Viral determinants that control the neuropathogenicity of PVC-211 murine leukemia virus in vivo determine brain capillary endothelial cell tropism of the virus in vitro.
PVC-211 murine leukemia virus (MuLV) is a neuropathogenic, weakly leukemogenic variant of the nonneuropathogenic, highly leukemogenic Friend MuLV (F-MuLV). Chimeric viruses constructed from PVC-211 MuLV clone 3d and F-MuLV clone 57 indicate that the env gene of PVC-211 MuLV contains the determinant(s) responsible for pathological changes in the central nervous system. However, sequences within the 5' one-third (AatII-EcoRI region) of the PVC-211 MuLV genome, which include the 5' leader sequence, the gag gene, and the 5' quarter of the pol gene, are also needed in conjunction with the env gene determinant(s) to cause clinically evident neurological disease in the majority of virus-infected animals after a short latency. In the presence of the AatII-EcoRI region of the PVC-211 MuLV genome, the PVC-211 MuLV env gene sequences encoding the amino-terminal half of the SU protein, which contains the receptor-binding region of the protein, were sufficient to cause rapidly progressive neurological disease. When PVC-211 MuLV, F-MuLV, and various chimeric viruses were tested for their ability to replicate in cultured brain capillary endothelial cells (BCEC), the primary site of PVC-211 MuLV replication within the central nervous system, there was a direct correlation between the replication efficiency of a virus in BCEC in vitro and its ability to cause neurological disease in vivo. This observation indicates that the sequences in PVC-211 MuLV that render it neuropathogenic affect its replication in BCEC and suggests that rapid and efficient replication of the virus in BCEC is crucial for the pathological changes in the central nervous system that result in development of neurological disease.
Laboratory of Molecular Oncology, National Cancer Institute, Frederick, Maryland 21702-1201.
M
M
Masuda
P M
PM
Hoffman
S K
SK
Ruscetti
D016475:3T3 Cells; D000818:Animals; D001483:Base Sequence; D001921:Brain / Q000382:microbiology* / Q000473:pathology; D002678:Chimera; D015686:Gene Products, env / Q000235:genetics / Q000378:metabolism*; D015752:Genes, env; D016679:Genome, Viral; D009052:Leukemia Virus, Murine / Q000235:genetics / Q000472:pathogenicity* / Q000502:physiology; D051379:Mice; D008969:Molecular Sequence Data; D015345:Oligonucleotide Probes; D016133:Polymerase Chain Reaction; D051381:Rats; D011916:Rats, Inbred F344; D011991:Receptors, Virus / Q000378:metabolism; D015183:Restriction Mapping; D014162:Transfection; D016662:Virus Integration; D014779:Virus Replication
D015686:Gene Products, env; D015345:Oligonucleotide Probes; D011991:Receptors, Virus