Truncation of the enzootic nasal tumor virus envelope protein cytoplasmic tail increases Env-mediated fusion and infectivity

Enzootic nasal tumor virus (ENTV) and Jaagsiekte sheep retrovirus (JSRV) are highly related ovine betaretroviruses that induce nasal and lung tumours in small ruminants, respectively. While the ENTV and JSRV envelope (Env) glycoproteins mediate virus entry using the same cellular receptor, the glycosylphosphatidylinositol-linked protein hyaluronoglucosaminidase, ENTV Env pseudovirions mediate entry into cells from a much more restricted range of species than do JSRV Env pseudovirions. Unlike JSRV Env, ENTV Env does not induce cell fusion at pH 5.0 or above, but rather requires a much lower pH (4.0-4.5) for fusion to occur. The cytoplasmic tail of retroviral envelope proteins is a key modulator of envelope-mediated fusion and pseudotype efficiency, especially in the context of virions composed of heterologous Gag proteins. Here we report that progressive truncation of the ENTV Env cytoplasmic tail improves transduction efficiency of pseudotyped retroviral vectors and that complete truncation of the ENTV Env cytoplasmic tail increases transduction efficiency to wild-type JSRV Env levels by increasing fusogenicity without affecting sensitivity to inhibition by lysosomotropic agents, subcellular localization or efficiency of inclusion into virions. Truncation of the cytoplasmic domain of ENTV Env resulted in a significant advantage in viral entry into all cell types tested, including foetal ovine lung and nasal cells. Taken together, we demonstrate that the cytoplasmic tail modulates the fusion activity of the ENTV Env protein and that truncation of this region enhances Eenv-mediated entry into target cells.