Journal
JOURNAL OF EXPERIMENTAL MEDICINE
Volume 199, Issue 7, Pages 905-915Publisher
ROCKEFELLER UNIV PRESS
DOI: 10.1084/jem.20031982
Keywords
CD8 T cell responses; viral evolution; immune evasion; antigen presentation
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Funding
- NIAID NIH HHS [R01 AI28568, R01 AI028568, R01 AI46995-01A1, R01 AI046995] Funding Source: Medline
- PHS HHS [N01-A1-15442] Funding Source: Medline
- Wellcome Trust Funding Source: Medline
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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-ternnnal 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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