Pathogenesis of ovine betaretroviruses

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The study of oncogenic retroviruses has contributed significantly to our understanding of the genetic and molecular basis of cancer and research in this area continues to reveal new insights into fundamental cellular processes. My research program aims to uncover novel and potentially transformative concepts in retroviral pathogenesis by studying cell entry and oncogenesis of ovine betaretroviruses. Jaagsiekte sheep retrovirus (JSRV) and enzootic nasal tumor virus (ENTV), the etiologic agents of ovine pulmonary adenocarcinoma (OPA) and enzootic nasal adenocarcinoma (ENA), respectively, are unique among oncogenic retroviruses. They are the only retroviruses known to infect the respiratory tract and unlike most replication-competent oncogenic retroviruses, which cause cancer by insertional activation of cellular proto-oncogenes or through acquisition of cellular proto-oncogenes, the envelope (Env) glycoproteins of JSRV and ENTV function as potent oncogenes representing an entirely novel mechanism of viral transformation. Several signal transduction pathways have been implicated in Env-mediated transformation and it is known that the cytoplasmic tail (CT) and specifically YxxØ motifs within this region are critical for transformation. However, it is still not clear what cellular proteins interact with the JSRV and ENTV Env proteins to induce cellular transformation in vitro or tumor formation in animals nor is it known how YxxØ motifs in the JSRV and ENTV Env CT contribute to transformation. Moreover, while JSRV and ENTV are highly related retroviruses that utilize the same cell surface receptor for virus entry, they have distinct tumor-inducing capabilities and the reason for this is not known. The long-term objective of my research program, therefore, is a clearer understanding of the molecular mechanisms involved in the induction of lung and nasal cancer by JSRV and ENTV, with particular attention to the role of Env in cellular transformation and tissue tropism. My short-term objectives are to answer the following questions: 1) What role do YxxØ motifs play in Jenv- and Eenv-mediated transformation? 2) How do proteins that interact with Jenv and Eenv function to promote cellular transformation? 3) What region of the viral genome is responsible for the distinct tissue tropism of JSRV and ENTV? 4) Does ENTV utilize a co-receptor to mediate virus attachment and entry? ******This research program combines expertise with large animal models uniquely available at the Ontario Veterinary College with molecular virology approaches to yield an understanding of the mechanisms of viral transformation in distinct epithelial cell populations. This research is poised to uncover novel mechanisms for betaretrovirus tropism and entry and may reveal potential targets for therapeutic intervention in the treatment of respiratory epithelial cancers of animals and humans.