Characterization of Immunodominant BK Polyomavirus 9mer Epitope T Cell Responses

Abstract

Uncontrolled BK polyomavirus (BKPyV) replication in kidney transplant recipients (KTRs) causes polyomavirus‐associated nephropathy and allograft loss. Reducing immunosuppression is associated with clearing viremia and nephropathy and increasing BKPyV‐specific T cell responses in most patients; however, current immunoassays have limited sensitivity, target mostly CD4+ T cells, and largely fail to predict onset and clearance of BKPyV replication. To characterize BKPyV‐specific CD8+ T cells, bioinformatics were used to predict 9mer epitopes in the early viral gene region (EVGR) presented by 14 common HLAs in Europe and North America. Thirty‐nine EVGR epitopes were experimentally confirmed by interferon‐γ enzyme‐linked immunospot assays in at least 30% of BKPyV IgG–seropositive healthy participants. Most 9mers clustered in domains, and some were presented by more than one HLA class I, as typically seen for immunodominant epitopes. Specific T cell binding using MHC class I streptamers was demonstrated for 21 of 39 (54%) epitopes. In a prospective cohort of 118 pediatric KTRs, 19 patients protected or recovering from BKPyV viremia were experimentally tested, and 13 epitopes were validated. Single HLA mismatches were not associated with viremia, suggesting that failing immune control likely involves multiple factors including maintenance immunosuppression. Combining BKPyV load and T cell assays using immunodominant epitopes may help in evaluating risk and reducing immunosuppression and may lead to safe adoptive T cell transfer.

Deep-Sequence Identification and Role in Virus Replication of a JC Virus Quasispecies in Patients with Progressive Multifocal Leukoencephalopathy

“…Generally, replication of polyomavirus is associated with the immune status of patients (7). Recently, immunoepitopes targeted by HLA-restricted T cells were identified in the early viral gene region of BK polyomavirus (38). Interestingly, a prediction of immunoepitopes (http://www.syfpeithi.de/bin/MHCServer.dll/EpitopePrediction.htm) identified the V392 in TAg of JCV as an immunodominant epitope with a top 20 score for HLA-A02 and -A24 nonamers, which are major HLA types in members of the Japanese population (39).…”

Imperfect Symmetry of Sp1 and Core Promoter Sequences Regulates Early and Late Virus Gene Expression of the Bidirectional BK Polyomavirus Noncoding Control Region

“…These miRNAs are transcribed in the late direction and target the EVGR transcripts, thus mediating repression of LTag expression (55). Thereby, persistent archetype BKPyV infection maintains a double-stitched mechanism to ensure tight control of LTag expression below the radar of the immune system (55,56). In turn, activating rearrangements not only switch on EVGR expression but also overcome miRNA suppression, an alteration that requires the absence of a functional immune response (31).…”

The “ABC” of Virus-Specific T Cell Immunity in Solid Organ Transplantation

“…A dominant cytotoxic CD4 T cell activity has been identified for an LTag‐derived 15mer peptide from the conserved helicase region . Recent characterization of CD8 T cell responses by ELISpot and MHC class I streptamers identified >30 immunodominant 9mer epitopes in the EVGR proteome that might be further developed for clinical monitoring of risk and recovery and for potential vaccination and adoptive T cell transfer . A key obstacle to deployment of these data in clinical practice is selecting the most informative epitopes and the fact that a positive response might indicate protection, whereas a negative result has a poor predictive value for subsequent viremia or protection.…”