|Abstract:||Ts1 Moloney murine leukemia virus (MoMuLV) is a neurovirulent mutant of wild type (wt) MoMuLV that causes a progressive, fatal neurodegenerative disease characterized by generalized tremors and progressive hind-limb paralysis associated with non-inflammatory spongiform lesions and motor neuron degeneration within selected nuclei of the brainstem and ventral horns of the cervical and lumbar enlargements of the spinal cord. To determine the biologic basis of ts1 MoMuLV neurovirulence, newborn CFW/D mice were inoculated with neurovirulent ts1 MoMuLV, non-neurovirulent wt MoMuLV, or conditioned media from control cell cultures, and the temporal response to virus infection in the CNS, spleen, and thymus studied comparatively using transmission electron microscopy, single and double-labeling in situ immunohistochemistry with selective morphometric analyses, and steady-state immunoblotting of viral proteins. Cellular targets for virus infection were identical for both ts1 and wt MoMuLV and consisted sequentially of: (1) splenic megakaryocytes, (2) splenic and thymic lymphocytes, (3) CNS capillary endothelial cells, and (4) CNS pericytes and microglia. Splenic megakaryocytes, platelets, and cell free viremia contributed to systemic dissemination of virus to the CNS. Resident microglia served as the major reservoir and amplifier of virus infection in the CNS of ts1 MoMuLV-infected mice; a similar but much less significant role was played by microglia in wt MoMuLV-infected mice. Direct virus infection of neurons was not observed. CNS spongiform lesions originated from both neuronal and oligodendroglial degeneration as a result of dilation of the cytocavitary system of proximal neuronal processes and vacuolization of myelin sheaths, respectively. When compared to wt MoMuLV, the neurovirulence of ts1 MoMuLV occurred by an enhanced ability to replicate in the CNS and to infect and activate increased numbers of microglia, rather than by a fundamental change in cellular tropism or topography of virus infection. The identification of microglia as the major CNS cell target for virus infection, and the absence of virus infection of neurons suggest an indirect mechanism for murine retroviral-induced neuronal dysfunction.