Viruses like HIV and SIV escape from containment by CD8+ T lymphocytes through generating mutations that interfere with epitope peptide:MHC class I binding. However, mutations in some viral epitopes are selected for that have no impact on this binding. We explored the mechanism underlying the evolution of such epitopes by studying CD8+ T lymphocyte recognition of a dominant Nef epitope of SIVmac251 in infected Mamu-A*02+ rhesus monkeys. Clonal analysis of the p199RY-specific CD8+T lymphocyte repertoire in these monkeys indicated that identical T cell clones were capable of recognizing wild-type (WT) and mutant epitope sequences. However, we found that the functional avidity of these CD8+ T lymphocytes for the mutant peptide: Mamu-A*02 complex was diminished. Using surface plasmon resonance to measure the binding affinity of the p199RY-specific TCR repertoire for WT and mutant p199RY peptide:Mamu-A*02 monomeric complexes, we found that the mutant p199RY peptide:Mamu-A*02 complexes had a lower affinity for TCRs purified from CD8+ T lymphocytes than did the WT p199RY peptide:Mamu-A*02 complexes. These studies demonstrated that differences in TCR affinity for peptide:MHC class I ligands can alter functional p199RY-specific CD8+ T lymphocyte responses to mutated epitopes, decreasing the capacity of these cells to contain SIVmac251 replication.
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