OA08.03
Background: HIV exposed seronegative (HESN) individuals provide a unique opportunity to study natural immunity to HIV-1. Our previous studies on HESN women from the Pumwani sex worker cohort showed that A*01:01 is associated with slower seroconversion while B*07:02 is associated with rapid seroconversion. Understanding why these alleles associate with different infection rates and their epitope characteristics may provide clues for design of an effective HIV vaccine.
Methods: We screened 1820 peptides (9mer overlapping by 8aa) of HIV-1 clade A/D Env for A*01:01 and B*07:02 epitopes using iTopia Epitope Discovery System. Binding eptiopes were analyzed for affinity, off-rates and validated by IFNγ ELISpot. Selected tetramers were used (A*0101:VI/VK, B*0702:SL/KL) for flow cytometry analysis of CD8 T cell memory (CCR7/CD45Ra) and differentiation (CD27/CD28) phenotypes.
Results: A*01:01 bound 20 epitopes, while B*0702 bound 64. No differences where seen in peptide binding affinity or off-rate between the two alleles. ELISpot responses were stronger in A*01:01+patients (p<0.0001) and a higher proportion of A*01:01 epitopes is in the constant regions. Tetramer specific CD8s had distinct memory and differentiation profiles than non-specific CD8s (p=0.0002). Additionally, CD8 T cells specific for A*01:01 epitope YI were more likely to have an effector memory (CCR7-CD45RA-) phenotype than B*07:02 specific-CD8 T cells (p=0.0002). Moreover, CD8 T cells specific for both A*01:01 epitopes (YI/VK) were highly antigen experienced (CD27-CD28-) compared to those specific for B*07:02 epitopes (p<0.0001).
Conclusions: These data are consistent with our previous study of HIV-1 Gag epitopes of these alleles. A*01:01 recognizes fewer epitopes than B*07:02, suggesting narrow immune responses targeting conserved regions may be better than broad immune responses. Additionally, A*01:01 associates with higher effector memory and higher antigen experience, suggesting high cytolytic activity and potentially more effective responses.
