The Pathogenesis of Murine Retroviral Infection of the Central Nervous System

Abstract

Several decades have lapsed since the original description of retroviral infection of the central nervous system (CNS) appeared. With the recent arrival of the autoimmune deficiency syndrome (AIDS) epidemic and the associated human retroviral encephalitis, interest in murine models has been rekindled. In most of the published studies, susceptible mouse strains are infected as neonates with molecularly cloned type-C retroviruses. In most models, a spongiform encephalopathy follows an early CNS endothelial cell infection. The subsequent pathogenesis of this encephalopathy is unknown. In some models neuronal and glial infection is seen, while in others only non-neuroglial elements are infected. This variation can be traced to differences in strains of mice and viruses in addition to differences in assays. The different models offer fertile experimental ground to decipher the role of direct versus indirect neuroglial damage. Reconciliation of these various models where the final neuropathology appears so similar, may be the key to understanding their pathogenesis.

Disparate Regions of Envelope Protein Regulate Syncytium Formation versus Spongiform Encephalopathy in Neurological Disease Induced by Murine Leukemia Virus TR

“…This surprising discovery allowed us to map sequences that regulate acute vascular disease versus neuronal degeneration on a common genetic background. The non-syncytium-forming molecular clone TRM induced a noninflammatory spongiform encephalopathy that appears remarkably similar to that previously described for other neuropathogenic MLV (54).…”

“…Although there is scant evidence for direct infection of affected neurons, multiple other CNS cell types are infected by MLV (54). Thus, it is important to clarify whether infection of these cells triggers a common cascade of events that lead to neuronal degeneration or virus strain-specific inductive events.…”

“…MLV model systems provide important tools to dissect fundamental questions of CNS tropism, cell and tissue pathology, and the impact of the viral genome on disease type and course (54). A number of MLV strains have been utilized in this approach, and our laboratory has focused studies on the MLV TR1.3 (4,(35)(36)(37)(38).…”

“…Murine leukemia viruses (MLV) provide a facile system for analysis of the complicated dynamics of retrovirus infections in the CNS (20,28,41,52). MLV induce a variety of neurological deficiencies depending on the virus isolate and mouse strain (54). One common pathological feature is the induction of spongiform encephalomyelopathy in the CNS and linked deterioration of peripheral motor function (10,11,17,25,34,54); characteristic examples of this include infection of mice with CasBrE, FrCasE, or Moloney ts1 virus (7,33,56) and of rats with PVC-211, NT-40, or A8 virus (5,18,50).…”

Viral load and its relationship to quinolinic acid, TNFα, and IL-6 levels in the CNS of retroviral infected mice

“…Both viruses cause a chronic spongiform change predominantly involving brainstem and spinal cord. Unfortunately, there is substantial controversy regarding what cells are infected in these models (Wiley and Gardner, 1993). This has led several groups to suggest that the pathogenesis of the murine neurologic disease may involve either direct infection of neuronal and glial elements, or indirect effects of toxic factors secreted by infected or affected cells.…”