Betaretroviruses of sheep include two exogenous viruses, Jaagsiekte sheep retrovirus (JSRV) and enzootic nasal tumor virus (ENTV), and a group of endogenous viruses known as enJSRVs. The exogenous JSRV and ENTV are the etiological agents of ovine pulmonary adenocarcinoma (OPA) and enzootic nasal tumor (ENT), respectively. Sheep affected by OPA or ENT do not show an appreciable antibody response to JSRV or ENTV. Consequently, it is conceivable that enJSRV expression in the fetal lamb tolerizes sheep to the related exogenous viruses. In this study, possible mechanisms of interference between the sheep exogenous and endogenous betaretroviruses were investigated. In situ hybridization detected enJSRV RNAs in lymphoid cells associated with the lamina propria of the small intestine and in the thymus of sheep fetuses. Low-level expression of enJSRVs was also detected in the lungs. In addition, expression of enJSRVs was found to block entry of the exogenous JSRV, presumably via mechanisms of receptor interference. Indeed, enJSRVs, like JSRV and ENTV, were found to utilize hyaluronidase-2 as a cellular receptor.The ability of retroviruses to integrate in the host cell genome has provided a means for these viruses to colonize during the evolution of the genome of virtually all vertebrates. Consequently, retroviruses are transmitted horizontally as "exogenous" viruses or vertically as "endogenous" viruses (28). The majority of endogenous retroviruses have accumulated deletions and/or mutations that render them inactive. However, some endogenous retroviruses are transcriptionally active, and both detrimental and beneficial effects to the host have been hypothesized and, more rarely, substantiated (2-4, 14, 15).Several exogenous retroviruses have endogenous counterparts. For example, feline leukemia virus in cats, mouse mammary tumor virus and murine leukemia viruses (MLVs) in mice, and avian leukemia viruses in chickens have endogenous counterparts in the germ line of their host species (4).The exogenous sheep betaretroviruses, Jaagsiekte sheep retrovirus (JSRV) and enzootic nasal tumor virus (ENTV), are pathogenic viruses that cause neoplasms in the respiratory tract of small ruminants (8,18,19). JSRV induces ovine pulmonary adenocarcinoma (OPA), a contagious lung tumor of sheep originating from the differentiated epithelial cells of the distal tract of the lung (23). ENTV causes the enzootic nasal tumor of sheep and goats, wherein the tumor originates from the olfactory mucosa of the nasal or ethmoid turbinates (5-7).Fifteen to 20 copies of endogenous elements related to JSRV and ENTV (enJSRVs) are present in the genome of sheep, goats, and most wild members of the Ovis and Capra genera (11,12,29). Interestingly, enJSRVs are highly expressed along the epithelium of the genital tract of the ewe and, in particular, in the luminal and glandular epithelia of the endometrium of the uterus (20,21,26). The fixation of these elements in the ovine and caprine genome, combined with their high levels of expression, suggest that thes...