Abstract
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 IC50 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.
Highlights
The development of a safe, globally effective and affordable vaccine offers the best hope for the future control of the HIV pandemic
Of major importance for preventative vaccine development is the identity of regions within the HIV-1 proteome that can be targeted by T-cells and that are crossreactive between different viral clades
Because of the significant sequence variation that exists between HIV-1 clades (7–15%, [23]), there is an acknowledgement that the HIV clades on which vaccines are based will have an impact on the immune response elicited, and very likely the subsequent efficacy of vaccines
Summary
The development of a safe, globally effective and affordable vaccine offers the best hope for the future control of the HIV pandemic. We examined intra- and inter-clade crossreactivity of HIV-1-specific T-cell responses to Gag, using peptides matching candidate South African and Chinese clade C vaccine contructs and compared these with clades A, B and D consensusbased peptides. We performed this study using a South African clade C-infected population, where we sequenced the infecting virus from each individual and assessed Tcell responses to the different peptide sets. This allowed us to explore two inter-related aims: a) to identify the location of commonly and exclusively targeted epitope regions in Gag and relate these to the level of virus variability; b) to identify the extent of intra- and inter-clade recognition using peptide sets that match vaccine inserts
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