SV40 association with human malignancies and mechanisms of tumor immunity by large tumor antigen

Abstract

SV40 was discovered as a contaminate of poliovirus vaccine lots distributed to millions of individuals in the United States between 1955 and 1963 while contaminated vaccine batches were later circulated worldwide. After SV40 was observed to cause in vitro animal and human cell transformations and in vivo tumor formations in animals, the search for a connection between the virus and human malignancies has continued to the present day. Different molecular methods have been used to detect SV40 gene products in a variety of human cancers, though SV40 causality in these tumor types has yet to be established. These data, however, are not without controversial issues related to inconclusive SV40 serological and epidemiological evidence alongside tools and methodologies that may contribute to false-positive results in human specimens. This review will also explore how vaccination against SV40 protein products may be used to help prevent and treat individuals with SV40-expressing cancers.

Human Polyomaviruses in Skin Diseases

“…However, the role of BKV, JCV, and SV40 in human cancers remains controversial [24–27], while the role of LPV, KIPyV, WUPyV, HPyV6, HPyV7, TSPyV, and HPyV9 in human tumourigenesis has not been studied yet. The only human PyV that is a candidate oncovirus is MCPyV, which seems to be a causal factor in Merkel cell carcinoma (see below).…”

CD4+T Lymphocytes Are Critical Mediators of Tumor Immunity to Simian Virus 40 Large Tumor Antigen Induced by Vaccination with Plasmid DNA

“…This virus was initially discovered as a contaminant of polio vaccines in the 1960s and has since been studied extensively due to its ability to transform human and rodent cell lines in vitro (27). The transforming capacity of SV40 can largely be attributed to the virally encoded protein large tumor antigen (Tag), which plays a critical role in viral replication and also inactivates host p53 and retinoblastoma family tumor suppressor proteins.…”

“…While the direct oncogenic potential of SV40 infection has been thoroughly demonstrated in neonatal hamster models (13,15,23), the ability of this virus to promote analogous disease in humans remains controversial. An association between SV40 and multiple human cancers has been reported via meta-analysis (48); however, the validity of such findings has been questioned due to apparent inconsistencies, as well as concerns regarding the specificity of SV40 nucleic acid and protein detection protocols (14,27). Interestingly, SV40 appears to have a unique ability to transform human mesothelial cells and, in conjunction with asbestos, has been identified as a possible cocarcinogen for malignant pleural mesothelioma (4).…”

Tumor Immunity against a Simian Virus 40 Oncoprotein Requires CD8+T Lymphocytes in the Effector Immune Phase

“…By understanding the immunologic pathways involved in antitumor responses and tumor immunity, more efficacious immunotherapeutic strategies can be implemented to halt the progression of tumorigenic growth. Relative to our study with the tumor-specific antigen SV40 Tag, a variety of cancers, including non-Hodgkin's lymphoma and malignant pleural mesothelioma, have demonstrated amplifiable SV40 Tag gene sequences (11,24). Since our murine system typifies the requirement for a primary antibody response followed by activation of the cell-mediated arm of the immune system, it may be advantageous for development of cancer vaccine strategies to elicit both arms of the immune system in SV40 Tagexpressing human tumors.…”

“…We are not aware of another published report that formulates a role for ADCC activity against a viral oncoprotein in this manner in order to engage CD8 ϩ T-cell activation. SV40 Tag has been reported to be expressed in a number of human cancers, including malignant pleural mesothelioma and non-Hodgkin's lymphoma, although a causal link between SV40 infection and tumorigenesis is uncertain (11,24,35). The results of this study have direct implications for the construction of an appropriate immunotherapeutic strategy for patients suffering malignancies expressing the SV40 Tag tumor-specific antigen.…”