Pathogenesis of ovine betaretroviruses

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Animal models of retrovirus-induced tumors have provided us with much of the foundation for our current understanding of oncogenesis. This proposal focuses on two economically important oncogenic ovine retroviruses, jaagsiekte sheep retrovirus (JSRV), which is the etiologic agents of ovine pulmonary adenocarcinoma, and enzootic nasal tumor virus (ENTV), which is associated with enzootic nasal adenocarcinoma. JSRV and ENTV are unique among oncogenic retroviruses as they are the only retroviruses known to infect the respiratory tract and, unlike most replication-competent retroviruses, which cause cancer by insertional activation of cellular proto-oncogenes or through acquisition of cellular proto-oncogenes, the envelope (Env) protein of JSRV and ENTV is oncogenic and thus represents a unique mechanism of transformation. Several signalling pathways have been implicated in Env-mediated transformation and the cytoplasmic tail (CT), in particular YxxØ motifs in this region, are essential for transformation. Most retroviral Env proteins harbor YxxØ motifs in their CT that act as endocytosis, intracellular targeting, or virion incorporation signals. How YxxØ motifs contribute to transformation by JSRV and ENTV Env is not known. 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. Given the high nucleotide identity shared between these two viruses, this provides an unique system for studying determinants of disease tropism especially because our research efforts suggest that neither the LTR nor the Env alone dictate tropism. For these reasons we propose experiments to investigate the determinants of disease tropism, and to ascertain the role of Env binding partners and motifs within the CT of Env in cellular transformation, virus entry, and virus assembly. It is anticipated that this research program will contribute to our understanding of virally-induced cancers, uncover a potentially novel mechanism for retrovirus assembly, and shed light on mechanisms governing neoplastic transformation of respiratory epithelium.