A Molecular Basis for the Control of Preimmune Escape Variants by HIV-Specific CD8+ T Cells

The capacity of the immune system to adapt to rapidly evolving viruses is a primary feature of effective immunity, yet its molecular basis is unclear. Here, we investigated protective HIV-1-specific CD8(+) T cell responses directed against the immunodominant p24 Gag-derived epitope KK10 (KRWIILGLNK(263-272)) presented by human leukocyte antigen (HLA)-B*2705. We found that cross-reactive CD8(+) T cell clonotypes were mobilized to counter the rapid emergence of HIV-1 variants that can directly affect T cell receptor (TCR) recognition. These newly recruited clonotypes expressed TCRs that engaged wild-type and mutant KK10 antigens with similar affinities and almost identical docking modes, thereby accounting for their antiviral efficacy in HLA-B*2705(+) individuals. A protective CD8(+) T cell repertoire therefore encompasses the capacity to control TCR-accessible mutations, ultimately driving the development of more complex viral escape variants that disrupt antigen presentation.