Development of spongiform encephalopathy in retroviral infected mice.

The Cas-Br-E strain of murine leukemia virus is a neurovirulent retrovirus that induces progressive noninflammatory degeneration of the central nervous system (CNS). The molecular clone pNE-8 retains pathogenic properties of Cas-Br-E. The neurotropic determinants are known; however, the mechanism of neuropathogenesis is unknown. We examined the temporal development of disease after infection of SWR/J mice with pNE-8 virus. Development of CNS lesions, cellular targets of viral replication, accumulation of ubiquitinated proteins and integrity of blood-brain barrier were determined in mice infected with pNE-8 virus; and compared with uninfected, sham-infected, and nonneuropathogenic virus-infected mice. During 24 weeks of pNE-8 infection, noninflammatory spongiform lesions developed initially in the lumbar spinal cord and progressed to involve the brainstem and deep cerebellar nuclei. Virions and viral antigens accumulated for 18 weeks postinfection and then declined. Major sites of viral infection outside the CNS were splenic megakaryocytes, and skeletal muscle. Cellular targets of viral replication in the CNS included neurons, oligodendrocytes, and capillary endothelium. No astrocytic infection was observed; however, a reactive gliosis marked the development of clinical symptoms and histopathology. Spongiform lesions began as swelling of perivascular astrocytic processes. Intramyelinic vacuoles with splitting of myelin at major dense lines were prominent around dystrophic axons at later time points. Dendritic processes showed vacuolization and local degeneration. Viral particles were most commonly observed in extracellular spaces and within rough endoplasmic reticulum of neurons, oligodendrocytes, and splenic megakaryocytes. Infected megakaryocytes and regions of spleen containing viral aggregates showed accumulation of ubiquitinated proteins. Areas of histopathology in the CNS showed accumulation of ubiquitinated proteins but unlike spleen, viral proteins were not highly ubiquitinated. Disruption of the blood brain barrier was only evident at late stages of infection. In conclusion, the neuropathogenic damage associated with pNE-8 infection appears to be tightly associated with direct viral infection of oligodendroglia and neurons.