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Conflicting selective forces affect T cell receptor contacts in an immunodominant human immunodeficiency virus epitope

Nature Immunology volume 7, pages 179–189 (2006)Cite this article

Abstract

Cytotoxic T lymphocytes (CTLs) are critical for the control of human immunodeficiency virus, but containment of virus replication can be undermined by mutations in CTL epitopes that lead to virus escape. We analyzed the evolution in vivo of an immunodominant, HLA-A2–restricted CTL epitope and found two principal, diametrically opposed evolutionary pathways that exclusively affect T cell–receptor contact residues. One pathway was characterized by acquisition of CTL escape mutations and the other by selection for wild-type amino acids. The pattern of CTL responses to epitope variants shaped which variant(s) prevailed in the virus population. The pathways notably influenced the amount of plasma virus, as patients with efficient CTL selection had lower plasma viral loads than did patients without efficient selection. Thus, viral escape from CTL responses does not necessarily correlate with disease progression.

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Figure 1: SLYNTVATL epitope evolution over approximately the first 10 years of disease progression in HIV+ patients.
Figure 2: Representative phylogenetic trees of p17 and p24 gag sequences (HXB2 coordinates 845–1260).
Figure 3: Differences in plasma viral load and HIV SLYNTVATL sequence.
Figure 4: The recognition of SLYNTVATL variants by PBMCs from A*02+ patients.
Figure 5: SLYNTVATL structure in p17 and HLA-A2.

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Acknowledgements

We thank patients for donating samples, N. Willcox for comments on the manuscript, P. Goulder for discussions and C. Siebold for assistance with crystallographic refinement. Supported by the Novo Nordisk Foundation, the Danish AIDS foundation, the University of Washington Center for AIDS Research, International AIDS Vaccine Initiative, Cancer Research UK (E.Y.J.) and Medical Research Council UK (A.K.N.I. and A.J.M.).

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Authors and Affiliations

  1. Medical Research Council Human Immunology Unit, Weatherall Institute of Molecular Medicine, John Radcliffe Hospital, Oxford, OX3 9AD, UK

    Astrid K N Iversen, Andrew E Armitage, Tara Beattie, Jean K Lee, Yanping Li, Tao Dong, Xiaoning Xu, Lars Fugger & Andrew J McMichael

  2. Structural Biology Group, Wellcome Trust Centre for Human Genetics, Oxford, OX3 7BN, UK

    Guillaume Stewart-Jones, Pojchong Chotiyarnwong & E Yvonne Jones

  3. Department of Microbiology, University of Washington, Seattle, 98195-8070, Washington, USA

    Gerald H Learn & James I Mullins

  4. Divisions of Clinical Science and Infectious Disease, Department of Medicine, University of Toronto, ON M5G 1X5, Ontario, Canada

    Natasha Christie, Rupert Kaul, Mark A Luscher & Kelly MacDonald

  5. Department of Microbiology and Immunology, University of Copenhagen, Copenhagen, 2200 Kbh N, Denmark

    Christina Sylvester-Hviid & Søren Buus

  6. Department of Infectious Diseases, Rigshospitalet, Copenhagen University Hospital, Copenhagen, 2100 Kbh Ø, Denmark

    Henrik Ullum, Bente Klarlund-Pedersen & Peter Skinhøj

  7. Department of Clinical Immunology, Skejby Sygehus, Aarhus University Hospital, Aarhus, 8200, Åvhus N, Denmark

    Lars Fugger

  8. Sir William Dunn School of Pathology, Oxford University, Oxford, OX1 3RE, UK

    P Anton van der Merwe

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  1. Astrid K N Iversen
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Correspondence to Astrid K N Iversen.

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Supplementary information

Supplementary Table 1

Additional clinical and sampling data (PDF 17 kb)

Supplementary Table 2

Crystallographic data (PDF 27 kb)

Supplementary Methods (PDF 59 kb)

Supplementary Note (PDF 31 kb)

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Iversen, A., Stewart-Jones, G., Learn, G. et al. Conflicting selective forces affect T cell receptor contacts in an immunodominant human immunodeficiency virus epitope. Nat Immunol 7, 179–189 (2006). https://doi.org/10.1038/ni1298

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