Background
HIV-1-specific CD8 T cell responses directed against genetically-conserved HIV-1 protein regions are associated with viral control. Therefore, we developed the Immunoinformatics Analysis Pipeline (IMAP) to identify 182 peptides (IMAP-peptides) from 5 HIV-1 protein regions (Gag, Pol, Vif, Vpr, and Env) which are mutation-constrained, genetically-conserved across global HIV-1 subtypes, and predicted to bind common HLA-1 alleles providing 99% worldwide coverage. To validate the predicted immunogenicity of these IMAP-peptides, we assessed the CD8 T cell responses to the total HIV-1 IMAP peptide pool (182 peptides) and IMAP-peptides pooled by HIV-1 protein.
Methods
We collected peripheral blood mononuclear cells (PBMCs) from 8 participants, including: transient-controllers (TCs) who controlled viral rebound after antiretroviral therapy (ART) was stopped (n=3); non-controllers who experienced viral rebound in the absence of ART (n=3); one participant on ART, and one elite controller. The PBMCs from these participants were expanded for 2 weeks and restimulated with the total HIV-1 IMAP peptide pool to induce the production of IFN-g and TNF-a detected by flow cytometry as markers for effector CD8 T cell responses. For participants with an adequate number of cells (n=7), the cells were also restimulated with the individual IMAP-HIV-1 protein pools to determine which antigens drove the immune response.
Results
The CD8 T cells from all participants responded to the total HIV-1 IMAP-peptide pool, supporting the predicted HLA coverage. Interestingly, CD8 T cells from TCs had the highest response to the total HIV-1 IMAP-peptide pool which was 12-fold more than NCs. We also found the response to the individual IMAP-HIV-1 protein pools is donor dependent with Gag, Pol, and Vpr IMAP-peptide pools eliciting a CD8 T cell response from 3 of the 7 partcipants. Of note, the Env IMAP-peptide pool did not elicit a CD8 T cell response from any participant.
Conclusions
Our results reveal that the IMAP-peptides from four HIV-1 proteins (Gag, Pol, Vif and Vpr) and the total HIV-1 IMAP-peptide pool elicited a CD8 T cell effector response. The higher potential of CD8 T cells from TCs to recognize and respond to these mutation-constrained HIV epitopes may contribute to their virological control. Therefore, therapeutic strategies using the IMAP-peptides have the potential to expand the number of CD8 T cells and redirect their response to these highly conserved and mutation-constrained epitopes within HIV-1 proteins.