CD8⁺ TCR bias and immunodominance in HIV1 infection

Immunodominance describes a phenomenon whereby the immune system consistently targets only a fraction of the available Ag pool derived from a given pathogen. In the case of CD8+ T cells, these constrained epitopetargeting patterns are linked to HLA class I expression and determine disease progression. Despite the biological importance of these predetermined response hierarchies, little is known about the factors that control immunodominance in vivo. In this study, we conducted an extensive analysis of CD8+ T cell responses restricted by a single HLA class I molecule to evaluate the mechanisms that contribute to epitopetargeting frequency and antiviral efficacy in HIV1 infection. A clear immunodominance hierarchy was observed across 20 epitopes restricted by HLAB∗42:01, which is highly prevalent in populations of African origin. Moreover, in line with previous studies, Gagspecific responses and targeting breadth were associated with lower viral load setpoints. However, peptide-HLAB∗42:01 binding affinity and stability were not significantly linked with targeting frequencies. Instead, immunodominance correlated with epitopespecific usage of public TCRs, defined as amino acid residue-identical TRB sequences that occur in multiple individuals. Collectively, these results provide important insights into a potential link between shared TCR recruitment, immunodominance, and antiviral efficacy in a major human infection.