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Antigen processing influences HIV-specific cytotoxic T lymphocyte immunodominance

Nature Immunology volume 10, pages 636–646 (2009)Cite this article

Abstract

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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Figure 1: SLYNTVATL evolution and HIV p17 epitopes.
Figure 2: Proteasomal digestion of p17.
Figure 3: Antigen processing and presentation of p17.
Figure 4: CTL recognition of SLYNTVATL sequence and length variants.
Figure 5: Structure of HLA-A*0201–SLFNTVATLY and comparison with previously determined 9–amino acid SLYNTVATL variant structures.
Figure 6: Antigen processing of p24.
Figure 7: Cell line–recognition patterns of KK10 peptide forms.

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Acknowledgements

We thank the patients for donating samples; B. Baadegaard and L.P. Jensen for patient management; D. Hass, T. Rostron, J. Frankland and J. Forsch for technical assistance; and N. Willcox for discussions. Supported by the Novo Nordisk Foundation, the Danish AIDS foundation, the Deutsche Forschungsgemeinschaft (Sonderforschungsbereich 490, E6, Z3), the Genomes2Vaccines Specific Targeted Research Project, Sixth Framework Programme (LSHB-CT-2003-503231), the Hochschulbauförderungsgesetz Program (HBFG-122-605), the Forschungszentrum Immunologie at the University of Mainz, the Nuffield Dominions Trust, Cancer Research UK, the European Union (LSHG-CT-2006-031220, LSHC-CT-2006-518234 and HEALTH-2007-222773), the Wellcome Trust, The James Martin 21st Century School at the University of Oxford, the National Institute for Health Research Biomedical Research Centre Programme, and the UK Medical Research Council.

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Authors and Affiliations

  1. Institute of Immunology, University of Mainz, Mainz, Germany

    Stefan Tenzer, Nadja Akkad & Hansjörg Schild

  2. Medical Research Council, Human Immunology Unit, Weatherall Institute of Molecular Medicine, John Radcliffe Hospital, Oxford University, Oxford, UK

    Edmund Wee, Guillaume Stewart-Jones, Lone Friis, Chih-hao Chang, Lars Fugger, Andrew J McMichael & Astrid K N Iversen

  3. Institut National de la Santé et de la Recherche Médicale, Unité 580, Paris, France

    Anne Burgevin, Mirjana Weimershaus & Peter van Endert

  4. Faculté de Médecine René Descartes, Université Paris-Descartes, Paris, France

    Anne Burgevin, Mirjana Weimershaus & Peter van Endert

  5. Laboratory of Experimental Immunology, University of Copenhagen, Copenhagen, Denmark

    Kasper Lamberth, Mikkel Harndahl & Søren Buus

  6. Department of Infectious Diseases, Rigshospitalet, The National University Hospital, Copenhagen, Denmark

    Jan Gerstoft

  7. Nuffield Department of Clinical Medicine, Peter Medawar Building for Pathogen Research, Oxford University, Oxford, UK

    Paul Klenerman

  8. Department of Clinical Neurology, John Radcliffe Hospital, Oxford University, Oxford, UK

    Lars Fugger

  9. Structural Biology Group, Wellcome Trust Centre for Human Genetics, Oxford University, Oxford, UK

    E Yvonne Jones

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  1. Stefan Tenzer
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Contributions

A.K.N.I. conceived and designed the overall study and wrote the manuscript; S.T., H.S., S.B., P.v.E. and A.K.N.I. planned and supervised experiments; S.T., E.W., A.B., G.S.-J., L.F., K.L., C.-h.C., M.H., M.W., N.A. and A.K.N.I. did experiments; S.T., H.S., S.B., G.S.-J., E.Y.J., P.K., P.v.E. and A.K.N.I. analyzed data; J.G. and A.K.N.I. provided patient samples; S.B., P.v.E., A.J.M., L.F., A.K.N.I. and H.S. provided reagents; and S.T., S.B., H.S., P.K., L.F., G.S.-J., E.Y.J. and P.v.E. contributed intellectual input.

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Correspondence to Astrid K N Iversen.

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Tenzer, S., Wee, E., Burgevin, A. et al. Antigen processing influences HIV-specific cytotoxic T lymphocyte immunodominance. Nat Immunol 10, 636–646 (2009). https://doi.org/10.1038/ni.1728

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