The 2020 Nobel Prize in Physiology or Medicine has been awarded to Harvey J. Alter, Michael Houghton and Charles M. Rice for the discovery of Hepatitis C virus. Hepatitis is a disease characterized by poor appetite, vomiting, fatigue and jaundice along with yellow discoloration of the skin and eyes. Until the 1960’s, exposure to blood from infected individuals was a major health hazard, with up to 30% risk of chronic hepatitis following surgery or multiple blood transfusions. This risk was only partially reduced by the discovery of the Hepatitis B virus (HBV) and the eventual elimination of HBV-contaminated blood through testing. A more insidious form of hepatitis, characterized by very mild symptoms in the acute phase and a high risk of progression to chronic liver damage and cancer, remained. The work of Alter, Houghton and Rice characterized this form of hepatitis to be a distinct clinical entity, now known as Hepatitis C virus (HCV).
In 1947, long before the discovery of the causative agents, a British hepatologist had classified infectious hepatitis into two subtypes: hepatitis A and hepatitis B. As is currently known, “Infectious or epidemic hepatitis” is mainly transmitted through contaminated food and water, has a short incubation period and manifests as an acute illness that usually resolves and is followed by life-long immunity. “Serum hepatitis on the other hand, spreads through contact with blood or other bodily fluids, has a long incubation period during which apparently healthy individuals can transmit the disease.
As a young doctor, Harvey J. Alter had collaborated with Baruch Blumberg, making important contributions to the discovery of “the Australia-antigen”, part of a virus particle found in the serum of individuals affected by post-transfusion hepatitis. In the 1970s, it was recognized that the exclusion of HBV antibody-positive blood donors prevented only 20% of post-transfusion associated hepatitis, while the remaining 80% of cases appeared to be unrelated to HBV infection. This new form of “non-B” hepatitis became increasingly prevalent and differed in the clinical manifestations it caused with a shorter incubation period and milder symptoms during the acute phase. He concluded that at least two different viruses could cause post-transfusion hepatitis.
The initial assumption that the agent responsible for hepatitis A might under certain conditions cause serum hepatitis was abandoned soon after the discovery of the hepatitis A virus. In 1975, Alter utilizing his vast collection of serum samples from non-B hepatitis patients, he reported that a substantial fraction of non-B hepatitis cases were not caused by HAV or any other know n virus.
In 1982, Michael Houghton, while working at Chiron Corporation, initiated his search for the NANBH (non-A, non-B Hepatitis) virus using a molecular approach based on the screening of DNA fragments isolated from infected chimpanzees. Screening one million bacterial colonies resulted in the identification of one colony that did not contain chimpanzee or human DNA sequences. This was the viral signal they were looking for. This allowed classification of the virus, which they named Hepatitis C virus (HCV), as a new member of the Flaviridae family.
While the work of Alter and Houghton established a critical link between NANBH and HCV infection, it failed to constitute a definitive proof of causality. To conclusively demonstrate causality, the isolation of a virus capable of reproducing the clinical hallmarks of the disease was required. A first step towards achieving this goal was made when Charles Rice successfully engineered a set of RNA genomes which he injected into the liver of chimpanzees. Replicative infection was established, the animals developed clinical signs of hepatitis and infectious virus was found in their blood for several months. The work of Charles Rice provided conclusive evidence that HCV alone could cause hepatitis and persist long-term and stimulate a specific antibody response.
The discoveries of the viruses that cause hepatitis are among the most impactful scientific accomplishments of the 20th century. Through the development of novel technologies, protective vaccines against HAV and HBV are now widely available. The discoveries of HBV and HCV, and the establishment of effective screening routines, have virtually eliminated the risk of transmission via blood products in many parts of the world. With the development of highly effective drugs against HCV, it is now possible, for the first time in human history, to foresee a future where the threat of this virus infection is substantially reduced and hopefully soon eliminated.
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