The year 2011 marks the centenary of Francis Peyton Rous's landmark experiments on an avian cancer virus. Since then, seven human viruses have been found to cause 10-15% of human cancers worldwide. Viruses have been central to modern cancer research and provide profound insights into both infectious and non-infectious cancer causes. This diverse group of viruses reveals unexpected connections between innate immunity, immune sensors and tumour suppressor signalling that control both viral infection and cancer. This Timeline article describes common features of human tumour viruses and discusses how new technologies can be used to identify infectious causes of cancer.

/pdf/why-do-viruses-cause-cancer-highlights-of-the-first-century-1zuyx05nsp.pdf

Why do viruses cause cancer? Highlights of the first century of human tumour virology

Plaque assays in cell culture monolayers under solid or semisolid overlay media are commonly used for quantification of viruses and antiviral substances. To overcome the pitfalls of known overlays, we tested suspensions of microcrystalline cellulose Avicel RC/CL™ as overlay media in the plaque and plaque-inhibition assay of influenza viruses. Significantly larger plaques were formed under Avicel-containing media, as compared to agar and methylcellulose (MC) overlay media. The plaque size increased with decreasing Avicel concentration, but even very diluted Avicel overlays (0.3%) ensured formation of localized plaques. Due to their low viscosity, Avicel overlays were easier to use than methylcellulose overlays, especially in the 96-well culture plates. Furthermore, Avicel overlay could be applied without prior removal of the virus inoculum thus facilitating the assay and reducing chances of cross-contamination. Using neuraminidase inhibitor oseltamivir carboxylate, we demonstrated applicability of the Avicel-based plaque reduction assay for testing of antiviral substances. Plaque assay under Avicel-containing overlay media is easier, faster and more sensitive than assays under agar- and methylcellulose overlays. The assay can be readily performed in a 96-well plate format and seems particularly suitable for high-throughput virus titrations, serological studies and experiments on viral drug sensitivity. It may also facilitate work with highly pathogenic agents performed under hampered conditions of bio-safety labs.

/pdf/new-low-viscosity-overlay-medium-for-viral-plaque-assays-1xupwqqmol.pdf

New low-viscosity overlay medium for viral plaque assays

Epstein Barr virus (EBV)+ Hodgkin's disease (HD) expresses clearly identified tumor antigens derived from the virus and could, in principle, be a target for adoptive immunotherapy with viral antigen-specific T cells. However, like most tumor-associated antigens in immunocompetent hosts, these potential targets are only weakly immunogenic, consisting primarily of the latent membrane protein (LMP)1 and LMP2 antigens. Moreover, Hodgkin tumors possess a range of tumor evasion strategies. Therefore, the likely value of immunotherapy with EBV-specific cytotoxic effector cells has been questioned. We have now used a combination of gene marking, tetramer, and functional analyses to track the fate and assess the activity of EBV cytotoxic T lymphocyte (CTL) lines administered to 14 patients treated for relapsed EBV+ HD. Gene marking studies showed that infused effector cells could further expand by several logs in vivo, contribute to the memory pool (persisting up to 12 mo), and traffic to tumor sites. Tetramer and functional analyses showed that T cells reactive with the tumor-associated antigen LMP2 were present in the infused lines, expanded in peripheral blood after infusion, and also entered tumor. Viral load decreased, demonstrating the biologic activity of the infused CTLs. Clinically, EBV CTLs were well tolerated, could control type B symptoms (fever, night sweats, and weight loss), and had antitumor activity. After CTL infusion, five patients were in complete remission at up to 40 mo, two of whom had clearly measurable tumor at the time of treatment. One additional patient had a partial response, and five had stable disease. The performance and fate of these human tumor antigen-specific T cells in vivo suggests that they might be of value for the treatment of EBV+ Hodgkin lymphoma.

/pdf/cytotoxic-t-lymphocyte-therapy-for-epstein-barr-virus-1755t7ckit.pdf

Cytotoxic T lymphocyte therapy for epstein-barr virus+ Hodgkin's disease

The non-Hodgkin lymphomas (NHL) are a heterogeneous group of B-cell and T-cell neoplasms that arise primarily in the lymph nodes NHL incidence rates in the US doubled between about 1970 and 1990, and stabilized during the 1990s NHL accounts for approximately 34% of cancer deaths in the US Although some of the observed patterns in NHL have been related to HIV/AIDS, these conditions cannot fully explain the magnitude of the changes; neither do changes in classification systems nor improved diagnostic capabilities Studies of occupational and environmental exposures (eg, pesticides, solvents) have produced no consistent pattern of significant positive associations Inverse associations with ultraviolet radiation exposure and alcohol and fish intake, and positive associations with meat and saturated fat intake have been reported in several studies; additional studies are needed to confirm or refute these associations Family history of NHL or other hematolympho-proliferative cancers and personal history of several autoimmune disorders are associated with increased risk of NHL, but are not likely to account for a large proportion of cases HIV and other infectious agents, such as human herpesvirus 8 and Epstein-Barr, appear to be associated with differing types of NHL, such as some B-cell lymphomas Future epidemiologic studies should evaluate associations by NHL type, enhance exposure information collected, and elucidate factors that may identify susceptible (or resistant) subpopulations because of genetic, immunologic or other characteristics The extent to which the etiology of NHL types may differ is important to resolve in ongoing and future studies

https://onlinelibrary.wiley.com/doi/pdf/10.1002/ijc.22719

The non‐Hodgkin lymphomas: A review of the epidemiologic literature

Complete responses of relapsed lymphoma following genetic modification of tumor-antigen presenting cells and T-lymphocyte transfer.

Human herpesvirus 8 (HHV-8) sensitivity to the nucleoside analog ganciclovir (GCV) suggests the presence of a virally encoded kinase that catalyzes the initial phosphorylation of GCV. Analysis of the HHV-8 genome identified two candidate kinases: proteins encoded by open reading frame (ORF) 21, with homology to the herpesvirus thymidine kinases (TK), and ORF 36, with homology to the herpesvirus phosphotransferases (PT). Experiments presented here show that both ORF 21 and ORF 36 encode GCV kinase activities as demonstrated by GCV phosphorylation and GCV-mediated cell death. In both regards the PT homologue ORF 36 was more active than the TK homologue ORF 21. ORF 21, but not ORF 36, weakly sensitized cells to killing by penciclovir. Neither ORF sensitized cells to killing by (E)-5-(2-bromovinyl)-2*-deoxyuridine. Human herpesvirus 8 (HHV-8) is a gammaherpesvirus found in Kaposi’s sarcoma (KS), primary effusion lymphoma (PEL), and in some cases of multicentric Castleman’s disease (10, 14, 15). The spectrum of sensitivity of HHV-8 to antiviral agents most closely resembles that of human cytomegalovirus (HCMV) (2, 24, 45). HHV-8 replication in PEL-derived cell lines is inhibited by ganciclovir (GCV), foscarnet, and cidofovir and to a much lesser extent by penciclovir (PCV) and (E)-5(2-bromovinyl)-29-deoxyuridine (BVDU) (33, 41, 46). Acyclovir (ACV) is inactive. Retrospective studies of cohorts of AIDS patients suggest that both GCV and foscarnet reduce the risk of KS, while ACV has no similar protective effect (25, 43). The nucleoside analogs GCV, PCV, BVDU, and ACV are activated by phosphorylation (7, 40). Two herpesvirus kinase gene families have been identified that activate these compounds. The herpes simplex virus (HSV) thymidine kinase (TK) and HCMV UL97 are prototypes of the TK and phosphotransferase (PT) gene families, respectively. Alpha- and gammaherpesviruses encode members of both families, while betaherpesviruses encode only a PT.

Human herpesvirus 8-encoded thymidine kinase and phosphotransferase homologues confer sensitivity to ganciclovir.

Epstein—Barr virus has been associated with a variety of malignancies. Originally discovered in African Burkitt’s lymphoma, it is also found in lymphoproliferative disease arising in immunocompromised populations, in Hodgkin’s disease, and in peripheral T-cell lymphoma. The association is of interest in terms of the pathogenesis of these tumors and is becoming important in terms of new approaches to treatment. The purpose of this chapter is to review aspects of the biology of the virus that are relevant to tumorigenesis, review the nature of the association with each of the tumors, and to consider therapeutic implications where these have been defined.

Epstein-Barr virus and lymphoma.

Epstein-Barr virus as a therapeutic target in Hodgkin's disease and nasopharyngeal carcinoma.

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Human herpesvirus 8-encoded thymidine kinase and phosphotransferase homologues confer sensitivity to ganciclovir.

Epstein-Barr virus and lymphoma.

Epstein-Barr virus as a therapeutic target in Hodgkin's disease and nasopharyngeal carcinoma.