The Journal of Experimental Medicine
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Published 5 April 2004. doi:10.1084/jem.20031982
Rockefeller University Press, 0022-1007 $8.00
JEM, Volume 199, Number 7, 905-915
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Immune Selection for Altered Antigen Processing Leads to Cytotoxic T Lymphocyte Escape in Chronic HIV-1 Infection

Rika Draenert1, Sylvie Le Gall1, Katja J. Pfafferott2, Alasdair J. Leslie2, Polan Chetty3, Christian Brander1, Edward C. Holmes7, Shih-Chung Chang5, Margaret E. Feeney1, Marylyn M. Addo1, Lidia Ruiz6, Danni Ramduth3, Prakash Jeena4, Marcus Altfeld1, Stephanie Thomas3, Yanhua Tang1, Cori L. Verrill1, Catherine Dixon2, Julia G. Prado6, Photini Kiepiela3, Javier Martinez-Picado6, Bruce D. Walker1, and Philip J.R. Goulder1,2

1 Howard Hughes Medical Institute and Partners AIDS Research Center, Massachusetts General Hospital, Harvard Medical School, Charlestown, MA 02129
2 Department of Paediatrics, Nuffield Department of Medicine, John Radcliffe Hospital, Oxford OX1 3SY, UK
3 HIV Pathogenesis Program, The Doris Duke Medical Research Institute
4 Department of Pediatrics, University of Natal, Durban 4015, South Africa
5 Department of Cell Biology, Harvard Medical School, Boston, MA 02115
6 irsiCaixa Foundation, Retrovirology Laboratory, University Hospital "Germans Trias I Pujol," 08916 Badalona, Spain
7 Department of Zoology, University of Oxford, Oxford OX1 3PS, UK

Address correspondence to Philip J.R. Goulder, The Peter Medawar Building for Pathogen Research, University of Oxford, South Parks Road, Oxford OX1 3SY, UK. Phone: 44-1865-281884; Fax: 44-1865-281236; e-mail: philip.goulder{at}clinical-medicine.oxford.ac.uk

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.

Key Words: CD8 T cell responses • viral evolution • immune evasion • antigen presentation

R. Draenert, S. Le Gall, and K.J. Pfafferott contributed equally to this work.

The online version of this article contains supplemental material.

Abbreviations used in this paper: ERAPI, ER aminopeptidase I; MOI, multiplicity of infection; TAP, transporter associated with antigen processing.


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