KINETIC-ANALYSIS OF SPONGIFORM NEURODEGENERATIVE DISEASE INDUCED BY AHIGHLY VIRULENT MURINE RETROVIRUS

BACKGROUND: A chimeric murine retrovirus, FrCas(E), causes a rapid non inflammatory spongiform neurodegenerative disease of the motor system with an incubation period of 15 to 16 days after neonatal inoculation. Neurovirulence is determined by the viral envelope gene, but the neur odegeneration is an indirect consequence of virus infection, because t he neurons that degenerate appear not to be infected. EXPERIMENTAL DES IGN: The current study was undertaken to compare the kinetics of lesio n development and the expression of viral envelope protein in the cent ral nervous system (CNS). Neonatal mice were inoculated with FrCas(E) intraperitoneally and were killed at various times for determination o f the kinetics of the CNS infection, the distribution of lesion in the CNS, and the distribution of viral envelope protein. In addition, qua litative features of both viral envelope and gag proteins were followe d by immunoblot analysis. RESULTS: The lesions induced by FrCas(E) con sisted of vacuolar degeneration but without associated astrocytosis, t he lack of an astroglial response being a consequence of the rapidity of the disease process. Vacuoles were observed primarily in the neurop il of the motor centers of spinal cord, brain stem, and cerebral corte x. Lesions appeared in all of these areas during a narrow window of ti me (less than or equal to 3 days). Cells in which viral envelope prote in was detected by immunohistochemistry before the appearance of spong iform degeneration included premigratory cerebellar cortical granule n eurons as well as vascular elements in the regions that would ultimate ly exhibit spongiform degeneration. Two forms of viral envelope protei n were detected in the CNS. A 70-kilodalton species appeared first, fo llowed by an approximately 64-kilodalton species, which was detected c oincident with the first appearance of spongiform lesions. CONCLUSIONS : Astrocytosis is a secondary reaction to the neuronal cytopathology i nduced by FrCas(E) and appears to be dependent on the developmental st ate of the CNS. The abrupt, diffuse nature of lesion development in th is disease suggests a global effect of the virus infection. Cells of t he CNS vasculature (either endothelial cells, perivascular microglial cells, or both) as well as cerebellar granule neurons appear to be sem inally involved in the pathogenesis of the spongiform degeneration. Th e two species of viral envelope protein appear to be expressed by diff erent cell types in the CNS.