FrC6 murine leukemia virus (MuLV) is a replication-competent, neuropathogenic variant derived from Friend MuLV (F-MuLV) complex. The A8 virus (a molecular clone of the FrC6 virus) induced marked spongiform degeneration in the brain similar to the FrC6 virus, but only mild lesions were found in the spinal cord. In contrast, PVC211 virus, which is also a neuropathogenic F-MuLV variant, caused marked spongiform degeneration in the spinal cord. Virus recovery from the spinal cord of A8 virus-infected rat was the same as that of PVC211-infected rat, indicating that there is no direct correlation between the titer of virus and the intensity of lesions. Furthermore, rats infected with the A8 virus at 3 weeks of age did not undergo spongiform degeneration, although recovery of high titer of virus occurred in the central nervous system (CNS). Studies using chimeric viruses between the A8 virus and nonneuropathogenic F-MuLV clone 57 also indicated that the sequences responsible for virus titers in the CNS and neuropathogenicity are different. The chimeric virus studies proved that the env gene and the LTR and/or 5' leader sequence of A8 are critical for the induction of neuropathogenicity. These sequences in A8 and PVC211 were compared, focusing in on the sites that account for neurovirulence and viral lesional tropism.