Retrovirus-induced murine motor neuron disease: mapping the determinant of spongiform degeneration within the envelope gene.

Abstract

The Cas-Br-E murine leukemia virus (MuLV) induces a degenerative myeloencephalopathy leading to hindlimb paralysis when inoculated into newborn mice. To map the viral DNA sequences encoding the determinant of neurological degeneration, we constructed chimeric viruses in vitro with parental genomes from Cas-Br-E MuLV and from nonparalytogenic MuLVs. We found that a 1.5-kilobase-pair env Cas-Br-E fragment was sufficient to confer the full paralysis-inducing potential to chimeric viruses. This region encodes the 19 carboxyl-terminal residues of the leader sequence, all of gp7O, and the 45 amino-terminal residues of the transmembrane protein (pl5E). Within this env region, we identified a 372-base-pair fragment which was necessary for the full paralysis-inducing potential of the virus and which influenced the development of the disease in a strain-dependent manner. This domain encodes the 19 carboxyl-terminal residues of the leader peptide and the first 67 amino-terminal residues of gp7O. We propose that Cas-Br-E MuLV induces spongiform degeneration through binding of its gp7O to a specific cellular receptor.The Cas-Br-E wild mouse ecotropic murine leukemia virus (MuLV) has been shown to induce a progressive form of hind-limb paralysis after inoculation into susceptible laboratory mice (for review, see refs. 1 and 2). This clinical syndrome is the consequence of a spongiform myeloencephalopathy predominantly involving the brainstem and the anterior horn of the lumbosacral region of the spinal cord (3-6). Using chimeric viruses constructed in vitro, we have previously mapped the primary determinant of this spongiform degeneration within a 3.9-kilobase-pair (kbp) pol-env fragment of the viral genome (7). Sequencing of this region revealed that the pol gene product and piSE diverged very little from homologous proteins of other nonparalytogenic MuLVs, while the Cas-Br-E gp7O sequence was found to diverge significantly from that of other nonparalytogenic MuLVs (8). We also showed that the long terminal repeat (LTR) region of the genome harbors a second determinant of pathogenicity influencing the incidence of the disease and determining in which region of the central nervous system (CNS) this virus induces the spongiform lesions (9).To determine more precisely which viral gene harbors the primary determinant of the spongiform lesions, we constructed additional chimeric viruses with DNA from parental paralytogenic Cas-Br-E and nonparalytogenic amphotropic, endogenous ecotropic, or Moloney MuLVs. We show here that chimeric viruses harboring only the env gene of Cas-Br-E MuLV genome induce spongiform lesions and remain paralytogenic. MATERIALS AND METHODSMice. SWR/J pregnant females were purchased from The Jackson Laboratory. SIM.S and NFS/N mice were from our breeding colony. The virus suspensions were filtered through a HAWP nitrocellulose filter (pore size, 0.45 um; Millipore) and injected intraperitoneally (0.15 ml) into newborn (<48 hr) mice.Cells and Viruses. The Cas-Br-E (pNE-8) molecularly cloned parental M...

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Lentivirus Infection in the Brain Induces Matrix Metalloproteinase Expression: Role of Envelope Diversity

“…Viral envelope gene variability was also reported to influence the occurrence of neurological disease in several retroviral systems (33,45,67). Previous studies have demonstrated that HIV-1 strains derived from AIDS patients with dementia differ from viruses derived from nondemented patients primarily in the V3 sequences of the gp120 envelope protein (29,55).…”

TVB Receptors for Cytopathic and Noncytopathic Subgroups of Avian Leukosis Viruses Are Functional Death Receptors

“…Viral determinants required for the CPE have been mapped to the Env proteins of ALV-B (7), HIV (5), Cas-Br-MLV (15), AHV (17), and FeLV (6), indicating that viral Env-receptor interactions are linked to retroviral CPEs. Indeed, the determinants on the ALV-B surface (SU) Env protein that are required for cell killing appear to be the same as those needed for receptor recognition (7).…”