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 S-C., 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 PJR.
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.
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Michelle Fernandes
Clinical Lecturer & MRC Clinical Research Training Fellow
