Harald zur Hausen hypothesis linking HPV to cervical cancer

In the mid-1970s, the dominant hypothesis in cervical cancer research held that herpes simplex virus type 2 was the causal agent. The case for herpes rested mainly on antibody studies of women with the disease. Harald zur Hausen, head of the new Institute of Clinical Virology at Erlangen-Nuremberg since 1972, took a different view after reports of genital warts turning into squamous cell carcinomas. In 1976, in a one-page paper in Cancer Research, he proposed the genital wart virus as the likelier cause, reasoning that tumor cells should carry viral DNA that a deliberate search could find.

The hypothesis was not warmly received. Zur Hausen moved to the University of Freiburg in 1977, and there in 1979 Lutz Gissmann and Ethel-Michele de Villiers cloned HPV-6 from genital warts, which was then used as a probe for related types in cancers. His students Mathias Dürst and Michael Boshart cloned HPV-16 in 1983 and HPV-18 in 1984; in the 1983 paper HPV-16 DNA was found in 11 of 18 cervical cancers from German patients but in only 2 of 33 genital warts. That year zur Hausen became scientific director of the German Cancer Research Center in Heidelberg. WHO now attributes around 76 percent of cervical cancers worldwide to the two types.

The molecular mechanism followed over the subsequent decade. Integration of HPV DNA into the host genome disrupts the viral E2 gene, removing repression of the E6 and E7 oncoproteins. E6 targets p53 for proteasomal degradation; E7 binds and inactivates the retinoblastoma protein. The result is loss of two critical tumor suppressor pathways simultaneously. Zur Hausen's early approaches to drug companies about a vaccine failed after one firm's market analysis concluded there would be no market.

Zur Hausen received half of the 2008 Nobel Prize in Physiology or Medicine; the other half went to Francoise Barre-Sinoussi and Luc Montagnier for discovering HIV. The Nobel Assembly noted that vaccines against HPV-16 and HPV-18 give at least 95 percent protection against infection. In the United States, Gardasil, which covers types 6, 11, 16 and 18, was licensed in June 2006 and Cervarix in October 2009; both are built on virus-like particles made from the L1 capsid protein.

WHO's elimination targets for 2030 are 90 percent of girls fully vaccinated by age 15, 70 percent of women screened and 90 percent of women with precancer or cancer treated; elimination means 4 or fewer new cases per 100,000 women a year. WHO describes vaccinating girls aged 9 to 14 as highly effective at preventing infection and cervical cancer. Some countries also vaccinate boys, to reduce circulation of the virus and prevent the cancers it causes in men, and a nine-valent Gardasil was approved in the United States in 2014.