Substitution of the U3 long terminal repeat region of the neurotropic Cas-Br-E retrovirus affects its disease-inducing potential.
The Cas-Br-E and ts-Mo BA-1 murine leukemia viruses (MuLV) induce a spongiform neurodegenerative disease with different clinical manifestations, namely, either hind limb paralysis (Cas-Br-E) or tremors, spasticity, and hind limb weakness (ts-Mo Ba-1). We constructed the chimeric NEBA-1 MuLV by replacing the long terminal repeat of Cas-Br-E MuLV with that of ts-Mo BA-1 MuLV. In SWR/J or CFW/D mice, NEBA-1 MuLV induced an ataxic neurological disease characterized by clinical signs different from those induced by both parents. Although NEBA-1 MuLV did not induce lesions in novel brain areas, the spongiform lesions were more severe in deep cerebellar nuclei and in the spinal cord than those found in paralyzed mice inoculated with Cas-Br-E MuLV. By in situ hybridization, we found that the distribution of the spongiform lesions closely correlated with the distribution of the infected central nervous system cells. In the spinal cord, a close correlation was found between the number of infected cells and the severity of the spongiform degeneration. Sequencing of the substituted ts-BA-1 MuLV fragment and comparison with homologous sequences of Cas-Br-E and Moloney MuLV showed differences mainly in the U3 tandem direct repeats. Our results show that a few modifications within the U3 long terminal repeat allow the virus to cause more severe lesions in some central nervous system regions and that the severity of the spongiform degeneration correlates with the level of viral replication.
Paquette
Y
Y
Laboratory of Molecular Biology, Clinical Research Institute of Montreal, Québec, Canada.
Kay
D G
DG
Rassart
E
E
Robitaille
Y
Y
Jolicoeur
P
P
D000818:Animals; D001483:Base Sequence; D002478:Cells, Cultured; D002525:Cerebellar Cortex / Q000473:pathology; D002678:Chimera; D005260:Female; D009052:Leukemia Virus, Murine / Q000235:genetics* / Q000472:pathogenicity; D051379:Mice; D008815:Mice, Inbred Strains; D008969:Molecular Sequence Data; D009154:Mutation; D009422:Nervous System Diseases / Q000382:microbiology* / Q000473:pathology; D009474:Neurons / Q000473:pathology; D009693:Nucleic Acid Hybridization; D011247:Pregnancy; D012367:RNA, Viral / Q000235:genetics / Q000302:isolation & purification; D012091:Repetitive Sequences, Nucleic Acid; D013116:Spinal Cord / Q000473:pathology; D014162:Transfection; D014774:Virulence / Q000235:genetics
D012367:RNA, Viral