12 Oct 2020
Issue #28: A virology Nobel
Setting it Straight - Issue #28
Written by Nobel Laureate Professor Peter Doherty
Over this past week we learned the names of the 2020 Nobel Laureates in the areas specified by Alfred Nobel’s will. This year, the year of COVID-19, it’s fitting that the 111th Nobel Prize for Physiology or Medicine was awarded to three virologists for their discovery of hepatitis C virus (HCV) – Canada’s Michael Houghton and the USA’s Harvey Alter and Charles Rice. The Nobel Foundation announcement tells us what this trio did and why it’s important. Apart from joining the pantheon of Nobel virologists, they also link to 1930’s Nobelist, Karl Landsteiner (discoverer of the ABO blood groups), in making a major contribution to transfusion by cleaning up the blood supply. And, at least in the viral hepatitis community, Harvey Alter is further known for his poetry!
Like the human immunodeficiency virus (HIV) and the influenza A viruses, and unlike the much larger SARS-CoV-2, HCV throws off enormous numbers of mutants. As with HIV, that very high mutation rate creates a massive challenge for vaccine development. Both viruses persist and, partly as a consequence of mutation, escape from immune control within an infected individual. There is no vaccine to protect against either infection, but patients are returned to good health by treatment with antiviral drugs that, in the case of HCV but not HIV, can lead to total virus elimination. Sadly, though, reinfection with HCV can occur.
Classified as a flavivirus, a group that includes the mosquito-borne viruses – West Nile, Dengue, Zika, Japanese encephalitis and, in Australia, Kunjin and Murray Valley encephalitis – HCV is largely transmitted by hypodermic needles rather than by ‘flying needles’. While the other flaviviruses multiply in their mosquito vectors, insects, apart from the occasional biting fly, are not involved in the HCV life cycle. The disease was spread extensively in Egypt by the re-use of needles in a major vaccination program and, though there can be occasional vertical transmission (mother to baby), HCV is principally transmitted via contaminated blood, with those who inject psychotropic drugs being at greatest risk.
Initially described as non-A non-B hepatitis the consistent presence of HCV in the livers of 70 per cent of infected people leads to continuing inflammation that drives both hepatic dysfunction and, as the damaged liver cells (hepatocytes) are replaced at a high rate, increased mutation and the emergence of liver cancer, hepatocellular carcinoma. Infection with the hepatitis B virus (HBV), a tiny DNA virus, also causes persistent inflammation and consequent liver cancer. The 1963 discovery of an HBV protein, ‘Australia antigen’, in blood from an Indigenous Australian earned Philadelphia geneticist, Baruj (Barry) Blumberg, one half of the 1996 Nobel Prize for Medicine. The HBV vaccine developed initially by Maurice Hilleman of the Merck Company in 1981, then progressively refined by others was, in effect, the world’s first anti-cancer vaccine. Even so, limited access to vaccination (HBV) or treatment (HCV) means that some 1.3 million people in the poorer countries die each year from HBV or HCV-induced liver cirrhosis and/or hepatocellular carcinoma.
While liver cancer is a side effect of HBV and HCV infection, another group of viruses, the human papilloma viruses (HPV 16 and 18) are a direct cause of cancers of the human reproductive tract, principally cervical carcinoma in women. The discovery of this link earned German virologist, Harald zur Hausen, one half of the 2008 Nobel Prize for Medicine, with the other half going to Paris-based Francoise Barre-Sinoussi and Luc Montagnier for their 1984 isolation of HIV. The reason that HIV (a retrovirus) is, unlike HCV, so difficult to eliminate by drug treatment is that it carries an enzyme called reverse transcriptase (RT) that copies the HIV gene sequence back into the human genome.
The discovery of RT was recognised by the 1975 Nobel award to Americans, Howard Temin and David Baltimore, and US-based Italian, Renato Dulbecco. Temin used a chicken retrovirus, Rous sarcoma virus (RSV) in his RT experiments. Later, RSV was also the experimental tool that allowed San Francisco-based Mike Bishop and Harold Varmus to establish the existence of the cancer-associated oncogenes, which led to their 1989 Nobel Prize. After showing in 1910 that a cancer (sarcoma) of chickens is caused by this ‘filterable’ virus, New York based physician/investigator Peyton Rous had to wait until 1966 for his RSV Nobel!
Australian medical scientists hope to see University of Queensland researcher, Ian Frazer, score a Nobel for developing the highly effective HPV vaccine that is saving many lives. But, partly because of the Zur Hausen award, it’s not a shoo-in! Harking back to polio, that Nobel went (in 1954) to Harvard’s John Enders, Tom Weller and Fred Robbins for growing the virus in cell culture (a big deal back then), not to Jonas Salk and Albert Sabin for making the vaccines used to (almost) eliminate this terrible pathogen from the planet.
And immunologists were anticipating that Melbourne’s Jacques Miller and Atlanta’s Max Copper, who shared the 2019 US Lasker Award, could be the 2020 Nobelists. Jacques discovered the role of the thymus and pioneered T cell research, while Max did much the same for B cells. Oxford’s Sir James Gowans would have been a logical member of that ticket for discovering the function of lymphocytes but, at age 96, Jim departed earlier this year. As it is, these guys have waited longer than Peyton Rous!