Drs. Harvey J. Alter, Michael Houghton, and Charles M. Rice were recipients of the 2020 Nobel Prize in Physiology or Medicine for their roles in the discovery of the hepatitis C virus (HCV) was met with both enthusiasm and pride by the hepatitis and liver disease research communities. The prize recognizes not just the contribution of these three outstanding scientists, but also the critical importance of hepatitis C in world health. The discovery of HCV was a major milestone in 20th-century medicine, and the awardees represent three critical periods of research on this important virus, whose discovery has led to elimination of post-transfusion hepatitis and a means to cure and possibly eradicate hepatitis C.  The existence of a third form of viral hepatitis was revealed when investigators (including Harvey Alter) at the National Institutes of Health (NIH) reported that cases of post-transfusion hepatitis that were not caused by hepatitis B were also not caused by hepatitis A. This report led to global efforts first to define the clinical features, complications, and epidemiology and second to discover the cause of what the authors termed “non-A, non-B hepatitis.” The clinical features were soon defined by many studies, but most clearly by those by Alter at the NIH Clinical Center, which were based on his prospective, long-term studies of post-transfusion hepatitis. Alter showed that acute hepatitis C was often asymptomatic and rarely severe or fatal but that it led to chronic infection in most patients. The chronic infection was also often asymptomatic but usually accompanied by chronic hepatitis that could result in cirrhosis, end-stage liver disease, and hepatocellular carcinoma, typically after decades of infection. Alter and his coworkers showed that non-A, non-B hepatitis was transmissible to chimpanzees and had characteristics of an enveloped virus. Without a specific test, however, it remained a diagnosis of exclusion: defined not by what it was, but by what it was not.The breakthrough in identification of the agent of non-A, non-B hepatitis came when Michael Houghton and his coworkers at Chiron Corporation reported finding a viral RNA fragment in the plasma of a chimpanzee that was a known carrier of the virus.

The technique they used combined the power of molecular biology with the specificity of antigen–antibody reactions. Using random oligonucleotide primers, they created a cDNA library representing all DNA and RNA found in pellets made from infected chimpanzee plasma by high-speed ultracentrifugation. The cDNAs were then ligated into a bacteriophage expression system, and the resulting clones were screened with serum from patients with chronic non-A, non-B hepatitis that they postulated would have antibody to the virus. More than a million clones were screened before they found one that appeared specific for non-A, non-B hepatitis. The specificity was clinched when serologic assays using the phage-expressed polypeptide were applied to Alter’s collection of samples from post-transfusion hepatitis. The antibody arose in patients who developed non-A, non-B hepatitis, was not present in pretransfusion blood samples, and did not arise in patients with other forms of hepatitis. Most patients could be shown to have received at least one unit of blood that also tested positive for antibody. The term non-A, non-B hepatitis was retired for what finally could be called hepatitis C.

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