Characterization of a murine leukemia virus that induces a novel form of central nervous system disease

Retroviruses can infect and induce degenerative changes in cells of the hemopoietic and nervous systems. In particular, murine leukemia viruses have been shown to induce leukemias and central nervous system disease when inoculated into susceptible mouse and rat strains. The neurotropism and neuropathogenicity of a molecularly cloned virus, TR1.3, that was derived from a T cell tropic MuLV was analyzed to gain insight into the mechanism of retroviral induced central nervous system disease. Initial studies using immunofluorescence and electron microscopy indicated that TR1.3 infected vessel endothelium and that in the brain induced degenerative changes to these cells. A striking feature of this pathology was the formation of multinucleated giant cells or syncytia. This selective degenerative effect in brain endothelium resulted in intracerebral hemorrhage, thrombosis and infarction that manifested as tremor, seizures and paralysis in infected hosts. Infection of different mouse strains indicated that susceptibility to TR1.3 induced disease is mediated by multiple host determinants, including an absolute requirement for neonatal inoculation. Recombinant viruses and site-directed mutagenesis were employed to map the viral determinants that regulate TR1.3 induced disease. These studies revealed that a single amino acid substitution of glycine for tryptophan at position 102 of the gp70 envelope glycoprotein was responsible for the endothelial cell pathology and subsequent neurologic disease induced by TR1.3. Finally, in vitro studies revealed that TR1.3 envelope proteins are necessary and sufficient to mediate syncytium formation. These data show that subtle changes within retroviral env genes can have dramatic consequences that result in overt clinical disease