CTL Escape Viral Variants: I. Generation and Molecular Characterization

摘要: Cytotoxic T lymphocytes (CTL) play a pivotal role in preventing persistent viral infections and aborting acute infections. H-2Db-restricted CTL optimally recognize specific peptide of 9 to 11 amino acids (aa) derived from protein held place (restricted) by MHC class I glycoprotein on the surfaces infected cells. Only three sequences with appropriate Db motif lymphocytic choriomeningitis virus Armstrong strain (LCMV) are known be presented H-2Db molecules; they glycoproteins (GP), residues 33-41 KAVYNFATC (GP1) 276-286 SGVENPGGYCL (GP2), nucleoprotein (NP), 396-404 FQPQNGQFI. Incubation virally H-2b cells clones that only GP1, GP2, or NP leads selection variants which upon infecting bearing molecules, escape recognition specificity. Nucleic acid sequencing showed single mutation GP1 (aa 38 F-->L), GP2 282 G-->D), 403 F-->L) variant viruses. When wild-type (wt) LCMV peptides (GP1, NP) were synthesized subjected competitive inhibition binding assay, no differences affinity for found between wt peptides. Uninfected coated recognized lysed clone vivo-primed bulk CTL, but similar targets not. This result, coupled computer graphic analysis these recently solved three-dimensional structure molecule, placed side chain mutated outer surface MHC-peptide complex accessible cell receptor. Ala substitution at GP residue also abrogated lysis. Inoculation any one into mice produced an effective response other two nonmutated peptides, suggesting production biologically relevant vivo requires mutations more than likely all epitopes, low probability event.