Why HIV Controllers Control: Force-Stabilized TCR—pMHC Interactions Boosts Sensitivity in Elite Controllers and Protective HLA Alleles 2267511

Abstract Introduction CD8+ T cells from HIV elite controllers (ECs) have TCRs with higher antigen sensitivity than those from vaccinees (VACs). However, within protective HLA alleles (B27:05, B57:01), standard functional avidity do not separate EC from VAC, and why B27:05/B57:01 are protective has remained unclear. Methods We applied single-molecule biophysical measurement–micropipette assay for 2D TCR affinity and biomembrane force probe for TCR catch-bond–to test whether TCR—pMHC interaction mechanics explain cohort differences and predict high sensitivity at low antigen dose. Results Across Gag-specific TCRs, we observed allele-specific discrimination. For B57:01, EC and VAC TCRs differ by higher 2D TCR affinity in ECs. For B27:05, 2D affinity overlaps, and catch bond lifetime uniquely separates EC from VAC TCRs. Dose-controlled activation with pMHC-coated beads at known site densities showed that TCRs with stronger catch bonds generate higher peak Ca²+ flux, which correlates directly with bond lifetime at the optimal force and also translates to higher CD69 expression, especially at low antigen densities. To probe allele effects, we coupled mechanics with structural modeling and molecular dynamics, revealing force-favorable contact consistent with the measurements. Protective-allele TCRs–especially B*27:05–exhibit markedly stronger catch bonds and longer lifetimes than TCRs restricted by non-protective alleles (A02:01, A03:01, B*08:01), including some TCRs from ECs, indicating that enhanced stability is allele-specific (restricted to protective allele), not universal. Conclusion Our findings identify TCR mechanics as the missing discriminator: B57:01 separates by higher 2D affinity; B27:05 separates by stronger catch-bond, and these features predict superior activation at low antigen density. Such mechanics is supported by structure/MD simulation which provides a mechanistic basis for EC and protective-allele advantage and offers practical measures for TCR selection in vaccines and T cell therapies. Funding Source n/a Topic Categories Immune Response Regulation: Molecular Mechanisms (IRM)