Early antigen presentation of protective HIV-1 KF11Gag and KK10Gag epitopes from incoming viral particles facilitates rapid recognition of infected cells by specific CD8⁺ T Cells

CD8⁺ T cells are major players in antiviral immunity against human immunodeficiency virus type 1 (HIV-1) through recognition of viral epitopes presented on the surface of infected cells. However, the early events involving HIV-1 epitope presentation to CD8⁺ T cells remain poorly understood but are nonetheless crucial for the rapid clearance of virus-infected cells. Here, we comprehensively studied the kinetics of antigen presentation of two protective epitopes, KF11Gag and KK10Gag, restricted by HLA alleles B*57:01 and B*27:05, respectively, and compared these to KY9Pol and VL9Vpr epitopes in a single cycle of HIV-1 replication. We consistently demonstrate differences in epitope presentation kinetics, with very early presentation, within 3 h postinfection, for the protective KF11Gag, KK10Gag epitopes, and KY9Pol but only late presentation for VL9Vpr. We show that this early presentation relies on the antigen being presented from incoming viral particles and is correlated with rapid CD8⁺ T cell activation and clearance of virus-infected cells. Additionally, our data indicate a dose-response dependency between the levels of CD8⁺ T cell activation and the amount of virus inoculum. These data reflect a proof of principle emphasizing the importance of identifying early-presented viral epitopes for rapid elimination of HIV-1-infected cells.