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

Journal article

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.

Authors: Draenert, R; Le Gall, S; Pfafferott, K; Leslie, A; Chetty, P

• Publication status: Published
• Journal: Journal of experimental medicine
• Volume: 199
• Issue: 7
• Pages: 905-915
• Publication date: 2004-04-01
• DOI: 10.1084/jem.20031982
• EISSN: 1540-9538
• ISSN: 0022-1007
• Language: English
• Keywords: HIV-1; Sequence Homology, Amino Acid; Humans; HIV Infections; Gene Products, gag; T-Lymphocytes, Cytotoxic; Epitopes; Molecular Sequence Data; DNA, Viral; Mutation; HLA-B Antigens; Base Sequence; Antigen Presentation; Genetic Variation; HIV Antigens; Alleles; Clone Cells; Amino Acid Sequence