Brain infection by neuroinvasive but avirulent murine oncornaviruses

The chimeric murine oncornavirus FrCas(E) causes a rapidly progressive noni nflammatory spongiform encephalomyelopathy after neonatal inoculation. The virus was constructed by the introduction of pol-env sequences from the wil d mouse virus CasBrE into the genome of a neuroinvasive but nonneurovirulen t strain of Friend murine leukemia virus (FMuLV), FB29. Although the brain infection by FrCasE as well as that by other neurovirulent murine retroviru ses has been described in detail, little attention has been paid to the neu roinvasive but nonneurovirulent viruses. The purpose of the present study w as to compare brain infection by FrCasE with that by FB29 and another nonne urovirulent virus, F43, which contains pol-env sequences from FMuLV 57. Bot h FB29 and F43 infected the same spectrum of cell types in the brain as tha t infected by FrCasE, including endothelial cells, microglia, and populatio ns of neurons which divide postnatally. Viral burdens achieved by the two n onneurovirulent viruses in the brain were actually higher than that of FrCa sE. The widespread infection of microglia by the two nonneurovirulent virus es is notable because it is infection of these cells by FrCasE which is tho ught to be a critical determinant of its neuropathogenicity. These results indicate that although the sequence of the envelope gene determines neurovi rulence, this effect appears to operate through a mechanism which does not influence either viral tropism or viral burden in the brain. Although all t hree viruses exhibited similar tropism for granule neurons in the cerebella r cortex, there was a striking difference in the distribution of envelope p roteins in those cells in vivo. The FrCas(E) envelope protein accumulated i n terminal axons, whereas those of FB29 and F43 remained predominantly in t he cell bodies. These observations suggest that differences in the intracel lular sorting of these proteins may exist and that these differences appear to correlate with neurovirulence.