TR1.3 viral pathogenesis and syncytium formation are linked to Env-Gag cooperation.
Infection with murine leukemia virus (MLV) TR1.3 or the related molecular construct W102G causes severe neuropathology in vivo. Infection is causally linked to the development of extensive syncytia in brain capillary endothelial cells (BCEC). These viruses also induce cell fusion of murine cell lines, such as SC-1 and NIH 3T3, which are otherwise resistant to MLV-induced syncytium formation. Although the virulence of these viruses maps within the env gene, the mechanism of fusion enhancement is not fully determined. To this end, we examined the capacity of the syncytium-inducing (SI) TR1.3 and W102G MLVs to overcome the fusion inhibitory activity inherent in the full-length Env cytoplasmic tail. These studies showed that the TR1.3 and W102G Envs did not induce premature cleavage of p2E, nor did they override p2E fusion inhibition. Indeed, in the presence of mutations that disrupt p2E function, the TR1.3 and W102G Envs significantly increased the extent of cell fusion compared to that with the non-syncytium-inducing MLV FB29. Surprisingly, we also observed that TR1.3 and W102G Envs failed to elicit syncytium formation in these in vitro assays. Coexpression of gag-pol with env restored syncytium formation, and accordingly, mutations within gag-pol were used to examine the minimal functional requirements for the SI phenotype. The results indicate that both gag-dependent particle budding and cleavage of p2E are required to activate the SI phenotype of TR1.3 and W102G viruses. Collectively, these data suggest that the TR1.3 and W102G viruses induce cell fusion by the fusion-from-without pathway.
Murphy
Samuel L
SL
The Children's Hospital of Philadelphia, and Department of Pathology and Laboratory Medicine, University of Pennsylvania, 354 BRB II/III, 421 Curie Blvd., Philadelphia, PA 19104-6142, USA.
Gaulton
Glen N
GN
D000818:Animals; D002478:Cells, Cultured; D015685:Fusion Proteins, gag-pol / Q000378:metabolism; D015686:Gene Products, env / Q000235:genetics / Q000378:metabolism*; D015683:Gene Products, gag / Q000235:genetics / Q000378:metabolism*; D015726:Giant Cells / Q000821:virology*; D009052:Leukemia Virus, Murine / Q000235:genetics / Q000378:metabolism / Q000472:pathogenicity*; D008561:Membrane Fusion; D051379:Mice; D009154:Mutation
D015685:Fusion Proteins, gag-pol; D015686:Gene Products, env; D015683:Gene Products, gag