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* Department of Paediatrics, Nuffield Department of Medicine, Peter Medawar Building for Pathogen Research, Oxford, United Kingdom;
Human Immunology Section, Vaccine Research Center, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, MD 20892;
HIV Pathogenesis Programme, Doris Duke Medical Research Institute, University of Natal, Durban, South Africa;
Partners AIDS Research Center, Massachusetts General Hospital, Boston, MA 02129;
¶ Department of Genitourinary Medicine, High Wycombe General Hospital, High Wycombe, United Kingdom;
|| The Harrison Clinic, Radcliffe Infirmary Hospital, Oxford, United Kingdom;
# Department of Microbiology, University of Washington School of Medicine, Seattle, WA 98195;
** Imperial College School of Medicine, St. Mary’s Hospital, London, United Kingdom; and
Great Ormond Street Hospital for Sick Children, London, United Kingdom
HLA diversity is seen as a major challenge to CTL vaccines against HIV. One current approach focuses on "promiscuous" epitopes, presented by multiple HLA alleles from within the same HLA supertype. However, the effectiveness of such supertype vaccines depends upon the functional equivalence of CTL targeting a particular epitope, irrespective of the restricting HLA. In this study, we describe the promiscuous HIV-specific CTL epitopes presented by alleles within the B7 supertype. Substantial differences were observed in the ability of CTL to select for escape mutation when targeting the same epitope but restricted by different HLA. This observation was common to all six promiscuous B7 epitopes identified. Moreover, with one exception, there were no significant differences in the frequency, magnitude, or immunodominance of the CTL responses restricted by different HLA alleles to explain these discrepancies. This suggests that the unique peptide/MHC complexes generated by even closely related HLA induce CTL responses that are qualitatively different. This hypothesis is supported by additional differences observed between CTL targeting identical epitopes but restricted by different HLA: first, the occurrence of distinct, HLA-specific escape mutation; second, the recruitment of distinct TCR repertoires by particular peptide/MHC complexes; and, third, significant differences in the functional avidity of CTL. Taken together, these data indicate that significant functional differences exist between CTL targeting identical epitopes but restricted by different, albeit closely related HLA. These findings are of relevance to vaccine approaches that seek to exploit HLA supertypes to overcome the problem of HLA diversity.
The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked advertisement in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.
1 This work was supported by the National Institutes of Health (Contract NO1-A1-15422, 2RO1AI46995-06) and the Wellcome Trust (to A.L. and P.J.R.G.). D.A.P. is a Medical Research Council (U.K.) Clinical Scientist; B.D.W. is a Doris Duke Distinguished Clinical Science Professor; P.J.R.G. is an Elizabeth Glaser Pediatric AIDS Foundation Scientist.
2 Address correspondence and reprint requests to Dr. Alasdair Leslie, University of Oxford, Department of Paediatrics, Peter Medawar Building, South Parks Road, Oxford OX1 3SY, United Kingdom. E-mail address: alleslie8{at}yahoo.co.uk
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