Pathogenesis of enzootic nasal tumor virus (ENTV)

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Animal models of retrovirus-induced tumors have provided us with much of the foundation for our current understanding of the oncogenic process. Two economically important retroviruses associated with tumors of secretory respiratory epithelial cells are the Jaagsiekte sheep retrovirus (JSRV) and Enzootic nasal tumor virus (ENTV) of sheep and goats. While JSRV and ENTV are highly related betaretroviruses that utilize the same cell surface receptor for virus entry, they have distinct tumor-inducing capabilities. JSRV transforms alveolar type II pneumocytes, while ENTV transforms nasal epithelial cells. The reason for this is not known. This proposal addresses the hypothesis that induction of tissue-specific tumor formation in the ovine host is either a function of cell-restricted activity of the long terminal repeat (LTR) or due to the fact that ENTV and JSRV require a coreceptor for virus entry and differences in affinity or coreceptor usage determines cellular tropism. To address these hypotheses, a molecular clone of ENTV will be constructed and used to generate infectious virus for in vivo studies. Upon demonstration that ENTV is the etiologic agent of enzootic nasal adenocarcinoma, a series of chimeric viruses generated via the exchange of genetic material between JSRV and ENTV will be constructed and used to map genetic elements responsible for tissue-specific tumor formation. Specifically, the potential for coreceptor usage and restricted LTR activity will be addressed in these experiments. It is anticipated that this research program will contribute to our understanding of virally-induced cancers, uncover a potentially novel mechanism for retrovirus entry, and shed light on the mechanisms governing neoplastic transformation of secretory respiratory epithelial cells. Currently, no antemortem diagnostic tools are available for ENTV. Therefore, creating an animal model for ENTV infection allows for analysis of the cellular and tissue distribution of ENTV and subsequent identification of sensitive template sources for ENTV nucleic acid amplification. PCR-based diagnostic assays could then be developed and implemented in test and removal programs aimed at eradicating ENTV from Canadian sheep and goat flocks.