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TWiV 80: How much X could a woodchuck chuck?

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Hosts: Vincent Racaniello, Alan Dove, Rich Condit, and Michael Bouchard

Vincent, Alan, and Rich speak with Michael Bouchard about hepatitis B virus discovery, replication, and pathogenesis.

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Virology lecture #19: Transformation and oncogenesis

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Visit the virology W3310 home page for a complete list of course resources.

Poliovirus vaccine, SV40, and human cancer

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SV40Deep sequencing – which identified a viral contaminant of the rotavirus vaccine Rotarix - could have revealed the presence of simian virus 40 (SV40) in the poliovirus vaccine, had the technique been available in the 1950s. Exposure of over 100 million Americans to SV40, and many more worldwide, could have been avoided, as well as the debate about the role of this monkey virus in human cancer.

SV40 was discovered by Maurice Hilleman in 1960 as a contaminant of poliovirus vaccine. It was present in batches of both the Salk and Sabin poliovirus vaccines produced and distributed from 1954 to 1963. The source was the rhesus and cynomolgous monkey kidney cells used to produce the vaccine. Even more troubling was the observation that SV40 could cause tumors in hamsters. By 1963 screening procedures were instituted to ensure the absence of SV40 in poliovirus vaccines. Ironically, monkey cells were used for poliovirus vaccine production because it was feared that human cells might contain unknown human cancer viruses.

SV40 does not cause tumors in its natural host – monkeys – because it kills infected cells. However, in the wrong host- such as a hamster – the viral replication cycle is incomplete and virions are not produced. At a very low frequency, pieces of the viral DNA become integrated into the host chromosomal DNA. Problems arise if these viral DNA fragments encode the viral T (tumor) antigen. This protein is essential for lytic replication (which takes place in monkey cells) because it kick-starts cellular DNA synthesis. The cellular DNA synthetic machinery is then co-opted for replication of the viral DNA. When only T antigen is present, the cells divide without stopping – they are transformed, and on the way to becoming a tumor. SV40 does not need to cause tumors as part of its life cycle; they are an aberrant result of having T antigen push the cells to divide. SV40 T antigen can transform human cells, and therefore in theory the virus could cause human tumors.

The results of epidemiological studies initiated in the 1960s through the 1970s, in which thousands of poliovirus vaccine recipients were studied, indicated that this population did not have an increased risk of developing cancer. More recent reports that SV40 viral DNA is present in human tumors have led to a debate on the contribution of this virus to human cancer. Some of the arguments for and against presence of SV40 in human cancers are presented below.

Evidence that SV40 is present in human tumors

  • SV40 DNA has been detected in several human tumors, including osteosarcoma, mesothelioma, and non-Hodgkin’s lymphoma. Similar tumors are induced by the virus in hamsters.
  • Poliovirus vaccine produced in 1954 contained a variant of SV40 that can be distinguished from common laboratory strains. This viral variant has been found in three non-Hodgkin’s lymphoma patients

Evidence that SV40 is not present in human tumors

  • SV40 DNA is not present in all samples of a cancer, and in some studies of mesotheliomas, it has not been detected in any.
  • SV40 viral DNA has been detected in tumors of those who could not have received contaminated poliovirus vaccine.
  • In a comparison of mesotheliomas and normal tissues, SV40 DNA has been detected as frequently in both.
  • Analysis of the SV40 sequences in mesotheliomas showed that the viral DNA was derived from a laboratory strain which contains a gap that is not present in the wild type viral genome.

Even if SV40 DNA were definitively shown to be present in human tumors, this would not answer the question of whether the virus caused the cancer. The debate on the role of SV40 in human malignancy illustrates the difficulty in establishing cause and effect, and provides ample impetus for using genomic technologies to ensure that vaccines and other biological products are free of adventitious agents.

Garcea, R., & Imperiale, M. (2003). Simian Virus 40 Infection of Humans Journal of Virology, 77 (9), 5039-5045 DOI: 10.1128/JVI.77.9.5039-5045.2003

López-Ríos F, Illei PB, Rusch V, & Ladanyi M (2004). Evidence against a role for SV40 infection in human mesotheliomas and high risk of false-positive PCR results owing to presence of SV40 sequences in common laboratory plasmids. Lancet, 364 (9440), 1157-66 PMID: 15451223

PEDEN, K. (2008). Recovery of strains of the polyomavirus SV40 from rhesus monkey kidney cells dating from the 1950s to the early 1960s Virology, 370 (1), 63-76 DOI: 10.1016/j.virol.2007.06.045

Merkel cell polyomavirus, a new oncogenic human virus?

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merkel-cell-polyomavirusNone of the four human polymaviruses that were known in early 2008 – JC, BK, KI and WU – had been shown to cause cancer. The subsequent identification of a new polyomavirus associated with Merkel cell carcinoma demonstrates the type of evidence that is required to prove that a virus is oncogenic in humans.

Merkel cell carcinoma (MCC) is a relatively rare human skin cancer, although its incidence has increased in the past twenty years from 500 to 1500 cases per year. This cancer occurs more frequently than expected in individuals who are immunosuppressed, such as those who have received organ transplants or who have AIDS. A similar pattern of susceptibility is also observed for Kaposi’s sarcoma, a tumor that is caused by the herpesvirus HHV-8. Therefore it was suggested that MCC might also be caused by an infectious agent.

To identify the etiologic agent of MCC, the nucleotide sequence of total mRNA from several MCC tumors was determined and compared with the sequence of mRNA from a normal human cell. This analysis revealed that the MCC tumors contained a previously unknown polyomavirus which the authors named Merkel cell polyomavirus (MCV or MCPyV). The viral genome was found to be integrated at different sites in human chromosomal DNA from MCC tumors.

If MCV infection causes MCC, then the viral genome should be present in tumors but not in normal tissues. MCC DNA was found in eight of ten MCC tumors, each obtained from a different patient. The viral genome was not detected in various tissues samples from 59 patients without MCC. Furthermore, the viral genome had integrated into one site in the chromosome of one tumor and a metastasis dervied from it. This observation indicates that integration of the viral genome occurs first, before division of the tumor cells.

In subsequent studies MCV DNA has been detected in 40-85% of the MCC tumors examined. The viral DNA is not found in small cell lung carcinoma, which, like MCC, is also a neuroendocrine carcinoma. MCV particles have also been detected by electron microscopy in the cytoplasm and nucleus of tumor cells from one patient, suggesting ongoing viral replication.

How might MCV cause Merkel cell carcinoma? Expression of the viral protein known as T antigen might be sufficient to transform cells. Alternatively, integration of the viral DNA into human DNA could lead to unregulated synthesis of a protein that transforms cells. To prove that MCV causes Merkel cell carcinoma, it will be necessary to demonstrate that infection with the virus, or transfection with viral DNA, transforms and immortalizes cells in culture.

Feng, H., Shuda, M., Chang, Y., & Moore, P. (2008). Clonal Integration of a Polyomavirus in Human Merkel Cell Carcinoma Science, 319 (5866), 1096-1100 DOI: 10.1126/science.1152586

Wetzels, C., Hoefnagel, J., Bakkers, J., Dijkman, H., Blokx, W., & Melchers, W. (2009). Ultrastructural Proof of Polyomavirus in Merkel Cell Carcinoma Tumour Cells and Its Absence in Small Cell Carcinoma of the Lung PLoS ONE, 4 (3) DOI: 10.1371/journal.pone.0004958

Harold Varmus on Daily Show

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Harold Various is a terrific scientist. He was awarded the 1989 Nobel Prize in Physiology or Medicine for discovery of the cellular origin of retroviral oncogenes. From 1993-1999 he was director of the National Institutes of Health, and is currently President of Memorial Sloan-Kettering Cancer Center in New York.

On top of all those accomplishments, he is a great advocate for science, and knows how to use traditional media, like TV and radio, to publicize his positions. Last night he was on the Daily Show with Jon Stewart.