Novel HIV-1 p24 Epitope Identified for the Amerindian HLA-B*39:02 Allele 2252620

Introduction HLA drives HIV evolution by selecting polymorphisms within the HIV proteome. HLA-B*39:02 is frequent in populations with Amerindian ancestry such as Mexico. It has been associated with better HIV outcomes and selection of p24-Gag polymorphisms. However, its HIV-specific responses remain unknown. Here, we characterized an HLA-B*39:02—restricted p24 epitope eliciting strong immune responses and show that polymorphisms alter peptide-HLA binding. Methods We recruited 14 men living with HIV and expressing HLA-B*39:02 with less than 60 days on TAR. The magnitude of cytotoxic T lymphocyte (CTL) responses were assessed by IFN-γ ELISpot using overlapping p24 9-mer peptides containing previously identified HLA-B*39:02—associated positions (315 and 319). Peptide binding affinity was assessed by peptide competition assays with substitutions at positions 315 (R, T, G) and 319 (D) using fluorescein-labeled peptides by flow cytometry. Positive CTL responses and IC50 values were compared by Mann-Whitney test. Results The p24 VKNWMTETL peptide, containing HLA-B*39:02 — associated positions 315 and 319) induced strong IFN-γ CTL responses (median of 574 SFU/million PBMCs). Position 315 variants showed distinct binding affinities: N315T maintained affinity, while N315R had lower affinity compared with N315T (IC50 406.2 vs. 204.0 nM; p = 0.0019). The E319D substitution appeared to have no effect on binding affinity compared with the wild-type peptide (IC50 237.9 nM vs. 204.0 nM; ns). In silico modeling of the HLA-B39:02 binding pocket confirmed these findings, indicating that N315G was the least favorable variant, markedly reducing peptide—HLA interaction. Conclusion We identified the first HIV p24 epitope presented by HLA-B*39:02 VKNWMTETL, which elicited strong CTL responses. Variations within this peptide altered its binding affinity to HLA-B*39:02. These findings support this new epitope is as a potential candidate for vaccine or immunotherapeutic strategies in populations with Amerindian ancestry.