Skip to main content

Thank you for visiting nature.com. You are using a browser version with limited support for CSS. To obtain the best experience, we recommend you use a more up to date browser (or turn off compatibility mode in Internet Explorer). In the meantime, to ensure continued support, we are displaying the site without styles and JavaScript.

MHC-I peptides get out of the groove and enable a novel mechanism of HIV-1 escape

Abstract

Major histocompatibility complex class I (MHC-I) molecules play a crucial role in immunity by capturing peptides for presentation to T cells and natural killer (NK) cells. The peptide termini are tethered within the MHC-I antigen-binding groove, but it is unknown whether other presentation modes occur. Here we show that 20% of the HLA-B*57:01 peptide repertoire comprises N-terminally extended sets characterized by a common motif at position 1 (P1) to P2. Structures of HLA-B*57:01 presenting N-terminally extended peptides, including the immunodominant HIV-1 Gag epitope TW10 (TSTLQEQIGW), showed that the N terminus protrudes from the peptide-binding groove. The common escape mutant TSNLQEQIGW bound HLA-B*57:01 canonically, adopting a dramatically different conformation than the TW10 peptide. This affected recognition by killer cell immunoglobulin-like receptor (KIR) 3DL1 expressed on NK cells. We thus define a previously uncharacterized feature of the human leukocyte antigen class I (HLA-I) immunopeptidome that has implications for viral immune escape. We further suggest that recognition of the HLA-B*57:01-TW10 epitope is governed by a 'molecular tension' between the adaptive and innate immune systems.

This is a preview of subscription content, access via your institution

Relevant articles

Open Access articles citing this article.

Access options

Buy article

Get time limited or full article access on ReadCube.

$32.00

All prices are NET prices.

Figure 1: HLA-B*57:01 in complex with the TW10 peptide.
Figure 2: Characterization of N-terminally extended peptides.
Figure 3: The HIV-1 Gag repertoire of HLA-B*57:01.
Figure 4: Cartoon representations of the crystal structure of HLA-B*57:01 (light gray) in complex with the TSTFEDVKILAF peptide (cyan).
Figure 5: Comparison of the HLA-B*57:01–TW10 and HLA-B*57:01–T3N ternary complex structures with KIR3DL1*001.
Figure 6: HLA-B*57:01 TW10 and T3N binding to KIR3DL1.

Accession codes

Primary accessions

Protein Data Bank

Referenced accessions

Protein Data Bank

Swiss-Prot

References

  1. Saper, M.A., Bjorkman, P.J. & Wiley, D.C. Refined structure of the human histocompatibility antigen HLA-A2 at 2.6 Å resolution. J. Mol. Biol. 219, 277–319 (1991).

    Article  CAS  PubMed  Google Scholar 

  2. Rammensee, H.G., Friede, T. & Stevanoviíc, S. MHC ligands and peptide motifs: first listing. Immunogenetics 41, 178–228 (1995).

    Article  CAS  PubMed  Google Scholar 

  3. Deres, K., Beck, W., Faath, S., Jung, G. & Rammensee, H.G. MHC/peptide binding studies indicate hierarchy of anchor residues. Cell. Immunol. 151, 158–167 (1993).

    Article  PubMed  Google Scholar 

  4. Wilson, I.A. & Fremont, D.H. Structural analysis of MHC class I molecules with bound peptide antigens. Semin. Immunol. 5, 75–80 (1993).

    Article  CAS  PubMed  Google Scholar 

  5. Garrett, T.P., Saper, M.A., Bjorkman, P.J., Strominger, J.L. & Wiley, D.C. Specificity pockets for the side chains of peptide antigens in HLA-Aw68. Nature 342, 692–696 (1989).

    Article  CAS  PubMed  Google Scholar 

  6. Speir, J.A., Stevens, J., Joly, E., Butcher, G.W. & Wilson, I.A. Two different, highly exposed, bulged structures for an unusually long peptide bound to rat MHC class I RT1-Aa. Immunity 14, 81–92 (2001).

    Article  CAS  PubMed  Google Scholar 

  7. Tynan, F.E. et al. High resolution structures of highly bulged viral epitopes bound to major histocompatibility complex class I. Implications for T-cell receptor engagement and T-cell immunodominance. J. Biol. Chem. 280, 23900–23909 (2005).

    Article  CAS  PubMed  Google Scholar 

  8. Malnati, M.S. et al. Peptide specificity in the recognition of MHC class I by natural killer cell clones. Science 267, 1016–1018 (1995).

    Article  CAS  PubMed  Google Scholar 

  9. Peruzzi, M., Parker, K.C., Long, E.O. & Malnati, M.S. Peptide sequence requirements for the recognition of HLA-B*2705 by specific natural killer cells. J. Immunol. 157, 3350–3356 (1996).

    CAS  PubMed  Google Scholar 

  10. Stewart-Jones, G.B. et al. Crystal structures and KIR3DL1 recognition of three immunodominant viral peptides complexed to HLA-B*2705. Eur. J. Immunol. 35, 341–351 (2005).

    Article  CAS  PubMed  Google Scholar 

  11. Fan, Q.R., Long, E.O. & Wiley, D.C. Crystal structure of the human natural killer cell inhibitory receptor KIR2DL1-HLA-Cw4 complex. Nat. Immunol. 2, 452–460 (2001).

    Article  CAS  PubMed  Google Scholar 

  12. Vivian, J.P. et al. Killer cell immunoglobulin-like receptor 3DL1-mediated recognition of human leukocyte antigen B. Nature 479, 401–405 (2011).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  13. 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  PubMed  Google Scholar 

  14. Tenzer, S. et al. Antigen processing influences HIV-specific cytotoxic T lymphocyte immunodominance. Nat. Immunol. 10, 636–646 (2009).

    Article  CAS  PubMed  Google Scholar 

  15. McMurtrey, C. et al. Toxoplasma gondii peptide ligands open the gate of the HLA class I binding groove. eLife 5, e12556 (2016).

    Article  PubMed  PubMed Central  Google Scholar 

  16. Stryhn, A., Pedersen, L.O., Holm, A. & Buus, S. Longer peptide can be accommodated in the MHC class I binding site by a protrusion mechanism. Eur. J. Immunol. 30, 3089–3099 (2000).

    Article  CAS  PubMed  Google Scholar 

  17. Schittenhelm, R.B., Dudek, N.L., Croft, N.P., Ramarathinam, S.H. & Purcell, A.W. A comprehensive analysis of constitutive naturally processed and presented HLA-C*04:01 (Cw4)-specific peptides. Tissue Antigens 83, 174–179 (2014).

    Article  CAS  PubMed  Google Scholar 

  18. Carrington, M. & O'Brien, S.J. The influence of HLA genotype on AIDS. Annu. Rev. Med. 54, 535–551 (2003).

    Article  CAS  PubMed  Google Scholar 

  19. Migueles, S.A. et al. HLA B*5701 is highly associated with restriction of virus replication in a subgroup of HIV-infected long term nonprogressors. Proc. Natl. Acad. Sci. USA 97, 2709–2714 (2000).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  20. Gao, X. et al. AIDS restriction HLA allotypes target distinct intervals of HIV-1 pathogenesis. Nat. Med. 11, 1290–1292 (2005).

    Article  CAS  PubMed  Google Scholar 

  21. 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  PubMed  Google Scholar 

  22. Mallal, S. et al. Association between presence of HLA-B*5701, HLA-DR7, and HLA-DQ3 and hypersensitivity to HIV-1 reverse-transcriptase inhibitor abacavir. Lancet 359, 727–732 (2002).

    Article  CAS  PubMed  Google Scholar 

  23. Illing, P.T. et al. Immune self-reactivity triggered by drug-modified HLA-peptide repertoire. Nature 486, 554–558 (2012).

    Article  CAS  PubMed  Google Scholar 

  24. Hetherington, S. et al. Genetic variations in HLA-B region and hypersensitivity reactions to abacavir. Lancet 359, 1121–1122 (2002).

    Article  CAS  PubMed  Google Scholar 

  25. Goulder, P.J. et al. Novel, cross-restricted, conserved, and immunodominant cytotoxic T lymphocyte epitopes in slow progressors in HIV type 1 infection. AIDS Res. Hum. Retroviruses 12, 1691–1698 (1996).

    Article  CAS  PubMed  Google Scholar 

  26. Klein, M.R. et al. Characterization of HLA-B57-restricted human immunodeficiency virus type 1 Gag- and RT-specific cytotoxic T lymphocyte responses. J. Gen. Virol. 79, 2191–2201 (1998).

    Article  CAS  PubMed  Google Scholar 

  27. Bailey, J.R., Williams, T.M., Siliciano, R.F. & Blankson, J.N. Maintenance of viral suppression in HIV-1-infected HLA-B*57+ elite suppressors despite CTL escape mutations. J. Exp. Med. 203, 1357–1369 (2006).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  28. Bernardin, F., Kong, D., Peddada, L., Baxter-Lowe, L.A. & Delwart, E. Human immunodeficiency virus mutations during the first month of infection are preferentially found in known cytotoxic T-lymphocyte epitopes. J. Virol. 79, 11523–11528 (2005).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  29. Ganusov, V.V. et al. Fitness costs and diversity of the cytotoxic T lymphocyte (CTL) response determine the rate of CTL escape during acute and chronic phases of HIV infection. J. Virol. 85, 10518–10528 (2011).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  30. Martinez-Picado, J. et al. Fitness cost of escape mutations in p24 Gag in association with control of human immunodeficiency virus type 1. J. Virol. 80, 3617–3623 (2006).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  31. Novitsky, V. et al. Dynamics and timing of in vivo mutations at Gag residue 242 during primary HIV-1 subtype C infection. Virology 403, 37–46 (2010).

    Article  CAS  PubMed  Google Scholar 

  32. Miura, T. et al. HLA-B57/B*5801 human immunodeficiency virus type 1 elite controllers select for rare gag variants associated with reduced viral replication capacity and strong cytotoxic T-lymphocyte [corrected] recognition. J. Virol. 83, 2743–2755 (2009).

    Article  CAS  PubMed  Google Scholar 

  33. Brackenridge, S. et al. An early HIV mutation within an HLA-B*57-restricted T cell epitope abrogates binding to the killer inhibitory receptor 3DL1. J. Virol. 85, 5415–5422 (2011).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  34. Crawford, H. et al. Compensatory mutation partially restores fitness and delays reversion of escape mutation within the immunodominant HLA-B*5703-restricted Gag epitope in chronic human immunodeficiency virus type 1 infection. J. Virol. 81, 8346–8351 (2007).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  35. Alter, G. et al. Differential natural killer cell-mediated inhibition of HIV-1 replication based on distinct KIR/HLA subtypes. J. Exp. Med. 204, 3027–3036 (2007).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  36. Martin, M.P. et al. Epistatic interaction between KIR3DS1 and HLA-B delays the progression to AIDS. Nat. Genet. 31, 429–434 (2002).

    Article  CAS  PubMed  Google Scholar 

  37. Qi, Y. et al. KIR/HLA pleiotropism: protection against both HIV and opportunistic infections. PLoS Pathog. 2, e79 (2006).

    Article  PubMed  PubMed Central  Google Scholar 

  38. Chessman, D. et al. Human leukocyte antigen class I-restricted activation of CD8+ T cells provides the immunogenetic basis of a systemic drug hypersensitivity. Immunity 28, 822–832 (2008).

    Article  CAS  PubMed  Google Scholar 

  39. Colaert, N., Helsens, K., Martens, L., Vandekerckhove, J. & Gevaert, K. Improved visualization of protein consensus sequences by iceLogo. Nat. Methods 6, 786–787 (2009).

    Article  CAS  PubMed  Google Scholar 

  40. O'Connor, G.M. et al. Mutational and structural analysis of KIR3DL1 reveals a lineage-defining allotypic dimorphism that impacts both HLA and peptide sensitivity. J. Immunol. 192, 2875–2884 (2014).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  41. Wang, C.R. et al. Nonclassical binding of formylated peptide in crystal structure of the MHC class Ib molecule H2-M3. Cell 82, 655–664 (1995).

    Article  CAS  PubMed  Google Scholar 

  42. Escobar, H. et al. Large scale mass spectrometric profiling of peptides eluted from HLA molecules reveals N-terminal-extended peptide motifs. J. Immunol. 181, 4874–4882 (2008).

    Article  CAS  PubMed  Google Scholar 

  43. Samino, Y. et al. A long N-terminal-extended nested set of abundant and antigenic major histocompatibility complex class I natural ligands from HIV envelope protein. J. Biol. Chem. 281, 6358–6365 (2006).

    Article  CAS  PubMed  Google Scholar 

  44. Petersen, J.L., Morris, C.R. & Solheim, J.C. Virus evasion of MHC class I molecule presentation. J. Immunol. 171, 4473–4478 (2003).

    Article  CAS  PubMed  Google Scholar 

  45. Jost, S. & Altfeld, M. Evasion from NK cell-mediated immune responses by HIV-1. Microbes Infect. 14, 904–915 (2012).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  46. Schwartz, O., Maréchal, V., Le Gall, S., Lemonnier, F. & Heard, J.M. Endocytosis of major histocompatibility complex class I molecules is induced by the HIV-1 Nef protein. Nat. Med. 2, 338–342 (1996).

    Article  CAS  PubMed  Google Scholar 

  47. Seeger, M., Ferrell, K., Frank, R. & Dubiel, W. HIV-1 tat inhibits the 20 S proteasome and its 11 S regulator-mediated activation. J. Biol. Chem. 272, 8145–8148 (1997).

    Article  CAS  PubMed  Google Scholar 

  48. Kutsch, O., Vey, T., Kerkau, T., Hünig, T. & Schimpl, A. HIV type 1 abrogates TAP-mediated transport of antigenic peptides presented by MHC class I. Transporter associated with antigen presentation. AIDS Res. Hum. Retroviruses 18, 1319–1325 (2002).

    Article  CAS  PubMed  Google Scholar 

  49. Iglesias, M.C. et al. Escape from highly effective public CD8+ T-cell clonotypes by HIV. Blood 118, 2138–2149 (2011).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  50. Liu, Y.C. et al. A molecular basis for the interplay between T cells, viral mutants, and human leukocyte antigen micropolymorphism. J. Biol. Chem. 289, 16688–16698 (2014).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  51. Ladell, K. et al. A molecular basis for the control of preimmune escape variants by HIV-specific CD8+ T cells. Immunity 38, 425–436 (2013).

    Article  CAS  PubMed  Google Scholar 

  52. Goulder, P.J. et al. Evolution and transmission of stable CTL escape mutations in HIV infection. Nature 412, 334–338 (2001).

    Article  CAS  PubMed  Google Scholar 

  53. 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  PubMed  PubMed Central  Google Scholar 

  54. Crawford, H. et al. Evolution of HLA-B*5703 HIV-1 escape mutations in HLA-B*5703-positive individuals and their transmission recipients. J. Exp. Med. 206, 909–921 (2009).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  55. Alter, G. & Altfeld, M. NK cells in HIV-1 infection: evidence for their role in the control of HIV-1 infection. J. Intern. Med. 265, 29–42 (2009).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  56. Lichterfeld, M. et al. A viral CTL escape mutation leading to immunoglobulin-like transcript 4-mediated functional inhibition of myelomonocytic cells. J. Exp. Med. 204, 2813–2824 (2007).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  57. Croft, N.P. et al. Kinetics of antigen expression and epitope presentation during virus infection. PLoS Pathog. 9, e1003129 (2013).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  58. Fadda, L. et al. Common HIV-1 peptide variants mediate differential binding of KIR3DL1 to HLA-Bw4 molecules. J. Virol. 85, 5970–5974 (2011).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  59. Saunders, P.M. et al. Killer cell immunoglobulin-like receptor 3DL1 polymorphism defines distinct hierarchies of HLA class I recognition. J. Exp. Med. 213, 791–807 (2016).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  60. Kostenko, L. et al. Rapid screening for the detection of HLA-B57 and HLA-B58 in prevention of drug hypersensitivity. Tissue Antigens 78, 11–20 (2011).

    Article  CAS  PubMed  Google Scholar 

  61. Dudek, N.L. et al. Constitutive and inflammatory immunopeptidome of pancreatic β-cells. Diabetes 61, 3018–3025 (2012).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  62. Purcell, A.W. & Gorman, J.J. The use of post-source decay in matrix-assisted laser desorption/ionisation mass spectrometry to delineate T cell determinants. J. Immunol. Methods 249, 17–31 (2001).

    Article  CAS  PubMed  Google Scholar 

  63. Clements, C.S. et al. The production, purification and crystallization of a soluble heterodimeric form of a highly selected T-cell receptor in its unliganded and liganded state. Acta Crystallogr. D Biol. Crystallogr. 58, 2131–2134 (2002).

    Article  PubMed  Google Scholar 

  64. Zhang, Z. & Marshall, A.G. A universal algorithm for fast and automated charge state deconvolution of electrospray mass-to-charge ratio spectra. J. Am. Soc. Mass Spectrom. 9, 225–233 (1998).

    Article  CAS  PubMed  Google Scholar 

  65. Collaborative Computational Project, Number 4. The CCP4 suite: programs for protein crystallography. Acta Crystallogr. D Biol. Crystallogr. 50, 760–763 (1994).

  66. Evans, P. Scaling and assessment of data quality. Acta Crystallogr. D Biol. Crystallogr. 62, 72–82 (2006).

    Article  PubMed  Google Scholar 

  67. Leslie, A.G.W. Recent changes to the MOSFLM package for processing film and image plate data. Joint CCP4 + ESF-EAMCB Newsletter on Protein Crystallography No. 26 (1992).

  68. McCoy, A.J. et al. Phaser crystallographic software. J. Appl. Crystallogr. 40, 658–674 (2007).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  69. Emsley, P. & Cowtan, K. Coot: model-building tools for molecular graphics. Acta Crystallogr. D Biol. Crystallogr. 60, 2126–2132 (2004).

    Article  PubMed  Google Scholar 

  70. Adams, P.D. et al. PHENIX: a comprehensive Python-based system for macromolecular structure solution. Acta Crystallogr. D Biol. Crystallogr. 66, 213–221 (2010).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  71. Chen, V.B. et al. MolProbity: all-atom structure validation for macromolecular crystallography. Acta Crystallogr. D Biol. Crystallogr. 66, 12–21 (2010).

    Article  CAS  PubMed  Google Scholar 

Download references

Acknowledgements

This work was supported by project grants from the National Health and Medical Research Council of Australia (NH&MRC; APP1063829 to A.W.P., and APP1099814 to J.P.V. and D.A.P.) and the Australian Research Council (ARC; DP150104503 to J.R. and A.W.P.). A.W.P. is an NH&MRC Senior Research Fellow. P.T.I. is an NH&MRC Early Career Fellow. S.H.R. is the recipient of an Australian Postgraduate Award. D.A.P. is supported by a Wellcome Trust Senior Investigator Award. J.R. is supported by an ARC Laureate Fellowship. This work was funded in part by the intramural program of the National Institutes of Health, National Cancer Institute. This research was carried out in part on the MX2 beamline at the Australian Synchrotron, Victoria, Australia. J. Mak (Deakin University, Melbourne, Victoria, Australia) provided the Gag plasmid and generated the antibody used to assay Gag expression in transfectants.

Author information

Authors and Affiliations

Authors

Contributions

P.P., P.T.I., S.H.R. and G.M.O'C. collected and analyzed the data and wrote the manuscript with guidance and intellectual input from D.W.M., A.G.B., A.W.P., J.R. and J.P.V. B.K.H. assisted with bioinformatics analysis. V.A.H. assisted with hydrogen deuterium assays. C.H. assisted with cell culture and protein purification. D.A.P. and all other authors contributed to intellectual discussions on the manuscript.

Corresponding authors

Correspondence to Anthony W Purcell, Jamie Rossjohn or Julian P Vivian.

Ethics declarations

Competing interests

The authors declare no competing financial interests.

Integrated supplementary information

Supplementary Figure 1 Hydrogen-deuterium exchange spectra for the TW10 peptide in complex with HLA-B*57:01 and free in solution.

(a) Peptide in complex with HLA-B*57:01 at 0 seconds showing the normal isotopic distribution for a singly charged peptide (b) The peptide in complex with HLA-B*57:01 after 10 seconds incubation in D2O showing a single Gaussian distribution indicative of a single bound conformation and (c) the peptide free in a solution of D2O for 10 seconds showing a bimodal distribution suggesting multiple conformations in solution. Spectra displayed are from a single experiment and represent data from three independent experiments.

Supplementary Figure 2 Circular dichroism readings taken at 222 nm over a temperature range of 20–90 °C for the HLA-B*57:01–TW10 complex (a) and the HLA-B*57:01-T3N complex (b).

Tm was calculated by fitting a sigmoidal dose-response curve and taking the IC50 value of the curve. Data represent a single experiment.

Supplementary information

Supplementary Text and Figures

Supplementary Figures 1–2 and Supplementary Note 1 (PDF 1206 kb)

Supplementary Table 1

Combined HLA-B*57:01 data set (XLSX 943 kb)

Supplementary Table 2

Alignment of N-terminally extended peptide sets (XLSX 441 kb)

Supplementary Table 3

Extended sets containing C-terminal or N- and C-terminal extensions (XLSX 47 kb)

Rights and permissions

Reprints and Permissions

About this article

Verify currency and authenticity via CrossMark

Cite this article

Pymm, P., Illing, P., Ramarathinam, S. et al. MHC-I peptides get out of the groove and enable a novel mechanism of HIV-1 escape. Nat Struct Mol Biol 24, 387–394 (2017). https://doi.org/10.1038/nsmb.3381

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1038/nsmb.3381

This article is cited by

Search

Quick links

Nature Briefing

Sign up for the Nature Briefing newsletter — what matters in science, free to your inbox daily.

Get the most important science stories of the day, free in your inbox. Sign up for Nature Briefing