Journal
NATURE IMMUNOLOGY
Volume 10, Issue 6, Pages 636-U109Publisher
NATURE PUBLISHING GROUP
DOI: 10.1038/ni.1728
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Funding
- Novo Nordisk Foundation
- Danish AIDS foundation
- Deutsche Forschungsgemeinschaft
- Genomes2Vaccines Specific Targeted Research Project
- Sixth Framework Programme [LSHB-CT-2003-503231]
- Hochschulbauforderungsgesetz Program [HBFG-122-605]
- Forschungszentrum Immunologie at the University of Mainz
- Nuffield Dominions Trust
- Cancer Research UK
- European Union [LSHG-CT-2006-031220, LSHC-CT-2006-518234, HEALTH-2007-222773]
- Wellcome Trust
- James Martin 21st Century School at the University of Oxford
- National Institute for Health
- UK Medical Research Council
- Medical Research Council [MC_U137884177, MC_U137884178, G9900061] Funding Source: researchfish
- MRC [G9900061, MC_U137884178, MC_U137884177] Funding Source: UKRI
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Although cytotoxic T lymphocytes (CTLs) in people infected with human immunodeficiency virus type 1 can potentially target multiple virus epitopes, the same few are recognized repeatedly. We show here that CTL immunodominance in regions of the human immunodeficiency virus type 1 group-associated antigen proteins p17 and p24 correlated with epitope abundance, which was strongly influenced by proteasomal digestion profiles, affinity for the transporter protein TAP, and trimming mediated by the endoplasmatic reticulum aminopeptidase ERAAP, and was moderately influenced by HLA affinity. Structural and functional analyses demonstrated that proteasomal cleavage 'preferences' modulated the number and length of epitope-containing peptides, thereby affecting the response avidity and clonality of T cells. Cleavage patterns were affected by both flanking and intraepitope CTL-escape mutations. Our analyses show that antigen processing shapes CTL response hierarchies and that viral evolution modifies cleavage patterns and suggest strategies for in vitro vaccine optimization.
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