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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 epitope-targeting 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 epitope-targeting frequency and antiviral efficacy in HIV-1 infection. A clear immunodominance hierarchy was observed across 20 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 important insights into a potential link between shared TCR recruitment, immunodominance, and antiviral efficacy in a major human infection.

Original publication

DOI

10.4049/jimmunol.1400854

Type

Journal article

Journal

J Immunol

Publication Date

01/06/2015

Volume

194

Pages

5329 - 5345

Keywords

Adult, Amino Acid Sequence, Antibody Affinity, Base Sequence, CD8-Positive T-Lymphocytes, DNA, Complementary, Epitope Mapping, Epitopes, T-Lymphocyte, Female, HIV Infections, HIV-1, HLA-B Antigens, Humans, Immunodominant Epitopes, Receptors, Antigen, T-Cell, Sequence Analysis, DNA, Viral Load, gag Gene Products, Human Immunodeficiency Virus