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Retroviral infection of the central nervous system (CNS) causes chronic functional and morphological damage in a wide variety of mammals. Neuropathological studies have focused on subcortical pathology, however, the neocortex is also affected. Because studies of human CNS pathology have been limited to the use of material from terminal stages of disease, we used two neuropathogenic murine leukemia virus (MuLV) models to study the development of neocortical damage. MuLV infection caused spongiform change in the spinal cord, brainstem and cerebellum but not in the cerebrum. However, over the course of disease, we observed a reduction of neocortical thickness, accompanied by diminished neuronal and dendritic spine density. Electron microscopic studies showed minimal to no ultrastructural alterations of dendritic spines. Since there was no evidence of extensive direct viral infection of the neocortical neurons or glia at the ultrastructural level, we hypothesize that neocortical damage may be an indirect effect of subcortical retroviral infection. more...

Central nervous system (CNS) damage occurs during retroviral infection in both man and animals. As a model of human disease, we studied the distribution and extent of CNS damage during retroviral infection with two molecularly cloned, neurotropic murine leukemia viruses. Both viruses mediate a spongiform encephalopathy involving predominantly the brainstem and spinal cord. During the course of disease, immune reactivity for synaptophysin (SYN) (to identify presynaptic elements) and microtubule-associated protein-2 (MAP-2) (to identify postsynaptic elements) were quantified using confocal laser microscopy. Immunostaining of SYN in the cerebral cortex (an area not exhibiting spongiform lesions) was similar in viral infected and age-matched control mice. However, compared to age matched controls, SYN staining in the brainstem (an area exhibiting spongiform lesions) of viral infected mice progressively declined during the course of disease. Quantitative analysis showed greater reduction of MAP-2 immunostaining in viral-infected mice compared to age-matched controls. In infected mice, both regions with and without spongiform lesions showed diminished MAP-2 staining. Widely distributed microscopic vacuolation of dendritic processes was observed in confocal preparations. These findings suggest primary dendritic damage in murine retroviral infection of the CNS similar to what has been described in human immunodeficiency virus-1 encephalitis. more...

Murine leukemia virus infection serves as a model for noninflammatory degeneration of the central nervous system (CNS). During the course of infection with either of the molecularly cloned viruses pNE-8 or ts-1, we observed that ts-1 spread twice as rapidly as pNE-8, and ascended higher in the neuraxis. Endothelial cells were infected first, followed by oligodendrocytes and neurons, while astrocytes containing glial fibrillary acidic protein were not infected. Additionally, ts-1 also infected macrophages/microglia. Major histocompatibility complex (MHC) class I beta 2-microglobulin expression was minimal in pNE-8 infected mice, while it was elevated in endothelial cells of early ts-1 lesions, and in macrophages/microglia during later stages. Occasional infected cells expressed beta 2-microglobulin while rare endothelial and parenchymal cells expressed MHC class II in both viral infections. Limited intra-CNS MHC expression may be one of the mechanisms of viral persistence and will present a barrier to developing immunotherapy for CNS retroviral infections. The few mice that escaped lethal infection had higher serum titers of neutralizing antibodies and showed no neuropathologic changes or detectable virus in the CNS. Higher titers of neutralizing antibodies may protect the CNS from infection. more...