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

Abstract

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 LSLMRKAYL 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.

Molecular Characterization of BK Polyomavirus Replication in Allogeneic Hematopoietic Cell Transplantation Patients

“…Thus, BKPyV replication after allogeneic HCT may result from (1) reactivation and high-level viruria of the recipient BKPyV during the allogeneic HCT immune gap; (2) exposure to immunosuppressive drugs for GVHD prophylaxis [ 9 , 43 ]; (3) impaired serotype Vp1 antibody and corresponding LTag genotype-specific T-cell control; and (4) viral variants escaping T-cell control [ 24 ]. Based on the findings of this study, prospective clinical studies can be designed to investigate the diagnostic and functional role as well as the prevalence and magnitude of these steps and may help to optimize antiviral strategies as well as vaccination and adoptive transfer of nAbs and T cells [ 41 , 44 , 45 ].…”

“…Single immunodominant 9mers are presented by several HLA types such as HLA-B7, HLA-B8, and HLA-B51 linked to protection from BKPyV replication [ 22 , 23 ]. Analyzing publicly available BKPyV genome sequences has revealed non-synonymous amino acid exchanges in immunodominant LTag 9mers, which significantly reduced HLA-A/HLA-B binding and reduced or abrogated 9mer-specific CD8 T-cell responses [ 24 ]. Based on these findings, we conducted a detailed molecular characterization of urine and plasma BKPyV loads in our allogeneic HCT patients [ 25 ].…”

Antivirals against human polyomaviruses: Leaving no stone unturned

“…The characterisation of the underlying molecular pathogenesis is highly relevant for effective treatment approaches in conjunction with HPyV-specific immunity. Although lasting immune control is the ultimate goal of antiviral therapy, be it by reconstitution, adoptive transfer or vaccination, [22][23][24] we focus here on small-molecule drugs and compounds potentially bridging this gap and disregard immune therapies. Antiviral treatment is needed for treating replicative HPyV diseases such as PyVAN and PyVHC, whereas specific inhibitors blocking the oncogenic activity of small T-antigen (sTag) or large T-antigen (LTag) may be needed for treating hyperproliferative and transforming activities seen HPyVassociated diseases and outright cancers.…”

“…Approximately 10% of healthy BKPyV-seropositive blood donors asymptomatically shed BKPyV in urine, 19 indicating regular escape from immune control, despite specific neutralizing antibodies and T-cells. 22,24,27 PyVAN occurs in 1%-15% of kidney transplant patients. 25 Uncontrolled BKPyV replication in renal tubule epithelial cells causes progressive cytopathology, denudation, interstitial and tubular inflammation, interstitial fibrosis, and eventually tubular atrophy (Figure 1), thereby leading to irreversible loss of allograft function and premature return to renal replacement therapy.…”

Structural implications of BK polyomavirus sequence variations in the major viral capsid protein Vp1 and large T-antigen: a computational study

“…Since there are no effective antiviral drugs for treatment or prevention of BKPyV replication and associated diseases (9), current clinical management relies on reconstituting BKPyV-specific humoral and cellular immunity. However, our earlier work has identified significant changes in 9mer epitopes which were associated with failure of CD8 T cells to activate polyfunctional responses, to kill and to proliferate (10)(11)(12).…”