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Cancer risk associated with simian virus 40 contaminated polio vaccine.
Abstract
The presence of SV40 in monkey cell cultures used in the preparation of the polio vaccine from 1955 through 1961 is well documented. Investigations have consistently demonstrated the oncogenic behavior of SV40 in animal models. Early epidemiologic studies were inadequate in demonstrating an increase in cancer incidence associated with contaminated vaccine. Recently, investigators have provided persuasive evidence that SV40 is present in human ependymomas, choroid plexus tumors, bone tumors, and mesotheliomas, however, the etiologic role of the virus in tumorigenesis has not been established.
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Unique Strains of SV40 in Commercial Poliovaccines from 1955 Not Readily Identifiable with Current Testing for SV40 Infection
Abstract
SV40 was first identified as a contaminant of poliovaccines used from 1955 until 1963. Recently, SV40 has been detected in several human tumors. The virus detected in human tumors often contained only one 72-bp enhancer in the regulatory region, in contrast to the SV40 originally isolated from poliovaccines, which contained two 72-bp enhancers. The origin of viruses with one 72-bp enhancer in humans was unknown, because it was thought that these viruses were not present in poliovaccines. It was also thought that all poliovaccine vials produced from 1955 until 1963 had been discarded, thus the possibility that one 72-bp virions contaminated those vials could not be tested. We unexpectedly obtained what appear to be the last available vials of poliovaccine produced in 1955. In these vials, we detected and sequenced SV40 containing only one 72-bp enhancer in the regulatory region. The tissue culture cytopathic test currently used in the United States to screen oral poliovaccines was designed to detect rapidly proliferating SV40 virions containing two 72-bp enhancers. We found that this test is not sensitive enough to detect low amounts of the slow-replicating SV40 virions containing one 72-bp enhancer. This virus was easily detected in the same cells by immunostaining and PCR. Twelve current vials of poliovaccines tested uniformly negative for SV40, suggesting that the precaution of preparing poliovaccines from kidneys obtained from monkeys bred in isolated colonies prevented SV40 contamination. Our data demonstrate that humans were exposed to SV40 viruses with both one 72-bp enhancer and two 72-bp enhancers SV40 through contaminated vaccines. Our data also suggest that instead of cytopathic tests, immunohistochemical and/or molecular studies should be used to screen poliovaccines for SV40 to completely eliminate the risk of occasional contamination.
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Simian Virus 40, poliovirus vaccines, and human cancer.
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Simian Virus 40 Infection of Humans
In 1960, Sweet and Hilleman first described an agent, which they named SV40, that induced cytopathic effects and vacuole formation in monkey cells (117). SV40 was isolated from normal monkey kidney cells, stocks of the Sabin poliovirus vaccine, and an adenovirus vaccine. The last two reagents were prepared in primary kidney cell cultures derived from rhesus monkeys. Subsequent analyses found that the Salk poliovirus vaccine administered from 1955 to 1963 in the United States was also contaminated with SV40, potentially exposing an estimated 100 million people (106). Although poliovirus in the Salk vaccine was inactivated by formalin treatment, the conditions were insufficient to completely inactivate SV40. Soon thereafter, it was demonstrated that SV40 could infect humans and also induce tumors in experimental animals
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Emergent Human Pathogen Simian Virus 40 and Its Role in Cancer
Absract>
The polyomavirus simian virus 40 (SV40) is a known oncogenic DNA virus which induces primary brain and bone cancers, malignant mesothelioma, and lymphomas in laboratory animals. Persuasive evidence now indicates that SV40 is causing infections in humans today and represents an emerging pathogen. A meta-analysis of molecular, pathological, and clinical data from 1,793 cancer patients indicates that there is a significant excess risk of SV40 associated with human primary brain cancers, primary bone cancers, malignant mesothelioma, and non-Hodgkin's lymphoma. Experimental data strongly suggest that SV40 may be functionally important in the development of some of those human malignancies. Therefore, the major types of tumors induced by SV40 in laboratory animals are the same as those human malignancies found to contain SV40 markers. The Institute of Medicine recently concluded that “the biological evidence is of moderate strength that SV40 exposure could lead to cancer in humans under natural conditions.” This review analyzes the accumulating data that indicate that SV40 is a pathogen which has a possible etiologic role in human malignancies. Future research directions are considered.
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SV40 large T antigen targets multiple cellular pathways to elicit cellular transformation
Abstract
DNA tumor viruses such as simian virus 40 (SV40) express dominant acting oncoproteins that exert their effects by associating with key cellular targets and altering the signaling pathways they govern. Thus, tumor viruses have proved to be invaluable aids in identifying proteins that participate in tumorigenesis, and in understanding the molecular basis for the transformed phenotype. The roles played by the SV40-encoded 708 amino-acid large T antigen (T antigen), and 174 amino acid small T antigen (t antigen), in transformation have been examined extensively. These studies have firmly established that large T antigen's inhibition of the p53 and Rb-family of tumor suppressors and small T antigen's action on the pp2A phosphatase, are important for SV40-induced transformation. It is not yet clear if the Rb, p53 and pp2A proteins are the only targets through which SV40 transforms cells, or whether additional targets await discovery. Finally, expression of SV40 oncoproteins in transgenic mice results in effects ranging from hyperplasia to invasive carcinoma accompanied by metastasis, depending on the tissue in which they are expressed. Thus, the consequences of SV40 action on these targets depend on the cell type being studied. The identification of additional cellular targets important for transformation, and understanding the molecular basis for the cell type-specific action of the viral T antigens are two important areas through which SV40 will continue to contribute to our understanding of cancer.
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Historical Vaccine Safety Concerns
Abstract
From 1955 to 1963, an estimated 10-30% of polio vaccines administered in the US were contaminated with simian virus 40 (SV40). The virus came from monkey kidney cell cultures used to make polio vaccines at that time. Most of the contamination was in the inactivated polio vaccine (IPV), but it was also found in oral polio vaccine (OPV). After the contamination was discovered, the U.S. government established testing requirements to verify that all new lots of polio vaccines were free of SV40.
Because of research done with SV40 in animal models, there has been some concern that the virus could cause cancer in humans.
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Some Oral Poliovirus Vaccines Were Contaminated with Infectious SV40 after 1961
Abstract
Some polio vaccines prepared from 1954 to 1961 were contaminated with infectious SV40. It has been assumed that all polio vaccines were SV40 free in the United States after 1961 and in other countries after 1962. Following a WHO requirement that was prompted by the detection of SV40 in some human tumors, we conducted a multilaboratory study to test for SV40 polio vaccines prepared after 1961. Vaccine samples from 13 countries and the WHO seed were initially tested by PCR. The possible presence of intact and/or infectious SV40 DNA in PCR-positive samples was tested by transfection and infection of permissive CV-1 cells. All results were verified by immunohistochemistry, cloning, and sequencing. All the vaccines were SV40 free, except for vaccines from a major eastern European manufacturer that contained infectious SV40. We determined that the procedure used by this manufacturer to inactivate SV40 in oral poliovirus vaccine seed stocks based on heat inactivation in the presence of MgCl2 did not completely inactivate SV40. These SV40-contaminated vaccines were produced from early 1960s to about 1978 and were used throughout the world. Our findings underscore the potential risks of using primary monkey cells for preparing poliovirus vaccines, because of the possible contamination with SV40 or other monkey viruses, and emphasize the importance of using well-characterized cell substrates that are free from adventitious agents. Moreover, our results indicate possible geographic differences in SV40 exposure and offer a possible explanation for the different percentage of SV40-positive tumors detected in some laboratories.
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Transgenic Mouse Models of SV40-Induced Cancer
Abstract
The SV40 viral oncogene has been used since the 1970s as a reliable and reproducible method to generate transgenic mouse models. This seminal discovery has taught us an immense amount about how tumorigenesis occurs, and its success has led to the evolution of many mouse models of cancer. Despite the development of more modern and targeted approaches for developing genetically engineered mouse models of cancer, SV40-induced mouse models still remain frequently used today. This review discusses a number of cancer types in which SV40 mouse models of cancer have been developed and highlights their relevance and importance to preclinical research.
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Simian virus 40 may be associated with developing malignant pleural mesothelioma
Malignant pleural mesothelioma (MPM) is associated with a history of heavy, long-term exposure to asbestos. However, MPM may also be associated with simian virus 40 (SV40), a polyomavirus. The association between SV40 and MPM remains unclear. The present study was conducted in order to investigate the proportion of SV40 presence in the histological specimens of Vietnamese patients with MPM. Histological specimens were obtained from 45 patients (19 men and 26 women) with MPM at the Pham Ngoc Thach Hospital in Ho Chi Minh City, Vietnam. The specimens were processed and examined in order to detect the presence of the SV40 large T antigen (SV40 Tag) expression using immunohistochemistry. Of the 45 patients, 23 (51%) were epithelioid, 7 (16%) were biphasic, 6 (13%) were sarcomatoid, 4 (9%) were desmoplastic, 4 (9%) were well-differentiated papillary and 1 (2%) was the anaplastic subtype. In total, 9/45 patients (20%) demonstrated SV40 Tag expression. The proportion of patients that demonstrated SV40 Tag expression was not significantly different between the epithelioid subtype and the other subtypes (22 vs. 18%; P=1.000) or between the patients with stage IV disease and other stages (20 vs. 20%; P=1.000). The median survival time was not significantly different between the patients with or without SV40 Tag expression (196 vs. 236 days, P=0.8949). In summary, a 5th of the Vietnamese patients with MPM were associated with infection with SV40. SV40 may be a potential cause of MPM in Vietnam and this potential association requires additional studies.
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SV40 Contamination of the 1953-1963 Polio Vaccine
Polio vaccines used in the late 1950s and early 1960s were contaminated with a virus called simian virus 40 (SV40) present in monkey kidney cells used to grow the vaccine. Subsequently, investigators found SV40 DNA in biopsy specimens obtained from patients with cancers such as mesothelioma (lung), osteosarcoma (bone) and non-Hodgkins lymphoma (lymph nodes).
- SV40 was present in cancers of people who either had or had not received the polio vaccines that were contaminated with SV40.
- SV40 has not been present in any vaccine since 1963.
- People with cancers who were born after SV40 was no longer a contaminant of the polio vaccine were found to have evidence for SV40 in their cancerous cells.
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