Examining the Role of Murine Papillomavirus (MmuPV-1) in Skin Tumorigenesis

Background:Papillomaviruses (PVs) are species tropic double-stranded DNA viruses that have been implicated in causing several forms of cancer in humans and other animals. PVs can infect mucosal or cutaneous epithelium and their life cycle is dependent upon the epithelial differentiation program thus limiting our ability to monitor and study the progression of the disease in their natural hosts in depth. Our lab and others have extensively studied mucosotropic high-risk Human papillomaviruses (HPVs) implicated in anogenital and head and neck cancers. However, the biology and progression of skin diseases associated with their cutaneous PVs is relatively less well understood.  The recent discovery of the murine papillomavirus (MmuPV1) provides us, for the first time, a unique opportunity to define the role of PV genes in viral associated pathogenesis and life cycle in vivo, in the context of a genetically manipulatable host organism. A naturally occurring PV infection in the laboratory mice can provide a major new means for investigating the molecular pathogenesis of cutaneous papillomaviruses, which are relatively less understood. Methods: We have developed an infection model to study MmuPV1 in vivo by using MmuPV1 quasivirions developed in 293FT cells to infect mice following scarification. Virus quantification was performed by means of a Southern hybridization assay using probes specific for MmuPV1. Viral proteins and DNA have been detected in situ by immunohistochemistry methods. Results: Using different immune deficient strains of mice, we have found that complete T-cell deficiency is required for MmuPV1 induced papillomatosis. While MmuPV1 failed to induce papillomatosis in immune competent strains of mice, we have made the novel discovery that ultraviolet radiation (UVR) assists MmuPV1 in causing wart formation and squamous cell carcinoma in such mice, most likely by immunosuppression. Conclusions: That UVR assists in development of MmuPV1 dependent disease is interesting as epidemiological evidence suggests a correlation between exposure to UVR and prevalence of cutaneous HPVs in healthy and more predominantly immunocompromised patients rendering them susceptible to HPV-associated skin disease. Our studies suggest that ultraviolet radiation appears to have a systemic effect on the biology of the host making it susceptible to MmuPV induced cancers. This is a novel finding and shows that MmuPV1 infection model can be used to study infection and pathogenesis of high-risk cutaneous papillomaviruses.