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Failing BK polyomavirus (BKPyV)-specific immune control is underlying onset and duration of BKPyV-replication and disease. We focused on BKPyV-specific CD8 T-cells as key effectors and characterized immunodominant 9mer epitopes in the viral large tumor-antigen (LTag). We investigated the variation of LTag-epitopes and their predicted effects on HLA-class 1 binding and T-cell activation. Available BKPyV sequences in the NCBI-nucleotide (N = 3263), and the NCBI protein database (N = 4189) were extracted (1368 sequences) and analyzed for non-synonymous aa-exchanges in LTag. Variant 9mer-epitopes were assessed for predicted changes in HLA-A and HLA-B-binding compared to immunodominant 9mer reference. We identified 159 non-synonymous aa-exchanges in immunodominant LTag-9mer T-cell epitopes reflecting different BKPyV-genotypes as well as genotype-independent variants altering HLA-A/HLA-B-binding scores. Decreased binding scores for HLA-A/HLA-B were found in 27/159 (17%). This included the immunodominant LPLMRKAYL affecting HLA-B*07:02-, HLA-B*08:01- and HLA-B*51:01-presentation. In two healthy BKPyV-seropositive HLA-B*07:02 blood donors, variant L S LMRKAYL showed reduced CD8 T-cell responses compared to LPLMRKAYL. Thus, despite LTag being highly conserved, aa-exchanges occur in immunodominant CD8 T-cell epitopes of BKPyV-genotypes as well as of genotypes -independent variants, which may contribute to genotype-dependent and genotype-independent failure of cellular immune control over BKPyV-replication. The data warrant epidemiological and immunological investigations in carefully designed clinical studies.

Variations in BK Polyomavirus Immunodominant Large Tumor Antigen-Specific 9mer CD8 T-Cell Epitopes Predict Altered HLA-Presentation and Immune Failure