NIAID Now | November 06, 2020
NIAID Narrative – 2020 Nobel Prize in Physiology or Medicine
The 2020 Nobel Prize for Physiology or Medicine was awarded to Charles Rice, Ph.D., of The Rockefeller University, Harvey Alter, M.D., of the National Institutes of Health, and Michael Houghton, Ph.D., of the University of Alberta, Canada. The award recognizes their discovery and molecular characterization of the hepatitis C virus (HCV). HCV is a major cause of severe illness and death globally. WHO data reports an estimated 71 million people are living with chronic HCV worldwide and are at high risk for developing cirrhosis or liver cancer. The work of Drs. Rice, Alter, and Houghton comes together as a remarkable story of the identification of an intractable virus that causes a serious disease, development of diagnostics that ensured the safety of transfusion blood supply, and provision of basic knowledge that has given the world drugs that can cure nearly all cases of chronic HCV infection.
Hepatitis is an inflammatory disease of the liver that can be caused by various infectious and non-infectious agents. Before the 1970s—prior to the discovery of HCV—two viruses, hepatitis A virus (HAV) and hepatitis B virus (HBV), were known to be major causes of hepatitis. The discovery of HBV by Baruch Blumberg, M.D., in 1960s, which led to the development of diagnostic tests and an effective vaccine, earned Dr. Blumberg the Nobel Prize in Physiology or Medicine in 1976.
In the early 1970s, Dr. Alter recognized that significant numbers of transfusion-associated hepatitis cases were not caused by either HAV or HBV; these cases were referred to as Non-A, Non-B hepatitis (NANBH). Further work by Dr. Alter suggested that NANBH was caused by a transmissible agent, likely an RNA virus. In 1989, Dr. Houghton and colleagues painstakingly isolated a complementary DNA (cDNA) fragment associated with the virus causing NANBH from cDNA libraries constructed from the livers of experimentally infected chimpanzees. Shortly thereafter, the entire genome of this newly identified RNA flavivirus–HCV– was assembled and sequenced. The discovery was the basis of diagnostic tests to test for the agent in blood and was critical to its elimination from transfused blood. Further analysis confirmed that 90% of NANBH was indeed related to HCV. According to the CDC, required blood screening has resulted in decreased transmission of HCV associated with transfusion, making it a rare occurrence.
In a series of ground-breaking studies, many supported by NIAID, Dr. Rice and his colleagues contributed to the elucidation of the structure of HCV and its protein products, including crystal structures and function of key proteins. Several of these proteins—NS3/4A serine protease, NS5B RNA polymerase, and NS5A phosphoprotein—are targeted by newly developed, highly effective antiviral drugs, capable of completely eliminating the virus in many people.
A major impediment to studies on HCV replication was the extreme difficulty in growing the virus in the lab. Early infection studies were done in chimpanzees, the only non-human animal that could be infected. Dr. Rice developed efficient techniques to achieve replication of the HCV genome in cultured human liver-derived cells. This system provided an excellent, albeit incomplete, tool to screen for potential antiviral drug candidates. The discovery of a strain of HCV (JFH-1) that could replicate in cultured cells by Dr. Takaji Wakita in Japan provided Dr. Rice the means to improve his culture system and allowed the efficient production of infectious HCV, both in cultured cells and chimpanzees, paving the way for the development of inhibitors against each step in the HCV life cycle. The use of chimpanzees in research is now prohibited in the United States, and there is currently no alternative animal model, making this cell culture system critical for HCV research.
HCV only infects humans (and chimpanzees) and it can only infect certain cells in the liver. Dr. Rice and his colleagues identified two host molecules, the tight junction proteins claudin-1 (CLDN-1) and occludin (OCLN), that the virus uses to infect cells. He also showed that HCV engages the previously described scavenger receptor type B1 (SR-B1) and a membrane protein, CD81, in order to infect cells. These advances are key to the development of new models of HCV infection and an urgently needed vaccine against HCV.