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Immune Selection for Altered Antigen Processing Leads to Cytotoxic T Lymphocyte Escape in Chronic HIV-1 Infection

2004; Rockefeller University Press; Volume: 199; Issue: 7 Linguagem: Inglês

10.1084/jem.20031982

1540-9538

Rika Draenert, Sylvie Le Gall, Katja Pfafferott, Alasdair Leslie, Polan Chetty, Christian Brander, Edward C. Holmes, Shih‐Chung Chang, Margaret E. Feeney, Marylyn M. Addo, Lidia Ruíz, Danni Ramduth, Prakash Jeena, Marcus Altfeld, Stéphanie Thomas, Yanhua Tang, Cori L. Verrill, Catherine Dixon, Julia G. Prado, Photini Kiepiela, Javier Martínez‐Picado, Bruce D. Walker, Philip Goulder,

vaccines and immunoinformatics approaches

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.