Three factors contribute to the observed variations in host range and/or cytopathicity of mouse ecotropic gammaretroviruses: specific sequence differences in the viral env, differences in the CAT-1 receptor, and glycosylation of cellular proteins. The role of specific env sequence variations in virus-induced syncytium formation was previously suggested by our identification of two MLV isolates that are uniquely cytopathic in M. dunni cells. Both isolates have amino acid substitutions at the same RBD residue that is critical for receptor binding: S82F in Spl574 and S84A in F-S MLV. That mutations in the viral receptor binding site contribute to cytopathicity is also supported by the observation that a third MLV variant, TR1.3, is cytopathic in SC-1 cells and brain endothelial cells because of a single substitution, W102G [13] , at a site that together with S82 and D84 forms the receptor binding site [3, 4] .