Intra- and inter-clade cross-reactivity by HIV-1 Gag specific T-cells reveals exclusive and commonly targeted regions: implications for current vaccine trials.
The genetic diversity of HIV-1 across the globe is a major challenge for developing an HIV vaccine. To facilitate immunogen design, it is important to characterize clusters of commonly targeted T-cell epitopes across different HIV clades. To address this, we examined 39 HIV-1 clade C infected individuals for IFN-γ Gag-specific T-cell responses using five sets of overlapping peptides, two sets matching clade C vaccine candidates derived from strains from South Africa and China, and three peptide sets corresponding to consensus clades A, B, and D sequences. The magnitude and breadth of T-cell responses against the two clade C peptide sets did not differ, however clade C peptides were preferentially recognized compared to the other peptide sets. A total of 84 peptides were recognized, of which 19 were exclusively from clade C, 8 exclusively from clade B, one peptide each from A and D and 17 were commonly recognized by clade A, B, C and D. The entropy of the exclusively recognized peptides was significantly higher than that of commonly recognized peptides (p = 0.0128) and the median peptide processing scores were significantly higher for the peptide variants recognized versus those not recognized (p = 0.0001). Consistent with these results, the predicted Major Histocompatibility Complex Class I IC(50) values were significantly lower for the recognized peptide variants compared to those not recognized in the ELISPOT assay (p<0.0001), suggesting that peptide variation between clades, resulting in lack of cross-clade recognition, has been shaped by host immune selection pressure. Overall, our study shows that clade C infected individuals recognize clade C peptides with greater frequency and higher magnitude than other clades, and that a selection of highly conserved epitope regions within Gag are commonly recognized and give rise to cross-clade reactivities.
Division of Medical Virology, Institute of Infectious Disease and Molecular Medicine, University of Cape Town, Cape Town, South Africa.
Lycias
L
Zembe
Wendy A
WA
Burgers
Heather B
HB
Jaspan
Linda-Gail
LG
Bekker
Helba
H
Bredell
Gwynneth
G
Stevens
Jill
J
Gilmour
Josephine H
JH
Cox
Patricia
P
Fast
Peter
P
Hayes
Eftyhia
E
Vardas
Carolyn
C
Williamson
Clive M
CM
Gray
D016915:AIDS Vaccines / Q000276:immunology*; D000328:Adult; D000595:Amino Acid Sequence; D017951:Antigen Presentation / Q000276:immunology; D002986:Clinical Trials as Topic; D003429:Cross Reactions / Q000276:immunology*; D000939:Epitopes / Q000737:chemistry / Q000276:immunology; D015497:HIV-1 / Q000145:classification* / Q000276:immunology* / Q000502:physiology; D015395:Histocompatibility Antigens Class I / Q000276:immunology; D006801:Humans; D008875:Middle Aged; D008969:Molecular Sequence Data; D010455:Peptides / Q000737:chemistry / Q000276:immunology; D011499:Protein Processing, Post-Translational; D013601:T-Lymphocytes / Q000276:immunology*; D055815:Young Adult; D054301:gag Gene Products, Human Immunodeficiency Virus / Q000737:chemistry / Q000235:genetics / Q000276:immunology*
D016915:AIDS Vaccines; D000939:Epitopes; D015395:Histocompatibility Antigens Class I; D010455:Peptides; D054301:gag Gene Products, Human Immunodeficiency Virus