Nature Medicine
10, 282 - 289 (2004)
Published online: 8 February 2004; | doi:10.1038/nm992
HIV evolution: CTL escape mutation and reversion after transmissionA J Leslie1, 12, K J Pfafferott1, 12, P Chetty2, R Draenert3, M M Addo3, M Feeney3, Y Tang3, E C Holmes4, T Allen3, J G Prado5, M Altfeld3, C Brander3, C Dixon1, D Ramduth2, P Jeena2, S A Thomas2, A St John6, T A Roach6, B Kupfer7, G Luzzi8, A Edwards9, G Taylor10, H Lyall10, G Tudor-Williams10, V Novelli11, J Martinez-Picado5, P Kiepiela2, B D Walker3
& P J R Goulder1, 31
Department of Pediatrics, Fuffield Department of Medicine, Peter Medawar Building for Pathogen Research, University of Oxford, Oxford OX1 3SY, UK. 2
HIV Pathogenesis Programme, The Doris Duke Medical Research Institute, University of Natal, Congella 4013, Durban, South Africa. 3
Partners AIDS Research Center and Harvard Medical School, Boston, Massachusetts 02129, USA. 4
Department of Zoology, University of Oxford, Oxford OX1 3SY, UK. 5
irsiCaixa Foundation, University Hospital 'Germans Trias i Pujol', 08916 Barcelona, Spain. 6
Queen Elizabeth II Hospital, Bridgetown, Barbados. 7
University of Bonn, 53105 Bonn, Germany. 8
Department of Genitourinary Medicine, High Wycombe General Hospital, HP11 2TT, UK. 9
The Harrison Clinic, Radcliffe Infirmary Hospital, Oxford, OX2 6HE, UK. 10
Imperial College School of Medicine, St Mary's Hospital, London W2 1NY, UK. 11
Great Ormond Street Hospital for Sick Children, London WC1N 3JH, UK. 12
These authors contributed equally to this work.
Correspondence should be addressed to P J R Goulder philip.goulder@ndm.ox.ac.ukWithin-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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