Human alpha and beta herpesviruses and cancer: passengers or foes?

Based on seroepidemiological studies, human herpes simplex virus types 1 and 2 (HSV-1, HSV-2) are put in relation with a number of cancer diseases; however, they do not appear to play a direct role, being only considered cofactors. Their ability to transform the cells in vitro could be demonstrated experimentally by removing their high lytic ability by a certain dose of UV radiation or by photoinactivation in the presence of photosensitizers, such as neutral red or methylene blue, or culturing under conditions suppressing their lytic activity. However, recent studies indicate that UV irradiated or photoinactivated HSV-1 and HSV-2, able to transform non-transformed cells, behave differently in transformed cells suppressing their transformed phenotype. Furthermore, both transforming and transformed phenotype suppressing activities are pertaining only to non-syncytial virus strains. There are some proposed mechanisms explaining their transforming activity. According to the "hit and run" mechanism, viral DNA induces only initiation of transformation by interacting with cellular DNA bringing about mutations and epigenetic changes and is no longer involved in other processes of neoplastic progression. According to the "hijacking" mechanism, virus products in infected cells may activate signalling pathways and thus induce uncontrolled proliferation. Such a product is e.g. a product of HSV-2 gene designated ICP10 that encodes an oncoprotein RR1PK that activates the Ras pathway. In two cases of cancer, in the case of serous ovarian carcinoma and in some prostate tumours, virus-encoded microRNAs (miRNAs) were detected as a possible cofactor in tumorigenesis. And, recently described herpes virus-associated growth factors with transforming and transformation repressing activity might be considered important factors playing a role in tumour formation. And finally, there is a number of evidence that HSV-2 may increase the risk of cervical cancer after infection with human papillomaviruses. A similar situation is with human cytomegalovirus; however, here, a novel mechanism named oncomodulation has been proposed. Oncomodulation means that HCMV infects tumour cells and modulates their malignant properties without having a direct effect on cell transformation.

Transformation of Cells by Photoinactivated Murine Gamma-Herpesvirus 68 during Nonproductive and Quiescent Infection.

Infection of human MRC-5 cells and mouse NIH-3T3 cells with a murine gamma-herpesvirus (MuHV-4 strain 68; MHV-68) photoinactivated by visible light in the presence of methylene blue (MB) resulted in nonproductive infection and the appearance of morphologically transformed cells. Two stably transformed cell lines were derived from both of these cell types and were confirmed to contain both viral DNA and antigen. Next, a quiescent MHV-68 infection in MRC-5 and NIH-3T3 cells was established after cultivation at 41°C in the presence of phosphonoacetic acid. Following the exposure of quiescently infected cells to visible light for 120 s (5 times daily for 6 days) in the presence of MB, both MRC-5 and NIH-3T3 cells were observed to acquire transformed phenotypes. The cytopathic effect was observed in cells after 4-5 passages, after which the cells degenerated. However, when human interferon (IFN)-α and mouse IFN-ß were added to the media of quiescently infected MRC-5 and NIH-3T3 cells during the photoinactivating procedure, 2 stable transformed cell lines containing both viral DNA and the antigen were obtained and resembled those attained following nonproductive infection with photoinactivated virus.

Murine gammaherpesvirus (MHV-68) transforms cultured cells in vitro.

Human dermal fibroblasts and mouse NIH/3T3 cells acquired the transformed phenotype ('criss-cross' pattern of growth) after infection with ultraviolet-irradiated murine gammaherpesvirus (MuHV-4 strain 68; MHV-68). These cells with changed phenotype could be serially cultured for 5-6 passages (35-40 days), and then they entered into crisis and most of them died. In a small number of cultures, however, foci of newly transformed cells appeared from which two stable cell lines were derived. After 6-9 cell culture passages of the MHV-68 transformed cell lines, MHV-68 DNA and virus antigen could be detected by PCR and immunofluorescence assay along with the disappearance of actin bundles, indicating that both transformed cell lines might be oncogenic.