Immune selection for altered antigen processing leads to cytotoxic T lymphocyte escape in chronic HIV-1 infection.
Draenert R., Le Gall S., Pfafferott KJ., Leslie AJ., Chetty P., Brander C., Holmes EC., Chang SC., Feeney ME., Addo MM., Ruiz L., Ramduth D., Jeena P., Altfeld M., Thomas S., Tang Y., Verrill CL., Dixon C., Prado JG., Kiepiela P., Martinez-Picado J., Walker BD., Goulder PJ.
Mutations within cytotoxic T lymphocyte (CTL) epitopes impair T cell recognition, but escape mutations arising in flanking regions that alter antigen processing have not been defined in natural human infections. In human histocompatibility leukocyte antigen (HLA)-B57+ HIV-infected persons, immune selection pressure leads to a mutation from alanine to proline at Gag residue 146 immediately preceding the NH2 terminus of a dominant HLA-B57-restricted epitope, ISPRTLNAW. Although N-extended wild-type or mutant peptides remained well-recognized, mutant virus-infected CD4 T cells failed to be recognized by the same CTL clones. The A146P mutation prevented NH2-terminal trimming of the optimal epitope by the endoplasmic reticulum aminopeptidase I. These results demonstrate that allele-associated sequence variation within the flanking region of CTL epitopes can alter antigen processing. Identifying such mutations is of major relevance in the construction of vaccine sequences.