Immune selection for altered antigen processing leads to cytotoxic T lymphocyte escape in chronic HIV-1 infection
Resource
J Exp Med. Apr 5;199(7):905-15
Journal
J Exp Med. Apr 5
Journal Volume
199
Journal Issue
7
Pages
905-15
Date Issued
2004
Date
2004
Author(s)
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
Abstract
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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