The SV40 virus was suspected to cause cancer. The history of this research is a medical thriller

Science deals not only with SARS-CoV-2, polio virus and HIV, for years it has been studying many others that can cause tragic infections. On the wave of interest in these microorganisms aroused by the coronavirus pandemic, we also have a chance to get to know the less popular ones. The “ideal killer” was created, inter alia, the oncogenic virus SV40, the discovery of which in polio vaccines used around the world caused a storm. As a result, it is now one of the best-studied pathogens, and at the beginning of the XNUMXst century, CDC experts exonerated it in an official statement.

1. The monkey virus was isolated from the macaque kidney cells used to grow the poliovirus for … the production of a vaccine
2. Contaminated SV40 preparations were administered between 1955 and 1963 to approximately 98 million Americans – children and adults. How did this come about?
3. Earlier, Maurice Hilleman showed in studies that SV40 can initiate neoplastic processes in experimental animals
4. The matter was thoroughly investigated, and in 2003 a report was released that would ultimately answer the question “Can SV40 cause cancer in humans?”
5. More information can be found on the Onet homepage

A dose of monkey virus in polio vaccines

Since its discovery, SV40, or monkey virus, has been one of the most extensively researched animal viruses, with a history reminiscent of a medical thriller.

It was first described in 1960 by scientists from Merck, led by Maurice Hilleman. The monkey virus was isolated from the macaque kidney cells used to grow the poliovirus for … the production of a vaccine. Contaminated SV40 preparations were administered between 1955 and 1963 to approximately 98 million Americans – children and adults. How did this come about?

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The poliovirus was inactivated with formalin, but SV40 was resistant to it. In addition, the oral polio vaccine used a live pathogen and did not undergo an inactivation process, resulting in even higher levels of SV40. When concerned scientists examined children vaccinated with a contaminated oral preparation, it turned out that shed the virus for at least 5 weeks after receiving the vaccine.

As if that wasn’t enough, Hilleman’s research showed that SV40 initiated neoplastic processes in experimental animals. Following this discovery, it was imperative to check whether the millions of people vaccinated with the contaminated polio preparation were at risk of developing cancer. Merck withdrew its vaccine from the market and later invested in research. Scientists were given the task of detecting all possible adverse effects of administering contaminated vaccines.

Since the discovery of Hilleman, the use of monkeys for tissue culture has also been discontinued, and subsequent batches of vaccines have been produced largely from human cells.

How does the SV40 work?

This virus belongs to the family of Polyomaviruses, which are double-stranded, non-enveloped viruses. The genome is wrapped in an icosahedron-shaped capsid about 40-50 nanometers in diameter.

The life cycle of the virus begins when it enters the host cell, and the effect of its action is unique as the infected cell quickly begins to multiply in an uncontrolled manner. This is mainly due to two proteins in the virus – the large T antigen (T antigen) and the small T antigen (t antigen). However, before this happens, the virus must attach to the cell surface through the appropriate receptors, penetrate the plasma membrane and enter its nucleus, where it is transcribed.

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Little is known about SV40 infection in the wild. In its natural host, the macaque, SV40 infects the renal epithelial cells. Because they are dormant, they do not produce, for example, proteins involved in DNA replication used by the virus to duplicate its DNA and create new virions. However, large and small T antigens work together to induce infected cells to divide, thus supplying the raw materials needed for the production of new viruses.

The genome of SV40 is very small and does not encode all the information necessary for its DNA to replicate. Therefore, it is important that the host cell enters the S phase (DNA replication), then its DNA and viral genome are duplicated together. Therefore, another function of the T antigen is to alter the cellular environment.

Infection of macaque kidney cells ultimately causes their death (in culture about 96 hours after infection), at the same time about 300 new viruses are formed from one infected cell.

Thanks to the SV40, we got to know the mechanism of neoplasm better

Oncogenic viruses produce proteins that are able to modify the life cycle of infected cells, and tumor transformation enables the cell to divide and survive indefinitely.

A healthy cell has a number of safeguards that prevent it from uncontrolled division. Meanwhile, in the course of research it was found that the monkey virus inhibits the action of proteins from the group of tumor growth suppressors – P53 and Rb.

The tumor suppressor P53 was discovered precisely because it bound to the large T antigen of the virus. P53, also known as the ‘genome guardian’, controls the phases of the cell cycle. It is released in the cell nucleus in response to DNA damage, acting in two phases – first, it stops the cell cycle until DNA repair is complete, and in the case of extensive and difficult to repair damage (i.e. when the risk of carcinogenesis is high), it starts the apoptosis program ( cell death).

The T antigen also binds to the RB1 protein (retinoblastoma susceptibility gene), which leads to the transcription of genes encoding proteins responsible for DNA replication, repair and the cell cycle. In other words, it blocks its ability to regulate cell division processes.

Scientists found that some lab animals infected with SV40 developed lymphomas, brain tumors, osteosarcomas, and mesotheliomas, and lab-grown mouse cells became cancerous. In addition, viral DNA fragments were found in some human tumors and later in healthy tissues.

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However, the monkey virus is harmless

Years of US epidemiological studies of cancer rates do not show significant differences between the populations who received the contaminated batches of the polio vaccine and those who did not. There was also no increased susceptibility to cancer among those who received contaminated vaccines as children. The increase in pulmonary mesothelioma was mainly seen in men over the age of 75 who had not been vaccinated at all. Meanwhile, mesothelioma rates fell in the age groups who received the vaccines.

In 2001, the CDC and the US National Institutes of Health (NIH) established an independent group of experts that spent three years looking for possible adverse effects of administering contaminated polio vaccines.. A report summarizing the results of her work was published in 2003. In a document available on the Internet, we find the answer to the question: “Can SV40 cause cancer in humans?”

As stated, admittedly, SV40 has the ability to generate tumors and can lead to tumor development in animals, however “Data on the relationship between SV40 and human neoplasms are inconsistent”. While viral DNA has been shown to be present in tumors, the report emphasizes that there is no causal link – just because the virus is present does not prove it caused the cancer.

All studies supporting the link between SV40 and cancer were based on the detection of the virus in the tumor. However, the detection technique was not perfect, mainly due to cross-reactivity with other polyomaviruses (BKV and JCV). In addition, SV40 DNA particles are widely used in laboratories and are a potential source of contamination. More recent studies using improved techniques have not replicated those found in human tumors with SV40. Therefore, no existing data link the SV40 included in the vaccine to the subsequent development of cancer.

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To date, the frequency of SV40 infections in humans is unknown. Research, based on PCR and serological tests, indicates that they occur in both children and adults. Comprehensive seroepidemiological testing (detecting the presence of anti-SV40 antibodies in the blood) would allow for a more accurate assessment. On their basis, seropositivity could be linked to disease or even disease predisposition.

We asked for a comment from prof. dr hab. Krzysztof Giannopoulos, an expert in the field of clinical and experimental hematology, head of the Department of Experimental Hematooncology at the Medical University of Lublin and a physician in charge of the Hematology Department of the St. John of Dukla.

— Laboratory and clinical experience allows me to say with certainty that the SV40 virus has no real significance in oncology. Let me start with the more important clinical side in this case – says prof. Giannopoulos. Although there has been contamination of polio vaccines with SV40, large studies have not shown that this has consequences in terms of tumorigenesis. Contaminated vaccines were not clinically associated with cancer. We are dealing here only with a statistical correlation, because cancer is a civilization disease and affects a large percentage of the population. The situation is analogous to the coronavirus pandemic. I am sure that research may show a correlation between coronavirus infection and cancer, but this will be due to the fact that cancer is a civilization disease that affects the majority of the population, such as the coronavirus pandemic, while a cause-and-effect relationship between cancer and coronavirus is not proven. It was similar with the SV40 virus.

– On the other hand, from the laboratory point of view, the situation is that there are known reports of the influence of SV40 on carcinogenesis. It has been found in cancer cell lines, but cell lines are not cancer. They can be compared to a model that tests cancer. In addition, cell lines are different from a living organism, they do not have a tumor microenvironment and, as an artificial creation, are more likely to become infected. A typical laboratory infection is mycoplasma infection. They even analyzed cell lines from large banks, and it turned out that a lot of them are infected with it. The SV40 virus is known in the scientific world, and the mechanisms of its action in the cell are also known. They are indeed related to neoplasia, but we do not have any evidence at a clinical level for a virus to be associated with human neoplasms. There are many similar viruses of silent clinical importance around us. Let us take latent viruses, i.e. viruses that are in our body and in most cases do not cause disease, although in individuals they can cause certain consequences. I am thinking of the cytomegalovirus or the Epstein-Barr virus. Due to their prevalence and unclear pathogenic mechanism, they definitely require further research. The time of the pandemic favors this type of work, we learn more and more about viral diseases. While we have a very effective weapon in the case of bacterial diseases, i.e. antibiotics, the weapons in the case of viruses are vaccines and antiviral drugs that are developing at different rates. It seems to me that the Epstein-Barr virus, the relationship of which with lymphomas we know much more, is a much bigger problem for us today. In addition, we have not developed vaccinations and antiviral drugs are ineffective. Sometimes we have to treat lymphoma with a bone marrow transplant, a dramatic procedure to replace the entire immune system. These topics are of great clinical interest, and the SV40 virus remains in their shadow.

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We can use the knowledge about the SV40 virus

Infection with some oncogenic viruses or the introduction of their genes into a human cell can stimulate cell division and lead to immortalization. The SV40 virus is capable of this in vascular epithelial and endothelial cells. The maximum number of divisions increases significantly both after infection with the SV40 virus and after the introduction of its genes encoding large T antigen. Although it has been observed that the growth of most of the cells changed in this way is inhibited, and only a few clones are immortalized.

However, scientists began to wonder whether this method could not be used to grow cells needed, for example, for transplantation, which is already a commonly used method of treatment. However, for it to be performed, tissues and organs must be accessible.

In neurodegenerative diseases such as Parkinson’s disease, transplant is not possible due to tissue inaccessibility. Therefore, in the future, a method of cultivating neurons could be developed based on the capabilities of SV40.

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