About My Research on the SV40 Virus
Simian Virus 40 (SV40) is a DNA virus that causes cancer when injected into hamsters.
It is a monkey virus and, since poliovaccines were made using monkey cells, polio vaccines made in the US and distributed throughout the world during the years 1954 through 1963 contained infectious SV40. Because SV40 was more resistant to the formaldehyde that was used to inactivate the polio virus, live SV40 virus was present in the poliovaccines. We discovered that all poliovaccines made in the former USSR and distributed through the Soviet empire--except for former Yugoslavia, as they made their own vaccines--remained contaminated with infectious SV40 until at least 19781. Thus hundreds of millions of people were injected with a monkey virus that is known to cause cancer in hamsters.
We discovered that when SV40 was injected intracardially it preferentially caused mesothelioma in hamsters. 2 Others discovered that when SV40 was injected in the brain it caused brain tumors, and when SV40 was injected in the tail vein, it caused leukemias and lymphomas. When it was injected subcutaneously it caused fibrosarcomas. All of this information is well established and accepted.
The controversy starts when you discuss whether SV40 injection in millions of humans caused--or contributed to--some human malignancies. We and several other laboratories around the world found traces of SV40 DNA and proteins in mesotheliomas, lymphomas and brain tumors. Others did not, or else they found SV40 in a much lower percentage of these malignancies. The issue became very controversial, also because of the risk of associated litigation that was seen as a major threat by some pharmaceutical companies.
One of the key criticisms against the argument that SV40 caused cancer in humans was that SV40 was not found integrated in the human DNA. Instead, it was always found integrated in the DNA of hamster tumor cells. So the criticisms was that because SV40 had to be integrated to cause cancer in hamster the same had to be true in humans, and since we did not find it integrated SV40 was not causing tumors in humans. “Integrated” means that the viral DNA becomes fused with the host DNA. According to the textbooks of virology, when SV40 was not integrated in the human cells, and the virus DNA was ‘free” –called episomal DNA--it would replicate, make thousands of viral particles and kill the cell: a death cell cannot become cancerous. This “dogma” was based on experiments in human fibroblasts, which--because they are the easiest human cells to grow in tissue culture and are easy to obtain--had been used for these experiments.
It turns out that SV40 had not read the textbook of virology! When we challenged the “dogma” and tested SV40 in different types of human cells, we discovered that human mesothelial cells and brain cells were much more resistant to episomal SV40 than fibroblasts or epithelial cells. We found that mesothelial and brain cells had devised a unique mechanism to prevent SV40 to produce the “capsid” proteins that are the viral protein that form the envelope of the virus and cause cell lysis (cell death). So SV40 was able to live episomally inside these cells without killing them. We reported these findings in: Carbone M et al., Cancer Research 2008 3 and Zhang L et al., Genes and Cancer 2010. 4 In addition, we discovered a critical mechanism by which SV40 contributed to the malignant growth of human mesothelial cells: it bound to the cellular proteins p53, pRb and p300 and together this complex activated the IGF-1 receptor required for tumor growth. 5 Moreover, SV40 infection induces telomerase activity. 6
By the time we reported these findings, however, I had become very much involved with my research in Cappadocia 7 and 8 and I did not have not enough time to deal also with SV40. Moreover, I was tired of the controversy about the role of SV40 in human tumors. So I devoted most of my time and energy to trying to identify the gene that according to my hypothesis was the cause of mesothelioma epidemics in Cappadocia and in some US families, and left SV40 on the back burner.
I hoped that one day I would have gone back to study SV40, but, now that we found the gene (BAP1), I am so busy studying it and with my studies about environmental exposure to asbestos and other carcinogenic fibers, that I have not found the time to go back to the SV40 research. In the papers listed above, you will find much more information about this research.
For a review of the topic I suggest you read Carbone M, et al. Oncogene. 15:1877-1888, 1997 9, Carbone M, et al., Oncogene, 26: 6959-6967, 2007 10 and Rizzo P et al., Cancer Res. 1999, 11 and Gazdar A, Butel J, and Carbone M, Nature Reviews Cancer 2002 12
Another reference is 2002 article in Oncogene by George Klein, Amy Powers and Carlo Croce, Association of SV40 with human tumors in Oncogene, 14 February 2002, Volume 21, Number 8, Pages 1141-1149. 13
Also a book was written about this issue, written with a careful analysis of the literature. The book is easy and fascinating to read: The Virus and the Vaccine by Debbie Bookchin and Jim Schumacher.
- Rochelle Cutrone, John Lednicky, Glynis Dunn, Paola Rizzo, Maurizio Bocchetta, Konstantin Chumakov, Philip Minor and Michele Carbone.Some Oral Poliovirus Vaccines Were Contaminated with Infectious SV40 after 1961. Cancer Research 2005, Volume 65, Issue 22, 15 Nov 2005. DOI: 10.1158/0008-5472.CAN-05-2028
- C. Cicala, F. Pompetti, and M. Carbone. SV40 induces mesotheliomas in hamsters, American Journal of Pathology 1993: May; 142(5): 1524–1533.
- Michele Carbone, Antonio Pannuti, Lei Zhang, Joseph R. Testa and Maurizio Bocchetta. A Novel Mechanism of Late Gene Silencing Drives SV40 Transformation of Human Mesothelial Cells. Cancer Research, 68:(22):948-996.
- Lei Zhang, Fang Qi, Giovanni Gaudino, Oriana Strianese, Haining Yang, Paul Morris, Harvey I Pass, Vivek R Nerurkar, Maurizio Bocchetta, Michele Carbone. Tissue Tropism of SV40 Transformation of Human Cells. Genes & Cancer, Volume I, Issue 10: 1008-1020.
- Maurizio Bocchetta, Sandra Eliasz, Melissa Arakelian De Marco, Jennifer Rudzinski, Lei Zhang and Michele Carbone The SV40 Large T Antigen-p53 Complexes Bind and Activate the Insulin-like Growth Factor-I Promoter Stimulating Cell Growth. Cancer Research 2008.
- Foddis R, De Rienzo A, Testa JR, Carbone M, et al. SV40 infection induces telomerase activity in human mesothelial cells. Oncogene 2002:21:1434-1442.
- Carbone M, Emri S, Dogan U, Steele I, Tuncer M, Pass HI, Baris YI. A mesothelioma epidemic in Cappadocia: scientific developments and unexpected social outcomes. Nature Reviews Cancer, 7:147-154, 2007.
- Michele Carbone, Haining Yang, Harvey I Pass, Thomas Krausz, Joseph R Testa, Giovanni Gaudino. Bap1 and Cancer. Nature Reviews Cancer, 13, 153-159 (March 2013).
- Carbone, Michele; Rizzo, Paola; Pass, Harvey I. Simian virus 40, poliovaccines and human tumors: a review of recent developments. Oncogene . 10/16/97, Vol. 15 Issue 16, p1877. 12p.
- M Carbone, S M Albelda, V C Broaddus, R M Flores, G Hillerdal, M-C Jaurand, K Kjaerheim, H I Pass, B Robinson and A Tsao. Eigth International Mesothelioma Interest Group. Oncogene (2007) 26, 6959–6967; doi:10.1038/sj.onc.1210515; published online 14 May 2007
- P Rizzo, I Di Resta, A Powers, H Ratner, M Carbone. Unique Strains of SV40 in Commercial Poliovaccines from 1955 Not Readily Identifiable with Current Testing for SV40 Infection Eigth International Mesothelioma Interest Group. Cancer Research, December 1999: Volume 59, Issue 24
- Gazdar AF, Butel JS, Carbone M. SV40 and human tumors: myth, association or causality? Nature Reviews Cancer, Volume 2:956-964 (2002)
- Klein G, Powers A, Croce C. Association of SV40 with human tumors. Oncogene (21):1141-1149 (2002)