Quantification of APOBEC3 Mutation Rates Affecting the VP1 Gene of BK Polyomavirus In Vivo

Area of Science:

• Virology
• Genetics
• Immunology

Background:

• BK polyomavirus (BKPyV) mutations accumulate in kidney transplant recipients with persistent replication.
• These mutations are linked to immune evasion and neutralization escape.
• APOBEC3A/B enzymes are suspected sources of these mutations via cytosine deamination.

Purpose of the Study:

• To investigate the mutagenic processes shaping the BKPyV genome in kidney transplant recipients.
• To identify and characterize mutational signatures in BKPyV from patient samples.
• To determine the role of APOBEC3A/B enzymes in BKPyV mutation accumulation.

Main Methods:

• Amplification and deep sequencing (5000-10,000×) of the BKPyV VP1 gene typing region.
• Analysis of mutations using COSMIC mutational signatures.
• Comparison of mutations in patient samples (urine, serum, kidney biopsy) with control plasmids and in vitro infected cells.

Main Results:

• Three distinct mutational signatures were consistently observed across patient sample types.
• Two signatures (SBS2, SBS13) were attributed to APOBEC3A/B activity.
• A novel signature (SBS89) was identified in patient samples and in vitro infected cells, with unknown etiology.
• APOBEC3A/B mutation rates correlated with urine viral load and varied individually.

Conclusions:

• APOBEC3A/B enzymes are a major source of BKPyV mutations in kidney transplant recipients.
• Other mutagenic factors, contributing to the SBS89 signature, also play a role in BKPyV evolution.
• Understanding these mutation patterns is crucial for managing BKPyV infection and preventing graft loss.