CD8+ T-cell receptor bias and immundominance in HIV-1 infection

Immunodominance describes a phenomenon whereby the immune system consistently targets only a fraction of the available antigen pool derived from a given pathogen. In the case of CD8 + T-cells, these constrained epitope targeting patterns are linked to human leukocyte antigen (HLA) class-I expression and determine disease progression. Despite the biological importance of these predetermined response hierarchies, however, 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 epitope targeting frequency and antiviral efficacy in HIV-1 infection. A clear immunodominance hierarchy was observed across 20 different epitopes restricted by HLA-B*42:01, which is highly prevalent in populations of African origin. Moreover, in line with previous studies, Gag-specific responses and targeting breadth were associated with lower viral load set-points. However, peptide-HLA-B*42:01 binding affinity and stability were not significantly linked with targeting frequencies. Instead, immunodominance correlated with epitope-specific usage of public TCRs, defined as amino acid residue-identical TRB sequences that occur in multiple individuals. Collectively, these results provide the first insights into a potential link between shared TCR recruitment, immunodominance and antiviral efficacy in a major human infection.