STINGing Defenses: Unmasking the Mechanisms of DNA Oncovirus-Mediated Immune Escape.

DNA oncoviruses represent an intriguing subject due to their involvement in oncogenesis. These viruses have evolved mechanisms to manipulate the host immune response, facilitating their persistence and actively contributing to carcinogenic processes. This paper describes the complex interactions between DNA oncoviruses and the innate immune system, with a particular emphasis on the cGAS-STING pathway. Exploring these interactions highlights that DNA oncoviruses strategically target and subvert this pathway, exploiting its vulnerabilities for their own survival and proliferation within the host. Understanding these interactions lays the foundation for identifying potential therapeutic interventions. Herein, we sought to contribute to the ongoing efforts in advancing our understanding of the innate immune system in oncoviral pathogenesis.

DNA tumor virus oncogenes antagonize the cGAS-STING DNA-sensing pathway.

Cyclic guanosine monophosphate-adenosine monophosphate synthase (cGAS) detects intracellular DNA and signals through the adapter protein STING to initiate the antiviral response to DNA viruses. Whether DNA viruses can prevent activation of the cGAS-STING pathway remains largely unknown. Here, we identify the oncogenes of the DNA tumor viruses, including E7 from human papillomavirus (HPV) and E1A from adenovirus, as potent and specific inhibitors of the cGAS-STING pathway. We show that the LXCXE motif of these oncoproteins, which is essential for blockade of the retinoblastoma tumor suppressor, is also important for antagonizing DNA sensing. E1A and E7 bind to STING, and silencing of these oncogenes in human tumor cells restores the cGAS-STING pathway. Our findings reveal a host-virus conflict that may have shaped the evolution of viral oncogenes.

The common mechanisms of transformation by the small DNA tumor viruses: The inactivation of tumor suppressor gene products: p53.

The small DNA tumor viruses, Polyoma virus, Simian Vacuolating Virus 40, the Papilloma viruses and the human Adenoviruses, were first described during a period of intense virus discovery (1930-1960s) and shown to produce tumors in animals. In each of these cases the viral DNA was shown to persist (commonly integrated into a host chromosome) and only a selected portion of this DNA was expressed as m-RNA and proteins in these cancers. The viral encoded tumor antigens were identified and shown to be required to both establish the tumor and maintain the transformed cell phenotype. The functions of these viral tumor antigens were explored and shown to have common features and mechanisms even though they appear to have evolved from diverse genes. The SV40 large tumor antigen, the human Papilloma virus E7 protein and the Adenovirus E1A protein were shown to bind to and inactivate the functions of the Retinoblastoma proteins in transformed cells. This resulted in the activation of the E2F and DP transcription factors and the entry of cells into the S-phase of DNA synthesis which was required for viral DNA replication. These events triggered the activation of p53 which promotes apoptosis of these virus infected cells limiting virus replication and tumor formation. These viruses responded by evolving and producing the SV40 large tumor antigen, the human Papilloma virus E6 protein and the Adenovirus E1b-55Kd protein which binds to and inactivates the p53 functions in both the infected cells and transformed cells. Some of the human Papilloma viruses and one of the Polyoma viruses have been shown to cause selected cancers in humans. Both the p53 tumor suppressor gene, which was uncovered in the studies with these viruses, and the retinoblastoma protein, have been shown to play a central role in the origins of human cancers via both somatic and germ line mutations in those genes.

Adenovirus subversion of immune surveillance, apoptotic and growth regulatory pathways: a model for tumorigenesis.

The adenovirus system provides a novel model for evaluating the roles of multiple factors involved in tumour progression. In common with other DNA tumour viruses, adenovirus employs a variety of strategies to evade immune surveillance and perturbs cellular apoptotic and growth regulatory pathways to ensure efficient replication of progeny virions. Such subversion of cellular networks is also found in tumour cells. The mechanism behind the avoidance of immune surveillance and the extent of cellular network interference achieved by adenovirus is still being uncovered and is predicted to have ramifications for the design of cancer therapeutics.

Surveillance against tumors--is it mainly immunological?

The concept of tumor surveillance was first formulated by immunologists Mcfarlane Burnet and Lewis Thomas, respectively. They assumed that the immune system would recognize precancerous and cancer cells as non-self and reject them. This concept is only valid for virally transformed cells, however. In humans, EBV, HHV-8, and the papilloma viruses are relevant viral agents in this context. Tumors arising without a contribution by these viruses are regarded by the immune system as "self", with possible rare exceptions like melanoma. Immunological attempts to influence them therefore implies the breaking of tolerance, a much more difficult proposition. Multicellular organisms have powerful surveillance mechanisms of a non-immunological nature against potential neoplastic cells that threaten to disrupt the organism. Four distinct categories can be recognized: (1) DNA repair. Deficiency of repair enzymes may lead to multiple tumors and/or to multicancer syndromes. (2) Epigenetic mechanisms are currently emerging as being capable of modulating the incidence of certain tumors. e.g., by determining the stringency of imprinting and by influencing chromatin structure. (3) Intracellular surveillance. DNA damage, illegitimate activation of oncogenes, and other pathological changes may activate one or several apoptotic pathways. (4) Intercellular surveillance. The tissue microenvironment influences the probability of disseminated tumor cell growth. Moreover, appropriate differentiation inducing signals may revert the tumor cell phenotype.

Recent developments in human papillomavirus vaccines.

The association of certain high-risk human papillomaviruses with the development of anogenital cancer in humans is well-established. Numerous preclinical studies have underwritten the development of both prophylactic and therapeutic vaccine candidates for clinical evaluation. Prophylactic strategies are utilising virus-like particles composed of the L1 viral capsid protein to induce neutralising antibodies while therapeutic approaches are aimed at generating specific T cells targeted at the viral E6 and/or E7 oncogene products. Thus far, human papillomavirus virus-like particle vaccines have proven to be clinically efficacious in the early trials looking at the prevention of infection. Important future milestones will be showing the prevention of high-grade cervical intraepithelial neoplasia and sufficient longevity for such protection. Different types of therapeutic vaccines including peptide, protein, DNA or viral vector-based vaccines have proven to be safe and immunogenic in patients, although there is often no correlation with clinical outcome. The possibility of combined prophylactic and therapeutic vaccines may offer the best chance for a significant reduction in the incidence of death from cervical cancer worldwide.

Cellular immunity and immunotherapy against deoxyribonucleic acid virus-induced tumors.

An important role in the immune defense against deoxyribonucleic acid virus induced tumors is mediated by T-cells, as is evident from aetiological, animal model, and clinical data. In this review the most recent observations in this field are described for three prominent members of this family of viruses, namely human papillomavirus associated with human cervical cancer, human adenovirus associated with lung infections in humans and tumors in rodents, and simian virus 40 associated with rodent tumors and human mesothelioma, osteosarcoma and ependymoma.

[Dynamics of the appearance and disappearance of S-antigen in cells abortively of lytically infected with OV40 virus]. / Dinamika poiavleniia i utraty S-antigena v kletkakh, abortivno ili liticheski infitsirovannykh virusom OV40.

A highly sensitive mized hemadsorption test and blocking of it were used to study the size of the S-antigen-inducing dose of OV40 virus and the dynamics of the appearance of S-antigen under conditions of abortive and lytic infection. The data on the loss and persistence of this antigen in stationary and multiplying cultures of hamster and monkey cell are presented. S-antigen could be detected in OV40 virus-infected hamster and monkey cells long before their morphological transformation. No antigen was found upon passages of the infected hamster cells but it persisted in non-multiplying infected hamster cells as well as in productivity infected green monkey cells, irrespective of the number of passages, up to the onset cytopathic effect.