Differential glycosylation of the Cas-Br-E Env protein is associated with retrovirus-induced spongiform neurodegeneration

The wild mouse ecotropic retrovirus, Cas-Br-E, induces progressive, noninfl ammatory spongiform neurodegenerative disease in susceptible mice. Function al genetic analysis of the Cas-Br-E genome indicates that neurovirulence ma ps to the env gene, which encodes the surface glycoprotein responsible for binding and fusion of virus to host cells, To understand how the envelope p rotein might be involved in the induction of disease? we examined the regio nal and temporal expression of Cas-Br-E Env protein in the central nervous systems (CNS) of mice infected Kith the highly neurovirulent chimeric virus FrCas(E). We observed that multiple isoforms of Cas-Br-E Ene were expresse d in the CNS, dth different brain regions exhibiting unique patterns of pro cessed Env glycoprotein. Specifically, the expression of gp70 correlated wi th regions showing microglial infection and spongiform neurodegeneration, I n contrast, regions high in neuronal infection and without neurodegenerativ e changes (the cerebellum and olfactory bulb) were characterized by a gp65 Env protein isoform, Sedimentation analysis of brain region extracts indica ted that gp65 rather than gp70 was Incorporated into virions, Biochemical a nalysis of the Cas-Br-E Env isoforms indicated that they result from differ ential processing of N-linked sugars. Taken together, these results indicat e that differential posttranslational modification of the Cas-Br-E Env is a ssociated with a failure to incorporate certain Env isoforms into virions i n vivo, suggesting that defective viral assembly may be associated dth the induction of spongiform neurodegeneration.