Viral variants with different biological properties predominate in the central nervous system (CNS) and lymphoid tissues of carrier mice infected at birth with the Armstrong strain of lymphocytic choriomeningitis virus. The CNS isolates have the same phenotype as the parental strain and cause acute infections in adult mice, while the spleen-derived isolates cause chronic infections associated with suppressed T-cell responses and susceptibility to opportunistic infections. Our previous studies have identified a single amino acid change in the viral glycoprotein, a phenylalanine-to-leucine (F-->L) mutation at residue 260, that correlates with the tissue-specific selection and the persistent and immunosuppressive phenotype of the spleen isolates (R. Ahmed, C.S. Hahn, T. Somasundaram, L. Villarete, M. Matloubian, and J. H. Strauss, J. Virol. 65:4242-4247, 1991). In this study, we screened viral isolates obtained from the spleen, liver, kidney, and brain of carrier mice for the presence of this mutation and determined the temporal selection of variants as they appear in these organs. We found that this F-->L amino acid change is common to > 90% of the spleen and liver isolates and is selected for rapidly by day 32 postinfection (p.i.). Although the kinetics observed in the kidney are relatively slower than in the spleen and liver, this F-->L mutation predominates in the kidney-derived isolates by 250 days p.i. In contrast, the majority of the CNS isolates retain the parental sequence up to 250 days p.i. In addition, most of the brain isolates replicated efficiently in a neuronal cell line, and this enhanced growth phenotype in neurons correlated with the parental F genotype. This linkage with neurotropism, along with our earlier finding that the F-->L mutation is necessary for enhanced infection of macrophages (M. Matloubian, S. R. Kolhekar, T. Somasundaram, and R. Ahmed, J. Virol. 67:7340-7349, 1993), provides a cellular basis for the molecular changes associated with tissue-specific selection. Taken together, these results suggest that tropism for macrophages is a critical determinant in selection of variants with the F-->L mutation in tissues such as spleen and liver, and tropism for neurons is important in retention of the F genotype in the CNS.