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Immune selection for altered antigen processing leads to cytotoxic T lymphocyte escape in chronic HIV-1 infection.

  • Author(s): Draenert, Rika
  • Le Gall, Sylvie
  • Pfafferott, Katja J
  • Leslie, Alasdair J
  • Chetty, Polan
  • Brander, Christian
  • Holmes, Edward C
  • Chang, Shih-Chung
  • Feeney, Margaret E
  • Addo, Marylyn M
  • Ruiz, Lidia
  • Ramduth, Danni
  • Jeena, Prakash
  • Altfeld, Marcus
  • Thomas, Stephanie
  • Tang, Yanhua
  • Verrill, Cori L
  • Dixon, Catherine
  • Prado, Julia G
  • Kiepiela, Photini
  • Martinez-Picado, Javier
  • Walker, Bruce D
  • Goulder, Philip JR
  • et al.
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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