Analysis of viral inhibitory activity of cytotoxic T. Lymphocytes targeting identical epitopes restricted by different class 1 HLA alleles from the same HLA supertype.
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Date
2015
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Abstract
Human leukocyte antigen (HLA) polymorphism and the genetic diversity of human
immunodeficiency virus (HIV) are the major obstacles for designing an effective HIV
Cytotoxic T Lymphocytes (CTLs) based vaccine. Interestingly, recent studies have
demonstrated that multiple class I alleles can recognize common epitopes “supertopes” due to
the homology of amino acids within the major binding pockets of the peptide binding cleft.
The implications of this for vaccine design is that a vaccine containing a small number of highly
promiscuous supertopes can confer protection against a wide range of HIV variants. This
notion makes supertopes immunogen design an attractive option. However, it is not clear
whether supertopes presented in the context of different class I HLA alleles would induce
functional equivalent CTL responses.
In this study, we investigated the inhibitory activity of CTLs targeting identical epitopes
presented by class I HLA alleles from the same superfamily. The viral inhibitory activity was
measured using a newly developed CEM-GFP reporter T-cell line (GXR-cell) as target cell.
We first compared the inhibitory activity of CTLs from 8 subjects targeting TPQDLNTML
(Gag p24 residue 180-188-TL9) epitope presented by HLA-B*81:01 or B*42:01 alleles. We
then assessed the inhibitory activity of the 8 subjects’ CTLs when presented with in-vivo
occurring mutant (Q182S)-TL9 epitope by HLA-B*81:01 or B*42:01 alleles. Furthermore, we
compared the inhibitory activity of CTLs from 4 subjects targeting ISPRTLNAW (Gag p24
residue 147-155-IW9) epitope presented by HLA-B*57:03 or B*58:01 alleles.
Comparative analysis of the inhibitory activity of the 8 subjects’ CTLs showed no
statistical significant difference when TL9 epitope was presented by HLA-B*81:01 or B*42:01
alleles (1:1; p-value = 0.8785, paired t test), even at low target to effector ratio (1:8; p-value =
0.4418). No statistical significant difference was observed in the inhibitory activity of the 8
subjects’ CTLs when mutant (Q182S)-TL9 epitope was presented by HLA-B*81:01 or
B*42:01 alleles (1:1; p-value = 0.8042), same result was observed at low target to effector ratio
(1:8; p-value = 0.9396).
Comparative analysis of the inhibitory activity of the 4 subjects’ CTLs targeting
identical IW9 epitopes presented by HLA-B*57:03 or B*58:01 alleles showed a trend towards
significance at target to effector ratio 1:1 (1:1; p-value = 0.0924), but at low target to effector
ratio, no significance difference was observed (1:8; p-value = 0.1496).
In conclusion, we have demonstrated that there is no observable significant difference
in the inhibitory activity of CTLs targeting wildtype TL9 or mutant (Q182S)-TL9 epitopes
presented in the context of HLA-B*81:01 or B*42:01 alleles. Thus, TL9 epitope could be
immunogenic for individuals expressing HLA-B*81:01 or B*42:01 alleles. We have also
shown that the inhibitory activity of CTLs targeting identical IW9 epitopes presented by HLAB*
57:03 or B*58:01 alleles is comparable. Indicating that IW9 epitope could be included in
immunogen design for individuals expressing HLA-B*57:03 or B*58:01 alleles. These
findings are relevant for HIV vaccine approach that seeks to identify immunogenic supertopes
that can be cross-presented in a broadly cross-reactive T cell based vaccine design.
Description
Master of Medical Sciences in Immunology. University of KwaZulu-Natal, Medical School 2015.
Keywords
HLA histocompatibility antigens., Antigenic determinants., HIV antibodies., Theses -- Immunology., Human leukocyte antigens (HLA)