable of neutralizing the viral genetic variants (quasispecies). This would only later prove to be a very important characteristic of the HCV, as a highly variable virus, as it is what leads to the establishing of permanent life-long infection, even with the presence of specific antibodies [4].

The next step in proving the existence of the new hepatitis virus was to decipher the virus genome, i.e. to identify the genome sequence responsible for the synthesis of viral products – virus antigens, which cause the synthesis of specific anti-HCV antibodies. Such an idea, to use the serum of patients with clinical presentations of the new viral hepatitis to prove the existence of a particular genome sequence, more precisely its products, was the scientific idea conceived by Michael Houghton, who, during the 1980s, worked as a researcher at the pharmaceutical company Chiron Corporation in California, USA.

As the traditional techniques for isolating viruses were limited, and the experiment on the monkey model had clearly indicated the link between the virus and the new NANB hepatitis, the next missing piece of the hepatitis C puzzle was the molecular identification of the new virus. In 1982, Houghton and his associates created a collection of DNA fragments from nucleic acids extracted from blood samples of infected chimpanzees. Most of these fragments belonged to the genome of the chimpanzees themselves, however Houghton and his team believed that at least some sequence would originate from the genetic material of the new NANB virus. Under the assumption that anti-viral antibodies would be present in the blood taken from patients with hepatitis, the scientists used the patients’ serum for identifying cloned viral fragments of complementary DNA (CDNA) encoding viral proteins. After many tests, one positive clone was found. Further work showed that this clone was derived from a new RNA virus belonging to the Flaviviridae family. The molecular identification of HCV was the climax of the team’s effort which lasted 7 years, and in 1989, as a result, the name of the NANB virus was changed to what it is called today, i.e. the hepatitis C virus [10].

In this way, Houghton, together with two of his colleagues, Qui-Lim Choo and George Kuo, became the first scientist to identify the virus and to formally name it the hepatitis C virus. Additionally, their research resulted in the designing of a diagnostic test for the identification of the virus in the blood, which enabled doctors to introduce, for the first time, routine hepatitis C screening, by testing both the donor and the recipient of blood transfusion. Dr. Angela Rasmussen, a virologist who carried out her postdoctoral studies in Dr. Houghton’s team, working on discovering the hepatitis C virus, described the HCV as an intriguing and cunning pathogen which was inspirational to work on. The scientific discovery achieved by Dr. Houghton’s, who isolated the genetic sequence of the HCV, very clearly indicated that a new virus, which was the cause of a new type of hepatitis, had been discovered, thus joining the group of already known hepatotropic viruses, A and B [11].

Research carried out by Alter and Horton was of crucial importance in discovering the hepatitis C virus. However, another, key component of the HCV puzzle was missing, which needed to provide an answer to the question: Can HCV cause hepatitis on its own? Charles Rice, a researcher at the Washington University in St. Louis, together with other research teams working on different RNA viruses, speculated that the region at the 5’ terminus of the HCV genome could be important for the initiation of virus replication [12]. Rice also noticed that certain other regions of the HCV genome can suppress virus replication with their gene products, as they inhibit the genome sequence that initiates it [13]. Through methods of genetic engineering, Rice designed HCV RNA, which included the region responsible for replication initiation, eliminating the regions suppressing it. When thus designed HCV RNA was injected directly into the liver of a chimpanzee, virions were replicated, which were detected in the blood of the animal, and pathological changes were also noted, similar to those observed in patients with chronic hepatitis C [14]. This was final proof that the hepatitis C virus could cause BB hepatitis on its own.

THIRTY YEARS LATER – WHAT IS KNOWN ABOUT THE HCV TODAY

During the thirty years since its discovery until now, HCV has been known as a highly variable, single-stranded, positive-sense RNA virus, with a high mutation rate. This biological characteristic is the result of its life cycle and the role of the viral RNA-dependent RNA polymerase, an enzyme involved in virus replication, which lacks the repair mechanism for correcting accidental mistakes. This enables the creation of different genome variants within the infected organism – quasispecies, but also different antigen variants [15]. It is this antigen variability of the HCV that enables it to skillfully avoid the immune response of the host, which, in turn, facilitates the establishing of persistent infection, at the same time posing a problem to the development of a successful vaccine. Due to a 30% difference in the length of the entire genome, a categorization into 8 different HCV genotypes, known today, has been made, while an even smaller genome difference classifies the HCV into 90 subtypes and 9 recombinant forms [16]. HCV genotypes differ amongst themselves significantly in their response to therapy, which is why their detection is a part of the routine laboratory protocol in patients who are candidates for antiviral therapy [17].

HCV can cause both acute and chronic infection. Around 30% of patients (15% – 45%) spontaneously eliminate the virus within 6 months of infection even without specific therapy. However, ~ 70% of patients (55% – 85%) develop chronic illness with a high risk (15% – 30%) of developing liver cirrhosis or HCC within a 20-year period [18].

More recent data estimate that there are around 110 million people in the world with proven previous HCV infection (detected anti-HCV antibodies) and 71 million chronically infected patients [19]. HCV infection is one of the rare infectious diseases whose mortality rate has been rising in the past decades. According to available data, mortality has risen since the year 2000, by 22%, and it is estimated that around 700,000 patients die, every year, as the result of HCV infection complications. In order to put a stop to this trend, it is necessary to establish efficient therapy for chronic HCV infection, which, according to the latest recommendations of the World Health Organization, proposes treatment with pan-genotypic direct-acting antiviral drugs (DAA). This is a new, interferon free regimen, which efficiently suppresses viral replication and, within a relatively short time period of 8 to 12 weeks, establishes a stabile virologic response (undetectable HCV-RNA) in as many as 95% of patients [20]. Depending on the subgenotype of the virus, the presence or absence of cirrhosis, HCV therapy protocols with the new DAA are different, i.e. the combinations of drugs vary [21].

With more testing, and with new anti-HCV therapy being made available, it is believed that, within the next decade, it will be possible to irradicate HCV infection, even without a vaccine. A large part of the HCV puzzle has been pieced together. The steps, without which there would be no other steps further, were made by Alter, Houghton and Rice. However, the HCV remains an intriguing pathogen, and, until it is eradicated, it will be the object of attention of expert and research teams.

SHORT BIOGRAPHIES OF THE 2020 NOBEL PRIZE IN MEDICINE LAUREATES

Harvey J. Alter was born in 1935, in New York City. He graduated from the University of Rochester Medical School and was a resident in internal medicine at Strong Memorial Hospital and the University Hospitals of Seattle. In In 1961, he joined the National Institutes of Health (NIH) as a clinical associate. He spent several years at the University of Georgetown. Alberta, before returning to the NIH, in 1969, where he joined the Clinical Center’s Department of Transfusion Medicine as a senior investigator.

Michael Houghton was born in the United Kingdom. He earned his doctoral degree in 1977, at King’s College, London. In 1982, he started working as a scientist-researcher at the pharmaceutical company Chiron Corporation, in Emeryville, California. In 2010 he became the head of a virology research team at the University of Alberta, where he remains to this day. He is also a Professor of Virology at the University of Alberta and the Director of the Applied Virology Institute, also in Alberta.

Charels M. Rice was born in 1952. in Sacramento. In 1981 he received his PhD from the California Institute of Technology, where he also remained for postdoctoral research between 1981-1985. He formed his research group in 1986 at the Washington University School of Medicine in St. Louis. In 1995, he became Full Professor at the same University. Since 2001, he is also Professor at the Rockefeller University in New York City. Between 2001 and 2018, he was the Scientific and Executive Director of the Center for the Study of Hepatitis C at the Rockefeller University, where he remains an active researcher to this day.

  • Conflict of interest:
    None declared.

Informations

Volume 1 No 2

December 2020

Pages 115-121
  • Keywords:
  • Received:
    15 November 2020
  • Revised:
    18 November 2020
  • Accepted:
    19 November 2020
  • Online first:
    25 December 2020
  • DOI:
  • Cite this article:
    Ćupić M. Hepatitis C: Three decades of the path from discovery to the Nobel prize. Serbian Journal of the Medical Chamber. 2020;1(2):115-21. doi: 10.5937/SMCLK2002115C
Corresponding author

Maja Ćupić
Institute of Microbiology and Immunology
Faculty of Medicine of the University of Belgrade
1 Dr Subotića Street, 11129 Belgrade, Serbia
E-mail: This email address is being protected from spambots. You need JavaScript enabled to view it.



REFERENCES

1. Masucc MG, Karlsson Hedestam KG. The discovery of Hepatitis C virus, Scientific background, Nobelforsamlingen. The Nobel Assembly at Karolonska Institute. 2020. Dostupno na: https://www.nobelprize.org/uploads/2020/10/advanced-medicineprize2020-2.pdf

2. CDC Recommendations for Hepatitis C Screening Among Adults — USA. Recommendations and Reports. Morbidity and Mortality Weekly Report. 2020; 69:2. Dostupno na: https://www.cdc.gov/mmwr/volumes/69/rr/pdfs/rr6902a1-H.pdf

3. Holmes JA, Rutledge SM, Chung RT. Direct-acting antiviral treatment for hepatitis C. Lancet 2019; 393:1392-4.[CROSSREF]

4. Alter HJ, Houghton M. Hepatitis C virus and eliminating post-transfusion hepatitis. Nature Medicine. 2000; 6:1082-4. Dostupno na: http://medicine.nature.com

5. Houghton M. The hepatitis C virus: A new paradigm for the identification and control of infectious disease. Nature Medicine. 2000; 6:1084-6. Dostupno na: http://medicine.nature.com

6. Alter HJ, Holland PV, Purcell RH. The emerging pattern of post-transfusion hepatitis. Am J Med Sci. 1975; 270: 329-34.[CROSSREF]

7. Alter HJ, Holland PV, Morrow AG, Purcell RH, Feinstone SM, Moritsugu Y. Clinical and serological analysis of transfusion-associated hepatitis. Lancet. 1997; 2:838-41.[CROSSREF]

8. Alter HJ, Purcell RH, Holland PV, Popper H. Transmissible agent in non-A, non-B hepatitis. Lancet. 1978; 1:459-63.[CROSSREF]

9. Feinstone SM, Mihalik KB, Kamimura T, Alter HJ, London WT, Purcell RH. Inactivation of hepatitis B virus and non-A, non-B hepatitis by chloroform. Infect Immun. 1983; 41:816-21.[CROSSREF]

10. Bergeron J. How an Alberta researcher’s discovery of hepatitis C led to the Nobel Prize and saved lives. The Conversation. Oct 7, 2020. Dostupno na: https://theconversation.com/how-an-alberta-researchers-discovery-of-hepatitis-c-led-to -the-nobel-prize-and-saved-lives-147553

11. Choo QL, Kuo G, Weiner AJ, Overby LR, Bradley DW, Houghton M. Isolation of a cDNA clone derived from a blood-borne non-A, non-B viral hepatitis genome. Science 1989; 244:359-62.[CROSSREF]

12. Kolykhalov AA, Feinstone SM, Rice CM. Identification of a highly conserved sequence element at the 3’ terminus of hepatitis C virus genome RNA. J Virol. 1996; 70:3363-71.[CROSSREF]

13. Tanaka T, Kato N, Cho MJ, Shimotohno K. A novel sequence found at the 3’ terminus of hepatitis C virus genome. Biochem Biophys Res Commun 1995; 215:744-9.[CROSSREF]

14. Kolykhalov AA, Agapov EV, Blight KJ, Mihalik K, Feinstone SM, Rice CM. Transmission of hepatitis C by intrahepatic inoculation with transcribed RNA. Science. 1997; 277:570-4.[CROSSREF]

15. Lapa D, Garbuglia AR, Capobianchi MR, Del Porto P. Hepatitis C Virus Genetic Variability, Human Immune Response, and Genome Polymorphisms: Which Is the Interplay? Cells. 2019; 8 ,305.[CROSSREF]

16. Table 1 - Confirmed HCV genotypes/subtypes (May 2019). ICTV. Dostupno na: https://talk.ictvonline.org/ictv_wikis/flaviviridae/w/sg_flavi/634/table-1---confirmed-hcv-genotypes-subtypes-may-2019

17. Dustin LB, Bartolini B, Maria R, Capobianchi MR, Pistello M. Hepatitis C virus: life cycle in cells, infection and host response, and analysis of molecular markers influencing the outcome of infection and response to therapy. Clin Microbiol Infect. 2016; 22:826–32.[CROSSREF]

18. Spearman WS, Dusheiko GM, Hellard M, Sondertup M. Hepatitis C. Lancet. 2019; 394:1451-66.[CROSSREF]

19. Dhawan VK. What is the global prevalence of hepatitis C virus (HCV) infection? Medscape. Oct 7, 2019. Dostupno na: https://www.medscape.com/answers/177792-3829/what-is-the-global-prevalence-of-hepatitis-c-virus- -hcv-infection

20. Younossi ZB, Mendel E, Singer ME, Mir HM, Henry L, Hunt S. Impact of interferon free regimens on clinical and cost outcomes for chronic hepatitis C genotype 1 patients. J Hepatol. 2014; 60:530-7.[CROSSREF]

21. Zoratti MJ, Siddiqua A, Morassut RE, Zeraatkar D, Chou R, Van Holten J, et al. Pangenotypic direct acting antivirals for the treatment of chronic hepatitis C virus infection: A systematic literature review and meta-analysis. E Clinical Medicine. 2020; 18: 100237.[CROSSREF]

1. Masucc MG, Karlsson Hedestam KG. The discovery of Hepatitis C virus, Scientific background, Nobelforsamlingen. The Nobel Assembly at Karolonska Institute. 2020. Dostupno na: https://www.nobelprize.org/uploads/2020/10/advanced-medicineprize2020-2.pdf

2. CDC Recommendations for Hepatitis C Screening Among Adults — USA. Recommendations and Reports. Morbidity and Mortality Weekly Report. 2020; 69:2. Dostupno na: https://www.cdc.gov/mmwr/volumes/69/rr/pdfs/rr6902a1-H.pdf

3. Holmes JA, Rutledge SM, Chung RT. Direct-acting antiviral treatment for hepatitis C. Lancet 2019; 393:1392-4.[CROSSREF]

4. Alter HJ, Houghton M. Hepatitis C virus and eliminating post-transfusion hepatitis. Nature Medicine. 2000; 6:1082-4. Dostupno na: http://medicine.nature.com

5. Houghton M. The hepatitis C virus: A new paradigm for the identification and control of infectious disease. Nature Medicine. 2000; 6:1084-6. Dostupno na: http://medicine.nature.com

6. Alter HJ, Holland PV, Purcell RH. The emerging pattern of post-transfusion hepatitis. Am J Med Sci. 1975; 270: 329-34.[CROSSREF]

7. Alter HJ, Holland PV, Morrow AG, Purcell RH, Feinstone SM, Moritsugu Y. Clinical and serological analysis of transfusion-associated hepatitis. Lancet. 1997; 2:838-41.[CROSSREF]

8. Alter HJ, Purcell RH, Holland PV, Popper H. Transmissible agent in non-A, non-B hepatitis. Lancet. 1978; 1:459-63.[CROSSREF]

9. Feinstone SM, Mihalik KB, Kamimura T, Alter HJ, London WT, Purcell RH. Inactivation of hepatitis B virus and non-A, non-B hepatitis by chloroform. Infect Immun. 1983; 41:816-21.[CROSSREF]

10. Bergeron J. How an Alberta researcher’s discovery of hepatitis C led to the Nobel Prize and saved lives. The Conversation. Oct 7, 2020. Dostupno na: https://theconversation.com/how-an-alberta-researchers-discovery-of-hepatitis-c-led-to -the-nobel-prize-and-saved-lives-147553

11. Choo QL, Kuo G, Weiner AJ, Overby LR, Bradley DW, Houghton M. Isolation of a cDNA clone derived from a blood-borne non-A, non-B viral hepatitis genome. Science 1989; 244:359-62.[CROSSREF]

12. Kolykhalov AA, Feinstone SM, Rice CM. Identification of a highly conserved sequence element at the 3’ terminus of hepatitis C virus genome RNA. J Virol. 1996; 70:3363-71.[CROSSREF]

13. Tanaka T, Kato N, Cho MJ, Shimotohno K. A novel sequence found at the 3’ terminus of hepatitis C virus genome. Biochem Biophys Res Commun 1995; 215:744-9.[CROSSREF]

14. Kolykhalov AA, Agapov EV, Blight KJ, Mihalik K, Feinstone SM, Rice CM. Transmission of hepatitis C by intrahepatic inoculation with transcribed RNA. Science. 1997; 277:570-4.[CROSSREF]

15. Lapa D, Garbuglia AR, Capobianchi MR, Del Porto P. Hepatitis C Virus Genetic Variability, Human Immune Response, and Genome Polymorphisms: Which Is the Interplay? Cells. 2019; 8 ,305.[CROSSREF]

17. Dustin LB, Bartolini B, Maria R, Capobianchi MR, Pistello M. Hepatitis C virus: life cycle in cells, infection and host response, and analysis of molecular markers influencing the outcome of infection and response to therapy. Clin Microbiol Infect. 2016; 22:826–32.[CROSSREF]

18. Spearman WS, Dusheiko GM, Hellard M, Sondertup M. Hepatitis C. Lancet. 2019; 394:1451-66.[CROSSREF]

19. Dhawan VK. What is the global prevalence of hepatitis C virus (HCV) infection? Medscape. Oct 7, 2019. Dostupno na: https://www.medscape.com/answers/177792-3829/what-is-the-global-prevalence-of-hepatitis-c-virus- -hcv-infection

20. Younossi ZB, Mendel E, Singer ME, Mir HM, Henry L, Hunt S. Impact of interferon free regimens on clinical and cost outcomes for chronic hepatitis C genotype 1 patients. J Hepatol. 2014; 60:530-7.[CROSSREF]

21. Zoratti MJ, Siddiqua A, Morassut RE, Zeraatkar D, Chou R, Van Holten J, et al. Pangenotypic direct acting antivirals for the treatment of chronic hepatitis C virus infection: A systematic literature review and meta-analysis. E Clinical Medicine. 2020; 18: 100237.[CROSSREF]


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