Murine leukemia virus induced central nervous system diseases.
The ts1 mutant of Moloney murine leukemia virus TB (MoMuLV-TB) causes a degenerative neurologic and immunologic disease in mice characterized by development of spongiform encephalomyelopathy that results in hind-limb paralysis, marked thymic atrophy associated with immunodeficiency, and generalized body wasting. T cells, particularly CD4+ helper T cells, play a key role in the pathogenesis of the disease induced by ts1. Therefore, ts1 is unique among the described murine retroviruses in its ability to afflict both the central nervous system (CNS) and the T-cell compartment of the immune system in the same host. This particular ability to cause degenerative diseases involving both the CNS and immune system is shared by the lentiviruses responsible for development of the acquired immunodeficiency syndromes of humans and macaques. Our goal has been to elucidate the specific cellular and molecular mechanisms that underlie this neuro- and immunopathogenicity of ts1. We have previously reported that the primary neuropathogenic determinant of ts1 maps to a single amino acid substitution, Val-25-Ile, in the precursor envelope protein gPr80env. Further, at the restrictive temperature, the Val-25-Ile substitution did not prevent oligomerization of the gPr80env proteins; however, the structure of the oligomer was incompetent for transport from the ER to the Golgi. These findings suggest that the cytopathic effect of ts1 in neural cells might be due to accumulation of the gPr80env oligomers in the ER. Since glial cells are targets of ts1 infection in vivo, primary astrocytic cultures were established and the cytopathic effect of ts1 and MoMuLV-TB on these cells assessed. Both viruses replicate well in astrocytes and their replication is cytopathic, albeit to different degrees. The ts1 mutant appears to produce greater cell killing than the wild-type virus. Furthermore, it was found that the rate of processing of gPr80env of ts1 in astrocytes is slower than that of MoMuLV-TB. Therefore, the inefficient transport and processing of gPr80env of ts1 appears to correlate with its cytopathic effect in these cells. Electron microscopic studies of the ts1-infected astrocytes revealed large numbers of aberrant particles in the ER. The in vitro cytopathic effect of ts1 on astrocytes may reflect what happens in vivo. An indirect mechanism of neuronal-cell killing by ts1 is proposed.
Wong
P K
PK
University of Texas M.D. Anderson Cancer Center, Science Park, Research Division, Smithville 78957.
Shikova
E
E
Lin
Y C
YC
Saha
K
K
Szurek
P F
PF
Stoica
G
G
Madden
R
R
Brooks
B R
BR
D000818:Animals; D001932:Brain Neoplasms / Q000209:etiology*; D015752:Genes, env / Q000235:genetics*; D007942:Leukemia, Experimental / Q000150:complications* / Q000378:metabolism / Q000382:microbiology; D051379:Mice; D008807:Mice, Inbred BALB C; D008979:Moloney murine leukemia virus / Q000145:classification / Q000235:genetics / Q000472:pathogenicity* / Q000502:physiology; D009154:Mutation / Q000235:genetics*; D013154:Spleen / Q000382:microbiology; D013601:T-Lymphocytes / Q000382:microbiology*; D014759:Viral Envelope Proteins / Q000378:metabolism*; D014779:Virus Replication
D014759:Viral Envelope Proteins