There is mounting evidence that some neurodegenerative diseases of man are associated with human retrovirus infection. The mechanisms by which retroviruses cause neurologic disease are not understood. This project focuses on the study of a murine neurodegenerative disease that is causes by a retrovirus (WM-E) which is indigenous to certain wild mouse populations in California and Asia. The virus is transmitted congenitally through maternal milk as well as horizontally in the semen though sexual intercourse. The pathology of this disease consists of the progressive death of motor neurons in the spinal cord, midbrain and cerebellum and in the regard resembles amyotropic lateral sclerosis of man. The primary goals of the project are to define the specific targets for the virus in the CNS, the mechanism of virus spread, host and viral factors which influence virus spread within the CNS and the mechanism of the cytolytic effect of this virus on neurons. Previous studies revealed that extravascular spread of WM-E within the CNS was mediated by the viral envelope gene. We now have evidence that the viral env gene also endows this virus with a unique tropism for neuronal as well as astrocytic cell lines in vitro, providing compelling evidence for the existence of specific receptors in the CNS for WM-E. We have recently found that large amounts of unintegrated DNA persist long after infection of fibroblastic cells in vitro. In this respect WM-E resembles the lentiviruses and cytopathic avian leukosis viruses in which similar accumulation of unintegrated viral DNA has been observed. It is thus possible that unintegrated WM-E DNA may persist in neurons in the CNS allowing viral gene expression without viral DNA integration. Further work in this area will involve studies of purified cell populations from the CNS.