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.

Original publication

DOI

10.1084/jem.20031982

Type

Journal article

Journal

J Exp Med

Publication Date

05/04/2004

Volume

199

Pages

905 - 915

Keywords

Alleles, Amino Acid Sequence, Antigen Presentation, Base Sequence, Clone Cells, DNA, Viral, Epitopes, Gene Products, gag, Genetic Variation, HIV Antigens, HIV Infections, HIV-1, HLA-B Antigens, Humans, Molecular Sequence Data, Mutation, Sequence Homology, Amino Acid, T-Lymphocytes, Cytotoxic