DELETIONS IN ONE DOMAIN OF THE FRIEND VIRUS-ENCODED MEMBRANE GLYCOPROTEIN OVERCOME HOST-RANGE RESTRICTIONS FOR ERYTHROLEUKEMIA

Although the Friend virus-encoded membrane glycoprotein (gp55) activat es erythropoietin receptors (EpoR) to cause erythroblastosis only in c ertain inbred strains of mice but not in other species, mutant viruses can overcome aspects of mouse resistance. Thus, mice homozygous for t he resistance allele of the Fv-2 gene are unaffected by gp55 but are s usceptible to mutant glycoproteins that have partial deletions in thei r ecotropic domains. These and other results have suggested that prote ins coded for by polymorphic Fv-2 alleles might directly or indirectly interact with EpoR and that changes in gp55 can overcome this defense ; A new viral mutant with an exceptionally large deletion in its ecotr opic domain is now also shown to overcome Fv-2(rr) resistance. In all cases, the glycoproteins that activate EpoR are processed to cell surf aces as disulfide-bonded dimers. To initiate analysis of nonmurine res istances, we expressed human EpoR and mouse EpoR in the interleukin 3- dependent mouse cell line BaF3 and compared the abilities of Friend vi rus-encoded glycoproteins to convert these cells to growth factor inde pendence. Human EpoR was activated in these cells by erythropoietin bu t was resistant to gp55. However, human EpoR was efficiently activated in these cells by the same viral mutants that overcome Fv-2(rr) resis tance in mice. By construction and analysis of human-mouse EpoR chimer as, we obtained evidence that the cytosolic domain of human EpoR contr ibutes to its resistance to gp55 and that this resistance is mediated by accessory cellular factors. Aspects of host resistance in both muri ne and nonmurine species are targeted specifically against the ecotrop ic domain of gp55.