TEMPORAL CENTRAL AND PERIPHERAL NERVOUS-SYSTEM CHANGES INDUCED BY A PARALYTOGENIC MUTANT OF MOLONEY MURINE LEUKEMIA-VIRUS TB

BACKGROUND: The temporal localization of cellular targets for viral re plication and the morphopathogenesis of neurodegeneration in the centr al nervous system (CNS) and peripheral nervous system induced by ts1, a neuropathogenic and lymphocytopathic mutant of Moloney murine leukem ia virus-TB, were studied in the highly susceptible FVB/N mouse strain in order to better understand the mechanisms of this neurodegenerativ e disease. EXPERIMENTAL DESIGN: Newborn FVB/N mice were inoculated int raperitoneally with 0.1 mi of viral suspension containing 10(6) to 10( 7) infectious units/ml. The mice were observed daily for clinical sign s of disease and killed at specific time points. Their nervous system tissues were collected and processed for light and electron microscopy and for immunohistochemical viral-antigen detection. RESULTS: ts1-Inf ected FVB/N mice developed a rapidly progressive wasting disease that culminated in hindleg paralysis or paraplegia 30 to 35 days postinocul ation (pi). CONCLUSIONS: Clear evidence of CNS lesions involving the c erebellar ventricular system, the grey and white matter of the brain s tem and the spinal cord were seen as early as 5 to 10 days pi. These l esions, which began as mild perivascular and paraventricular neuropil spongiform changes and cytoplasmic vacuolation of neuronal and glial c ell processes, progressed in severity with time and culminated in almo st complete destruction of the white and gray matter in the brain stem and the cervical and lumbar spinal cord. Viruses were detected as ear ly as 5 to 10 days pi in the fourth ventricle choroid plexus and ventr icular lumen and budding from endothelial cells within the brain stem and cerebellum. Endothelial, ependymal, microglial, astroglial, and ol igodendroglial cells were positive for gp70(env). Astroglial and micro glial cell proliferation with microglial syncytia formation was detect ed only within the areas showing spongiform degeneration. Viral replic ation was consistently high in the capillary endothelial cells of thos e areas showing spongiform degeneration, whereas in the glial cells, r elatively few budding viruses were present. Neurodegeneration was acco mpanied by demyelinization within the CNS and peripheral nervous syste m and by hindleg muscle degeneration and necrosis. Multiple cellular t argets for ts1 viral infection and replication were detected within th e nervous system. The presence of budding virus and the immunodetectio n of viral antigen in the choroid plexus and ependymal cells of the fo urth ventricle and the central cabal of the spinal cord demonstrated t hat cerebrospinal fluid as well as blood can disseminate virus within the CNS. Pathologic and functional changes within the blood-brain barr ier and glial system probably account for the neuronal necrosis and sp ongiform changes that result in paralysis induced by ts1 infection.