TISSUE-MEDIATED SELECTION OF VIRAL VARIANTS - CORRELATION BETWEEN GLYCOPROTEIN MUTATION AND GROWTH IN NEURONAL CELLS

Viral variants with different biological properties predominate in the central nervous system (CNS) and lymphoid tissues of carrier mice inf ected at birth with the Armstrong strain of lymphocytic choriomeningit is virus. The CNS isolates have the same phenotype as the parental str ain and cause acute infections in adult mice, while the spleen-derived isolates cause chronic infections associated with suppressed T-cell r esponses and susceptibility to opportunistic infections. Our previous studies have identified a single amino acid change in the viral glycop rotein, a phenylalanine-to-leucine (F-->t) mutation at residue 260, th at correlates with the tissue-specific selection and the persistent an d 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 isola tes obtained from the spleen, liver, kidney, and brain of carrier mice for the presence of this mutation and determined the temporal selecti on 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 stower than in the spleen and liver, this F-->L mutation predominates in the kidney deriv ed isolates by 250 days p.i. In contrast, the majority of the CNS isol ates retain the parental sequence up to 250 days p.i. In addition, mos t of the brain isolates replicated efficiently in a neuronal cell line , and this enhanced growth phenotype in neurons correlated with the pa rental F genotype. This linkage with neurotropism, along with our earl ier finding that the F-->L mutation is necessary for enhanced infectio n 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. Take n together, these results suggest that tropism for macrophages is a cr itical determinant in selection of variants with the F-->L mutation in tissues such as spleen and liver, and tropism for neurons is importan t in retention of the F genotype in the CNS.