Differential selection pressure exerted on HIV by CTL targeting identical epitopes but restricted by distinct HLA alleles from the same HLA supertype.
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.
Leslie
Alasdair
A
Department of Paediatrics, Nuffield Department of Medicine, Peter Medawar Building for Pathogen Research, South Parks Road, Oxford OX1 3SY, United Kingdom. alleslie8@yahoo.co.uk
Price
David A
DA
Mkhize
Pamela
P
Bishop
Karen
K
Rathod
Almas
A
Day
Cheryl
C
Crawford
Hayley
H
Honeyborne
Isobella
I
Asher
Tedi E
TE
Luzzi
Graz
G
Edwards
Anne
A
Rousseau
Christine M
CM
Rosseau
Christine M
CM
Mullins
James I
JI
Tudor-Williams
Gareth
G
Novelli
Vas
V
Brander
Christian
C
Douek
Daniel C
DC
Kiepiela
Photini
P
Walker
Bruce D
BD
Goulder
Philip J R
PJ
D000483:Alleles; D000595:Amino Acid Sequence; D018984:Epitopes, T-Lymphocyte / Q000235:genetics* / Q000276:immunology; D015658:HIV Infections / Q000276:immunology; D015497:HIV-1 / Q000235:genetics* / Q000276:immunology*; D015793:HLA-B7 Antigen / Q000235:genetics* / Q000276:immunology; D006801:Humans; D016056:Immunodominant Epitopes / Q000235:genetics; D008969:Molecular Sequence Data; D016133:Polymerase Chain Reaction; D012333:RNA, Messenger / Q000032:analysis; D012641:Selection, Genetic; D013602:T-Lymphocytes, Cytotoxic / Q000276:immunology*
D018984:Epitopes, T-Lymphocyte; D015793:HLA-B7 Antigen; D016056:Immunodominant Epitopes; D012333:RNA, Messenger