Reactivations of Latent Viral Infections Are Associated with an Increased Thr389 p70S6k Phosphorylation in Peripheral Lymphocytes of Renal Transplant Recipients.

Maxim Cherneha,Oliver Witzke,Andreas Kribben,André Hoerning,Meike Kaulfuß,Nina Babel,Sebastian Dolff,Hana Rohn,Marek Widera,Johannes Korth,Mirko Trilling

doi:10.3390/v13030424

Abstract

Reactivations of BK polyoma virus (BKPyV) and human cytomegalovirus (HCMV) frequently cause life- and graft-threatening complications after renal transplantation. Both viruses are dependent on the mTOR pathway for replication. In this study we investigated the association of viral replication with mTOR activity in peripheral lymphocytes of renal transplant recipients. A flow-cytometry based assay for the measurement of Thr389 p70S6k phosphorylation, a surrogate marker of the mTOR pathway was established. Forty-eight adult renal transplant recipients were recruited to measure p70S6k activity in their peripheral blood mononuclear cells. This data set in conjunction with information concerning previous replication of BKPyV and HCMV was examined for correlations. Episodes of BKPyV replication were significantly associated with increased p70S6k phosphorylation in CD4+ T lymphocytes (p = 0.0002) and CD19+ B lymphocytes (p = 0.0073). HCMV infection of patients with a high-risk HCMV constellation of donor and recipient (D+/R−) was associated with increased p70S6k phosphorylation in CD19+ B lymphocytes (p = 0.0325). These associations were found to be independent of the trough levels of the immunosuppressive drugs. Conclusion: P70S6k phosphorylation in peripheral lymphocytes is associated with BKPyV reactivations and to a lesser extent with HCMV infections in renal transplant recipients.

Highlights

BK polyoma virus (BKPyV) Viremia Is Associated with Increased p70 ribosomal S6 kinase (p70S6k) Phosphorylation
The relative difference in medians of p70S6k phosphorylation between groups was more pronounced in CD4+ T lymphocytes as compared to CD19+
Renal transplant recipients with a polyomavirus-associated nephropathy (PyVAN) showed a trend towards even higher levels of p70S6k phosphorylation in their CD4+ T and CD19+ B lymphocytes without reaching the predetermined significance level

Summary

Introduction

Due to advances in immunosuppression, especially through the action of calcineurin inhibitors (CNI), kidney transplantation has become the best treatment for end-stage renal disease with regard to long term survival and quality of life [1,2,3]. The management of transplant recipients poses a challenge since immunosuppression for transplant acceptance has to be balanced with sufficient immune competence to prevent infections. A leading cause of infections after transplantation are reactivations of opportunistic viruses from pre-existing latency reservoirs [4,5]. HCMV and BKPyV are responsible for most viral complications, threatening the life of patients and compromising graft survival. BKPyV shows the highest prevalence of viremia and causes polyomavirus-associated nephropathy (PyVAN)

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Results

Conclusion