Recipient HLA-C7 and Protection from Polyoma Virus Nephropathy.

To the Editor: In the March issue of this Journal, Wunderink describes recipient HLA-B51 status as a marker of protection from polyomavirus infection and proposes a potential underlying mechanism. We sought to replicate these findings in an Institutional Review Board–approved study of 1948 patients who underwent kidney transplantation between 2007 and 2018, using basiliximab/tacrolimus/mycophenolate/prednisolone immunosuppression, and with demographics characteristic of an urban UK cohort. HLA-B51 was present in 226 recipients (11.6%), similar to the previous report. Neither protocol biopsies nor protocolized blood viral load measurements were undertaken; on indication biopsies, polyomavirus interstitial nephropathy (PVIN) was detected in 55 patients (2.9%; median 8 mo post-transplantation), always in the presence of a detectable blood viral load. No protective effect of recipient HLA-B51 status on PVIN was evident (Cox model hazard ratio [HR]: 0.94; 95% confidence interval [CI]: 0.41-2.21; P = 0.9). On univariate analysis, only increased HLA-B mismatch was associated with time to PVIN (HR: 1.69; 95% CI: 1.06-2.69; P = 0.03). Subsequently, viral clearance (exclusively by virtue of immunosuppression reduction) occurred in 35 patients, with a further 3 demonstrating partial clearance below blood viral load of 7000 copies/mL, a cutoff suggested of relevance to tissue-invasive disease. No effect of HLA-B51 status was seen in time-to-total or -partial viral clearance (P > 0.8 for both). It is possible that the findings from Wunderink may represent a type 1 statistical error, particularly in light of the numerous HLA alleles studied during their investigation. But we also acknowledge the potential for a type 2 error in our current report and ultimately propose more validation (or otherwise) is required for clarifying the B51 effect. We also took the opportunity to investigate one other HLA association with PVIN, specifically the role of HLAC7, reported by Bohl as protective when present in kidney transplant donors and recipients and which also has a potential biological basis in regard to its role in modifying the interaction between HLA-E and the natural killer cell receptor NKG2A, thereby augmenting the innate immune response to viral infection. Of note, a previous attempt to replicate this finding in kidney transplantation was unsuccessful. HLA-C7 was present in 1006 (51.6%) recipients and 1088 (55.8%) donors in our cohort. Although no association between either recipient or donor HLA-C7 and the development of PVIN was seen (P > 0.4 for both), an association was seen between recipient HLA-C7 and reduced time to peripheral blood complete viral clearance, an effect which held on multivariate analysis adjusted for standard pretransplant demographic and clinical variables (HR: 4.75; 95% CI: 1.25-18.01; P = 0.02) which also showed faster viral clearance in live (versus deceased) donor kidneys (P = 0.05). Analysis of partial viral clearance showed similar results for the recipient HLA-C7 effect (multivariate HR: 9.11; 95% CI: 2.03-40.93; P = 0.004). No effect of donor HLA-C7 upon viral clearance was evident. Although this report is not an exact replicate of Bohl’s study (recipient versus recipient/donor, nephropathy versus viremia, and clearance versus development of infection, respectively), the investigations are clearly complementary. This, coupled with the biological plausibility of the phenomenon, suggests that further investigation of HLA-C7 in the context of PVIN and potentially other viral diseases may be warranted.