Journal Article

Persistent BK Polyomavirus Viruria Is Associated with Accumulation of VP1 Mutations and Neutralization Escape

Hourmant, Maryvonne, Liebert, Uwe, Halary, Franck, Przyrowski, Emilie, McIlroy, Dorian, Hönemann, Mario, Rodallec, Audrey, Barbier, Paul, Peltier, Cécile, Bressollette-Bodin, Céline, Nguyen, Ngoc-Khanh

2020

Overview

To investigate the relationship between neutralization escape and persistent high-level BK polyomavirus replication after kidney transplant (KTx), VP1 sequences were determined by Sanger and next-generation sequencing in longitudinal samples from KTx recipients with persistent high-level viruria (non-controllers) compared to patients who suppressed viruria (controllers). The infectivity and neutralization resistance of representative VP1 mutants were investigated using pseudotype viruses. In all patients, the virus population was initially dominated by wild-type VP1 sequences, then non-synonymous VP1 mutations accumulated over time in non-controllers. BC-loop mutations resulted in reduced infectivity in 293TT cells and conferred neutralization escape from cognate serum in five out of six non-controller patients studied. When taken as a group, non-controller sera were not more susceptible to neutralization escape than controller sera, so serological profiling cannot predict subsequent control of virus replication. However, at an individual level, in three non-controller patients the VP1 variants that emerged exploited specific “holes” in the patient’s humoral response. Persistent high-level BK polyomavirus replication in KTx recipients is therefore associated with the accumulation of VP1 mutations that can confer resistance to neutralization, implying that future BKPyV therapies involving IVIG or monoclonal antibodies may be more effective when used as preventive or pre-emptive, rather than curative, strategies.

• Publisher: MDPI AG,MDPI
• Subject: Adaptive immunology / Adult / Aged / Amino acids / Animals / BK Virus - genetics / BK Virus - immunology / blood serum / Capsid Proteins - genetics / Chlorocebus aethiops / Deoxyribonucleic acid / DNA / Female / Genotype & phenotype / HEK293 Cells / high-throughput nucleotide sequencing / Human polyomavirus 1 / Humans / humoral immunity / Immune Evasion / Immune response (humoral) / immunity / Immunoglobulins / Immunology / Infections / Infectivity / Intravenous administration / kidney transplant / Kidney transplantation / Kidney Transplantation - adverse effects / Kidneys / Life Sciences / Longitudinal Studies / Male / Microbiology and Parasitology / Middle Aged / Monoclonal antibodies / mutants / Mutation / neutralization / Neutralization Tests / Next-generation sequencing / Observational Studies as Topic / pathogenicity / Patients / polyomavirus / Polyomavirus Infections - blood / Polyomavirus Infections - immunology / Polyomavirus Infections - urine / Prospective Studies / Replication / Retrospective Studies / transplantation / Urine / Vero Cells / Viral Load / Virology / Viruria / Virus Replication / Viruses / VP1 protein