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

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BEING VIEWED BY OTHERS VIRAL IMMUNE EVASINS IMPACT ANTIGEN PRESENTATION BY ALLELE-SPECIFIC TRAPPING OF MHC I AT THE PEPTIDE-LOADING COMPLEX Article Open access 27 January 2022 CRYPTIC MHC-E

EPITOPE FROM INFLUENZA ELICITS A POTENT CYTOLYTIC T CELL RESPONSE Article 12 October 2023 HLA CLASS I SIGNAL PEPTIDE POLYMORPHISM DETERMINES THE LEVEL OF CD94/NKG2–HLA-E-MEDIATED REGULATION

OF EFFECTOR CELL RESPONSES Article 01 June 2023 ACCESSION CODES ACCESSIONS PROTEIN DATA BANK * 2V2X * 3GIV REFERENCES * Yewdell, J.W. Confronting complexity: real-world immunodominance in

antiviral CD8+ T cell responses. _Immunity_ 25, 533–543 (2006). Article  CAS  Google Scholar  * Altfeld, M. et al. HLA alleles associated with delayed progression to AIDS contribute strongly

to the initial CD8+ T cell response against HIV-1. _PLoS Med._ 3, e403 (2006). Article  Google Scholar  * Bihl, F. et al. Impact of HLA-B alleles, epitope binding affinity, functional

avidity, and viral coinfection on the immunodominance of virus-specific CTL responses. _J. Immunol._ 176, 4094–4101 (2006). Article  CAS  Google Scholar  * Goulder, P.J. et al. Substantial

differences in specificity of HIV-specific cytotoxic T cells in acute and chronic HIV infection. _J. Exp. Med._ 193, 181–194 (2001). Article  CAS  Google Scholar  * Chen, W., Anton, L.C.,

Bennink, J.R. & Yewdell, J.W. Dissecting the multifactorial causes of immunodominance in class I-restricted T cell responses to viruses. _Immunity_ 12, 83–93 (2000). Article  CAS  Google

Scholar  * Kloetzel, P.M. Antigen processing by the proteasome. _Nat. Rev. Mol. Cell Biol._ 2, 179–187 (2001). Article  CAS  Google Scholar  * Tenzer, S. et al. Quantitative analysis of

prion-protein degradation by constitutive and immuno-20S proteasomes indicates differences correlated with disease susceptibility. _J. Immunol._ 172, 1083–1091 (2004). Article  CAS  Google

Scholar  * Toes, R.E. et al. Discrete cleavage motifs of constitutive and immunoproteasomes revealed by quantitative analysis of cleavage products. _J. Exp. Med._ 194, 1–12 (2001). Article 

CAS  Google Scholar  * Van den Eynde, B.J. & Morel, S. Differential processing of class-I-restricted epitopes by the standard proteasome and the immunoproteasome. _Curr. Opin. Immunol._

13, 147–153 (2001). Article  CAS  Google Scholar  * _HIV Molecular Immunology 2006/2007_ (eds. Korber, B.T.M. et al.) 53–248 (Los Alamos National Laboratory, Theoretical Biology and

Biophysics, Los Alamos, New Mexico, 2006–2007). * Iversen, A.K. et al. Conflicting selective forces affect T cell receptor contacts in an immunodominant human immunodeficiency virus epitope.

_Nat. Immunol._ 7, 179–189 (2006). Article  CAS  Google Scholar  * Goulder, P.J. & Watkins, D.I. Impact of MHC class I diversity on immune control of immunodeficiency virus replication.

_Nat. Rev. Immunol._ 8, 619–630 (2008). Article  CAS  Google Scholar  * Kaslow, R.A. et al. Influence of combinations of human major histocompatibility complex genes on the course of HIV-1

infection. _Nat. Med._ 2, 405–411 (1996). Article  CAS  Google Scholar  * Goulder, P.J. et al. Late escape from an immunodominant cytotoxic T-lymphocyte response associated with progression

to AIDS. _Nat. Med._ 3, 212–217 (1997). Article  CAS  Google Scholar  * Schneidewind, A. et al. Structural and functional constraints limit options for cytotoxic T-lymphocyte escape in the

immunodominant HLA-B27-restricted epitope in human immunodeficiency virus type 1 capsid. _J. Virol._ 82, 5594–5605 (2008). Article  CAS  Google Scholar  * Schneidewind, A. et al. Escape from

the dominant HLA-B27-restricted cytotoxic T-lymphocyte response in Gag is associated with a dramatic reduction in human immunodeficiency virus type 1 replication. _J. Virol._ 81,

12382–12393 (2007). Article  CAS  Google Scholar  * Draenert, R. et al. Immune selection for altered antigen processing leads to cytotoxic T lymphocyte escape in chronic HIV-1 infection. _J.

Exp. Med._ 199, 905–915 (2004). Article  CAS  Google Scholar  * Milicic, A. et al. CD8+ T cell epitope-flanking mutations disrupt proteasomal processing of HIV-1 Nef. _J. Immunol._ 175,

4618–4626 (2005). Article  CAS  Google Scholar  * Zimbwa, P. et al. Precise identification of a human immunodeficiency virus type 1 antigen processing mutant. _J. Virol._ 81, 2031–2038

(2007). Article  CAS  Google Scholar  * Le Gall, S., Stamegna, P. & Walker, B.D. Portable flanking sequences modulate CTL epitope processing. _J. Clin. Invest._ 117, 3563–3575 (2007).

Article  CAS  Google Scholar  * Leslie, A. et al. Transmission and accumulation of CTL escape variants drive negative associations between HIV polymorphisms and HLA. _J. Exp. Med._ 201,

891–902 (2005). Article  CAS  Google Scholar  * Ossendorp, F. et al. A single residue exchange within a viral CTL epitope alters proteasome-mediated degradation resulting in lack of antigen

presentation. _Immunity_ 5, 115–124 (1996). Article  CAS  Google Scholar  * Shimbara, N. et al. Contribution of proline residue for efficient production of MHC class I ligands by

proteasomes. _J. Biol. Chem._ 273, 23062–23071 (1998). Article  CAS  Google Scholar  * Fruci, D., Niedermann, G., Butler, R.H. & van Endert, P.M. Efficient MHC class I-independent

amino-terminal trimming of epitope precursor peptides in the endoplasmic reticulum. _Immunity_ 15, 467–476 (2001). Article  CAS  Google Scholar  * Gubler, B. et al. Substrate selection by

transporters associated with antigen processing occurs during peptide binding to TAP. _Mol. Immunol._ 35, 427–433 (1998). Article  CAS  Google Scholar  * van Endert, P.M. et al. The

peptide-binding motif for the human transporter associated with antigen processing. _J. Exp. Med._ 182, 1883–1895 (1995). Article  CAS  Google Scholar  * Saric, T. et al. An IFN-γ-induced

aminopeptidase in the ER, ERAP1, trims precursors to MHC class I–presented peptides. _Nat. Immunol._ 3, 1169–1176 (2002). Article  CAS  Google Scholar  * Serwold, T., Gonzalez, F., Kim, J.,

Jacob, R. & Shastri, N. ERAAP customizes peptides for MHC class I molecules in the endoplasmic reticulum. _Nature_ 419, 480–483 (2002). Article  CAS  Google Scholar  * Altfeld, M. et al.

Cellular immune responses and viral diversity in individuals treated during acute and early HIV-1 infection. _J. Exp. Med._ 193, 169–180 (2001). Article  CAS  Google Scholar  * Lee, J.K. et

al. T cell cross-reactivity and conformational changes during TCR engagement. _J. Exp. Med._ 200, 1455–1466 (2004). Article  CAS  Google Scholar  * Martinez-Hackert, E. et al. Structural

basis for degenerate recognition of natural HIV peptide variants by cytotoxic lymphocytes. _J. Biol. Chem._ 281, 20205–20212 (2006). Article  CAS  Google Scholar  * Streeck, H. et al.

Recognition of a defined region within p24 gag by CD8+ T cells during primary human immunodeficiency virus type 1 infection in individuals expressing protective HLA class I alleles. _J.

Virol._ 81, 7725–7731 (2007). Article  CAS  Google Scholar  * Bouillot, M. et al. Physical association between MHC class I molecules and immunogenic peptides. _Nature_ 339, 473–475 (1989).

Article  CAS  Google Scholar  * Huet, S. et al. Structural homologies between two HLA B27-restricted peptides suggest residues important for interaction with HLA B27. _Int. Immunol._ 2,

311–316 (1990). Article  CAS  Google Scholar  * Jardetzky, T.S., Lane, W.S., Robinson, R.A., Madden, D.R. & Wiley, D.C. Identification of self peptides bound to purified HLA-B27.

_Nature_ 353, 326–329 (1991). Article  CAS  Google Scholar  * Nixon, D.F. et al. HIV-1 Gag-specific cytotoxic T lymphocytes defined with recombinant vaccinia virus and synthetic peptides.

_Nature_ 336, 484–487 (1988). Article  CAS  Google Scholar  * Urban, R.G. et al. A subset of HLA-B27 molecules contains peptides much longer than nonamers. _Proc. Natl. Acad. Sci. USA_ 91,

1534–1538 (1994). Article  CAS  Google Scholar  * Betts, M.R. et al. Putative immunodominant human immunodeficiency virus-specific CD8+ T-cell responses cannot be predicted by major

histocompatibility complex class I haplotype. _J. Virol._ 74, 9144–9151 (2000). Article  CAS  Google Scholar  * Altfeld, M.A. et al. Identification of dominant optimal HLA-B60- and

HLA-B61-restricted cytotoxic T-lymphocyte (CTL) epitopes: rapid characterization of CTL responses by enzyme-linked immunospot assay. _J. Virol._ 74, 8541–8549 (2000). Article  CAS  Google

Scholar  * Streeck, H. et al. Antigen load and viral sequence diversification determine the functional profile of HIV-1-specific CD8+ T cells. _PLoS Med._ 5, e100 (2008). Article  Google

Scholar  * Almeida, J.R. et al. Superior control of HIV-1 replication by CD8+ T cells is reflected by their avidity, polyfunctionality, and clonal turnover. _J. Exp. Med._ 204, 2473–2485

(2007). Article  CAS  Google Scholar  * Wearsch, P.A. & Cresswell, P. Selective loading of high-affinity peptides onto major histocompatibility complex class I molecules by the

tapasin-ERp57 heterodimer. _Nat. Immunol._ 8, 873–881 (2007). Article  CAS  Google Scholar  * Brumme, Z.L. et al. Evidence of differential HLA class I-mediated viral evolution in functional

and accessory/regulatory genes of HIV-1. _PLoS Pathog._ 3, e94 (2007). Article  Google Scholar  * Goulder, P.J. & Watkins, D.I. HIV and SIV CTL escape: implications for vaccine design.

_Nat. Rev. Immunol._ 4, 630–640 (2004). Article  CAS  Google Scholar  * Goulder, P.J. et al. Evolution and transmission of stable CTL escape mutations in HIV infection. _Nature_ 412, 334–338

(2001). Article  CAS  Google Scholar  * Collins, E.J., Garboczi, D.N. & Wiley, D.C. Three-dimensional structure of a peptide extending from one end of a class I MHC binding site.

_Nature_ 371, 626–629 (1994). Article  CAS  Google Scholar  * Wilson, J.D. et al. Oligoclonal expansions of CD8+ T cells in chronic HIV infection are antigen specific. _J. Exp. Med._ 188,

785–790 (1998). Article  CAS  Google Scholar  * Gao, X. et al. AIDS restriction HLA allotypes target distinct intervals of HIV-1 pathogenesis. _Nat. Med._ 11, 1290–1292 (2005). Article  CAS

  Google Scholar  * Burgevin, A. et al. A detailed analysis of the murine TAP transporter substrate specificity. _PLoS ONE_ 3, e2402 (2008). Article  Google Scholar  * Sylvester-Hvid, C. et

al. Establishment of a quantitative ELISA capable of determining peptide-MHC class I interaction. _Tissue Antigens_ 59, 251–258 (2002). Article  CAS  Google Scholar  Download references

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.

AUTHOR INFORMATION AUTHORS AND AFFILIATIONS * Institute of Immunology, University of Mainz, Mainz, Germany Stefan Tenzer, Nadja Akkad & Hansjörg Schild * 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 * Institut National de la Santé et de la Recherche Médicale, Unité 580, Paris, France Anne Burgevin, Mirjana Weimershaus & Peter van

Endert * Faculté de Médecine René Descartes, Université Paris-Descartes, Paris, France Anne Burgevin, Mirjana Weimershaus & Peter van Endert * Laboratory of Experimental Immunology,

University of Copenhagen, Copenhagen, Denmark Kasper Lamberth, Mikkel Harndahl & Søren Buus * Department of Infectious Diseases, Rigshospitalet, The National University Hospital,

Copenhagen, Denmark Jan Gerstoft * Nuffield Department of Clinical Medicine, Peter Medawar Building for Pathogen Research, Oxford University, Oxford, UK Paul Klenerman * Department of

Clinical Neurology, John Radcliffe Hospital, Oxford University, Oxford, UK Lars Fugger * Structural Biology Group, Wellcome Trust Centre for Human Genetics, Oxford University, Oxford, UK E

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this author inPubMed Google Scholar * E Yvonne Jones View author publications You can also search for this author inPubMed Google Scholar * Andrew J McMichael View author publications You

can also search for this author inPubMed Google Scholar * Søren Buus View author publications You can also search for this author inPubMed Google Scholar * Hansjörg Schild View author

publications You can also search for this author inPubMed Google Scholar * Peter van Endert View author publications You can also search for this author inPubMed Google Scholar * Astrid K N

Iversen View author publications You can also search for this author inPubMed Google Scholar 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. CORRESPONDING AUTHOR Correspondence to Astrid K N Iversen. SUPPLEMENTARY INFORMATION SUPPLEMENTARY TEXT AND FIGURES

Supplementary Figures 1–7 and Supplementary Tables 1–3 (PDF 5449 kb) RIGHTS AND PERMISSIONS Reprints and permissions ABOUT THIS ARTICLE CITE THIS ARTICLE 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 Download citation * Received: 22

December 2008 * Accepted: 12 March 2009 * Published: 03 May 2009 * Issue Date: June 2009 * DOI: https://doi.org/10.1038/ni.1728 SHARE THIS ARTICLE Anyone you share the following link with

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