Incoming HIV virion-derived Gag Spacer Peptide 2 (p1) is a target of effective CD8⁺ T cell antiviral responses

Persistence of HIV through integration into host DNA in CD4⁺ T cells presents a major barrier to virus eradication. Viral integration may be curtailed when CD8⁺ T cells are triggered to kill infected CD4⁺ T cells through recognition of histocompatibility leukocyte antigen (HLA) class I-bound peptides derived from incoming virions. However, this has been reported only in individuals with "beneficial" HLA alleles that are associated with superior HIV control. Through interrogation of the pre-integration immunopeptidome, we obtain proof of early presentation of a virion-derived HLA-A^∗02:01-restricted epitope, FLGKIWPSH (FH9), located in Gag Spacer Peptide 2 (SP2). FH9-specific CD8⁺ T cell responses are detectable in individuals with primary HIV infection and eliminate HIV-infected CD4⁺ T cells prior to virus production in vitro. Our data show that non-beneficial HLA class I alleles can elicit an effective antiviral response through early presentation of HIV virion-derived epitopes and also demonstrate the importance of SP2 as an immune target.