CTL ESCAPE VIRAL VARIANTS .2. BIOLOGIC ACTIVITY IN-VIVO

The proteins of lymphocytic choriomeningitis virus (LCMV) contain only three known peptide regions that are processed and then held in place by the MHC class I H-2(b) (D-b) glycoprotein on the cell's surface for recognition by LCMV-specific D-b-restricted cytotoxic T lymphocytes (CTL). These peptides are from the glycoprotein (GP), amino acids 33-41 KAVYNFATC (GP1) and 276-286 SGVENPGGYCL (GP2), and the nucleoprotein (NP), 396-404. We have used CTL clones that recognized only GP1, GP2, and NP to select viral variants that upon infecting cells bearing H-2(b) molecules escaped recognition by virus-specific CTL directed against the viral GP (GP1 + GP2) mutant, termed GPV, or the viral GP and NP (GP1 + GP2 + NP) mutant, termed GPV + NPV. These CTL ''escape'' variants nevertheless elicited sufficient host-protective activity in vivo to abort acute infection and prevent the occurrence of persistent infection. This protection was CD8(+) lymphocyte mediated and associated with the generation of a novel (for H-2(b) mice) CTL response to the viral L protein. Hence CTL epitopes form a hierarchy, in which responses to ''weak'' epitopes are suppressed in the presence of ''stronger'' epitopes. Mutation in the strong epitopes may be of limited biological significance since the host can mount a protective response directed against the second level (weak) epitopes. (C) 1995 Academic Press, Inc.