Brain Infection by Neuroinvasive but Avirulent Murine Oncornaviruses

Abstract

The chimeric murine oncornavirus FrCas E causes a rapidly progressive noninflammatory spongiform encephalomyelopathy after neonatal inoculation. The virus was constructed by the introduction of pol-env sequences from the wild mouse virus CasBrE into the genome of a neuroinvasive but nonneurovirulent strain of Friend murine leukemia virus (FMuLV), FB29. Although the brain infection by FrCas E as well as that by other neurovirulent murine retroviruses has been described in detail, little attention has been paid to the neuroinvasive but nonneurovirulent viruses. The purpose of the present study was to compare brain infection by FrCas E with that by FB29 and another nonneurovirulent virus, F43, which contains pol-env sequences from FMuLV 57. Both FB29 and F43 infected the same spectrum of cell types in the brain as that infected by FrCas E , including endothelial cells, microglia, and populations of neurons which divide postnatally. Viral burdens achieved by the two nonneurovirulent viruses in the brain were actually higher than that of FrCas E . The widespread infection of microglia by the two nonneurovirulent viruses is notable because it is infection of these cells by FrCasE which is thought to be a critical determinant of its neuropathogenicity. These results indicate that although the sequence of the envelope gene determines neurovirulence, this effect appears to operate through a mechanism which does not influence either viral tropism or viral burden in the brain. Although all three viruses exhibited similar tropism for granule neurons in the cerebellar cortex, there was a striking difference in the distribution of envelope proteins in those cells in vivo. The FrCas E envelope protein accumulated in terminal axons, whereas those of FB29 and F43 remained predominantly in the cell bodies. These observations suggest that differences in the intracellular sorting of these proteins may exist and that these differences appear to correlate with neurovirulence.

Ecotropic Murine Leukemia Virus Infection of Glial Progenitors Interferes with Oligodendrocyte Differentiation: Implications for Neurovirulence

“…Nonetheless, we did observe that Env expression in mTom ϩ astrocytes varied between cells, raising the possibility that virus expression could be suppressed with cellular differentiation. Given that astrocyte virus expression associated with neurodegeneration has only rarely been observed in animals infected with CasBrE-related viruses (14,20,22), these findings suggest that a complex interplay between virus and progenitor cell differentiation occurs within the CNS and thus warrants a more comprehensive qualitative and quantitative assessment.…”

“…NVs and nonneurovirulent MLVs (NNs) with the same host range show no CNS cellular-tropism differences (14,(20)(21)(22), indicating that neurodegeneration results from the expression of unique neurovirulent Env conformers within one or more neuronal support cells. The questions of which neural cells are important and how they alter neuronal function remain largely unresolved.…”

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

“…However, glial tropism is not itself sufficient to induce disease as the MLV F43 replicates in microglial cells without apparent pathology (1).…”

Characterization of a Novel Murine Retrovirus Mixture That Facilitates Hematopoiesis

“…The following antibodies (Abs) were used to stain cell lines and cell suspensions from mouse spleens: MAb 48, specific for Rauscher and Friend ecotropic MuLVs (12, 13) (ATCC); MAb 514, specific for MCF MuLVs (12) (ATCC); MAb 603, specific for xenotropic MuLV (42); and goat anti-F-MuLV gp70 polyclonal serum (1). FITC-labeled anti-mouse polyvalent immunoglobulins (Sigma) were used at the second step.…”