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HIV evolution: CTL escape mutation and reversion after transmission

Nature Medicine volume 10, pages 282–289 (2004)Cite this article

Abstract

Within-patient HIV evolution reflects the strong selection pressure driving viral escape from cytotoxic T-lymphocyte (CTL) recognition. Whether this intrapatient accumulation of escape mutations translates into HIV evolution at the population level has not been evaluated. We studied over 300 patients drawn from the B- and C-clade epidemics, focusing on human leukocyte antigen (HLA) alleles HLA-B57 and HLA-B5801, which are associated with long-term HIV control and are therefore likely to exert strong selection pressure on the virus. The CTL response dominating acute infection in HLA-B57/5801-positive subjects drove positive selection of an escape mutation that reverted to wild-type after transmission to HLA-B57/5801-negative individuals. A second escape mutation within the epitope, by contrast, was maintained after transmission. These data show that the process of accumulation of escape mutations within HIV is not inevitable. Complex epitope- and residue-specific selection forces, including CTL-mediated positive selection pressure and virus-mediated purifying selection, operate in tandem to shape HIV evolution at the population level.

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Figure 1: TW10 variants are escape mutations.
Figure 2: Reversion of TW10 variants after transmission to HLA-B57/5801-negative subjects.
Figure 3: Patterns of HLA-B57/5801-associated mutation and reversion before and after transmission.

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Acknowledgements

We thank those who made possible the collection of blood samples for this study, in particular the staff at Cato Manor Clinic, Durban (the largest single cohort). We also thank M. Hammond and M. Bunce for HLA typing; C. Hull-Jackson, B. Matz, C. Edwards and H. Coovadia for facilitating these studies; M. Maiden and L. Richardson for assisting with the sequencing; and P. Klenerman and R. Phillips for critically reviewing the manuscript. This work was supported by the Wellcome Trust (P.J.R.G. and A.L.), the Elizabeth Glaser Pediatric AIDS Foundation (P.J.R.G. and M.F.), the Spanish Health Department (BEFI, Red G03/173 to J.M.-P.), the National Institutes of Health (AI46995-01A1 and N01-AI-15442) and the Doris Duke Charitable Foundation. P.J.R.G. is an Elizabeth Glaser Scientist and B.D.W. is a Doris Duke Distinguished Clinical Science Professor.

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Author notes

  1. A J Leslie and K J Pfafferott: These authors contributed equally to this work.

Authors and Affiliations

  1. Department of Pediatrics, Fuffield Department of Medicine, Peter Medawar Building for Pathogen Research, University of Oxford, Oxford, OX1 3SY, UK

    A J Leslie, K J Pfafferott, C Dixon & P J R Goulder

  2. HIV Pathogenesis Programme, The Doris Duke Medical Research Institute, University of Natal, Congella 4013, Durban, South Africa

    P Chetty, D Ramduth, P Jeena, S A Thomas & P Kiepiela

  3. Partners AIDS Research Center and Harvard Medical School, Boston, 02129, Massachusetts, USA

    R Draenert, M M Addo, M Feeney, Y Tang, T Allen, M Altfeld, C Brander, B D Walker & P J R Goulder

  4. Department of Zoology, University of Oxford, Oxford, OX1 3SY, UK

    E C Holmes

  5. irsiCaixa Foundation, University Hospital 'Germans Trias i Pujol', Barcelona, 08916, Spain

    J G Prado & J Martinez-Picado

  6. Queen Elizabeth II Hospital, Bridgetown, Barbados

    A St John & T A Roach

  7. University of Bonn, Bonn, 53105, Germany

    B Kupfer

  8. Department of Genitourinary Medicine, High Wycombe General Hospital, HP11 2TT, UK

    G Luzzi

  9. The Harrison Clinic, Radcliffe Infirmary Hospital, Oxford, OX2 6HE, UK

    A Edwards

  10. Imperial College School of Medicine, St Mary's Hospital, London, W2 1NY, UK

    G Taylor, H Lyall & G Tudor-Williams

  11. Great Ormond Street Hospital for Sick Children, London, WC1N 3JH, UK

    V Novelli

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Correspondence to P J R Goulder.

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Leslie, A., Pfafferott, K., Chetty, P. et al. HIV evolution: CTL escape mutation and reversion after transmission. Nat Med 10, 282–289 (2004). https://doi.org/10.1038/nm992

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