zur-hausen

Harald zur Hausen received half the Prize for his discovery of HPV’s role in cervical cancer.

Nobel Prize in Physiology or Medicine: Human Papillomavirus and Human Immunodeficiency Virus

From influenza to smallpox to Ebola, viruses, some of the smallest and most intriguing infectious agents, have long plagued society. To scientists, understanding viral mechanisms of infection is critical to learning how to combat them. The 2008 Nobel Prize in Physiology or Medicine was awarded to recognize two enormously important discoveries that occurred about twenty years ago in the field of virology: cancer-causing strains of human papillomavirus (HPV), and the human immunodeficiency virus (HIV).

Harald zur Hausen, Human Papillomavirus, and Cervical Cancer
Harald zur Hausen of Germany was awarded half the prize for his discovery that certain HPV strains can cause cervical cancer. Zur Hausen specializes in oncovirology, the study of cancer-causing viruses, and his work has raised new questions about the nature of virus-host interactions.

Zur Hausen was one of the first medical scientists to postulate a connection between viral infection and cancer. In 1967, he contributed to a groundbreaking study in which a team of scientists led by researcher Werner Henle found that a herpes-like virus could transform healthy lymphocytes into cancerous ones (1). Henle’s team identified the presence of the Epstein-Barr virus (human herpesvirus 4) in a culture of cancer cells from a patient with Burkitt’s lymphoma. After lethally irradiating the cells, the team mixed them with a solution of normal peripheral leukocytes, which under normal circumstances do not divide. Surprisingly, after two to four weeks of incubation, these leukocytes began proliferating. In addition, the team discovered viral antigens in the culture, indicating that they had been infected by a virus (1). These results showed that the virus could induce cancerous growth in normal cells. Moreover, the results suggested that other cancer-causing viruses might also exist.

Throughout the 1970s, zur Hausen continued searching for cancer-causing viruses. His first breakthrough came when he succeeded in isolating HPV strain 6 from genital warts and showing that the virus was responsible for the warts. While many scientists believed that one type of HPV was responsible for all warts, zur Hausen was convinced that there were at least several, and that different types were responsible for non-genital warts and genital warts (2). He also suspected that some of these HPV types could be oncoviruses. In 1976, he boldly hypothesized that HPV infection was one of the primary causes of cervical cancer. The hypothesis was strongly contested by other scientists, who believed that a herpesvirus was the culprit. Zur Hausen spent nearly ten more years building evidence for his hypotheses.

Using molecular cloning methods, zur Hausen was finally able to isolate HPV 16 DNA from cervical cancer tumors in 1983 (3). He used similar methods to isolate HPV 18 a year later, proving that there were multiple types of HPV. Furthermore, zur Hausen discovered that DNA from the tumors would react to probes for HPV 16 and HPV18, proving that these viruses were involved in causing cancer (2). At the time, these two HPV types were responsible for over 70 percent of all cervical cancers.  Zur Hausen’s work has led to the development of Gardasil (Merck) and Cervarix (GlaxoSmithKline), the first vaccines against a preventable cancer. The vaccines, which target HPV 16 and 18, prime the body’s immune cells to recognize and attack the virus, thereby preventing the initial infection from occurring. The vaccine has been shown to be one hundred percent effective at eliminating the pre-cancerous lesions associated with HPV 16 and 18.

Luc Montagnier, Françoise Barré-Sinoussi, and the Human Immunodeficiency Virus

Luc Montagnier and Françoise Barré-Sinoussi of the Pasteur Institute in France were each awarded a quarter of the prize for their discovery of the human immunodeficiency virus (HIV) in 1983. At the time, Barré-Sinoussi was working under Montagnier. Both scientists were experts on retroviruses, viruses that use an enzyme called reverse transcriptase to encode DNA from an RNA template. In 1981, the US Centers for Disease Control reported a series of strange opportunistic infections in gay men. Similar cases began appearing in France in 1982. Over the next 18 months, the number of cases worldwide multiplied rapidly, and teams of scientists competed in a worldwide effort to identify the pathogen. Willy Rozenbaum, a clinician at the Hôpital Bichat in France, was convinced that the flurry of diseases was being caused by a new retrovirus (4).

hivtcell_cmyk

Scanning electron micrograph of HIV viruses (green) budding from a cultured T-lymphocyte.

The crucial sample was a biopsy from a swollen lymph node taken from one of Rozenbaum’s patients. Montagnier and his team immediately began working on the lymph node, mincing it and dissecting the fragments into cells. He then cultured the T-lymphocytes of the dissected lymph node with human interleukin-2 and an antiserum to interferon to coax the virus out of an inhibited state (5). Fifteen days later, Barré-Sinoussi detected the first traces of reverse transcriptase, a hallmark of retrovirus activity. The team attempted to precipitate the virus using antibodies against two other known retroviruses, but observed no precipitation and concluded that this virus was indeed a new type of retrovirus (5). After obtaining several other specimens from patients afflicted with the unknown disease, the team noticed cross-reactivity between the viral proteins of the specimens. The cross-reactivity implied that the same virus was present in each of the specimens.

By May 1983, Montagnier and Barré-Sinoussi had collected enough evidence to characterize the new retrovirus, naming it LAV for lymphadenopathy-associated virus. They had also collaborated with electron microscopist Charles Dauget to obtain the first electron microscope images of the virus (5). However, the team had no evidence that the LAV virus was the cause of the ongoing AIDS epidemic. That evidence would in fact come a year later from an American team led by biomedical researcher Robert Gallo. Gallo’s team, which had developed a method to grow T-lymphocytes in vitro in 1976, published a series of papers that proved Montagnier’s virus was the cause of AIDS (6).

Because of the perceived impact of such a discovery, the competition between the French and American scientists was tough and sometimes bitter. Despite proving the pathogenicity of the virus and developing most of the methods that allowed Montagnier’s team to conduct its experiments, Gallo was not included as a recipient of the Nobel Prize.

However, the overall result of this fierce competition was that the HIV virus was isolated and identified less than 3 years after the US Centers for Disease Control’s first reports of the disease. The first diagnostic tests were developed two years later, and the first antiretroviral drugs shortly thereafter. The result was that countless lives were saved due researchers’ efforts.

References
1. W. Henle  et al., Science, 157, 1064-1065, (1967).
2. Harald zur Hausen (2008). Available at http://www.gairdner.org/awards/awardees2/2008/2008awarde/haraldzurh (5 January 2009).
3. The Nobel Prize in Physiology or Medicine (2008). Available at http://nobelprize.org/nobel_prizes/medicine/laureates/2008/press.html (27 December 2008).
4.  The discovery of the AIDS virus in 1983. Available at http://www.pasteur.fr/ip/easysite/go/03b-000027-00i/the-discovery-of-the-aids-virus-in-1983 (3 January 2009).
5. L. Montagnier, Science, 298, 1727-1728, (2002).
6. D.A. Morgan, F.W. Ruscetti, R. Gallo, Science, 193, 1007-1008, (1976).