An unusually high substitution rate in transplant-associated BK polyomavirus in vivo is further concentrated in HLA-C-bound viral peptides

Pilar Domingo-Calap,Oliver Kohlbacher,Fernando González-Candelas,Benjamin Schubert,Nicodème Paul,Seiamak Bahram,Samira Fafi-Kremer,Mélanie Joly,Sophie Caillard,Philippe Georgel,Raphael Carapito,Morgane Solis,Meiggie Untrau,Marco Vignuzzi

doi:10.1371/journal.ppat.1007368

Abstract

Infection with human BK polyomavirus, a small double-stranded DNA virus, potentially results in severe complications in immunocompromised patients. Here, we describe the in vivo variability and evolution of the BK polyomavirus by deep sequencing. Our data reveal the highest genomic evolutionary rate described in double-stranded DNA viruses, i.e., 10−3–10−5 substitutions per nucleotide site per year. High mutation rates in viruses allow their escape from immune surveillance and adaptation to new hosts. By combining mutational landscapes across viral genomes with in silico prediction of viral peptides, we demonstrate the presence of significantly more coding substitutions within predicted cognate HLA-C-bound viral peptides than outside. This finding suggests a role for HLA-C in antiviral immunity, perhaps through the action of killer cell immunoglobulin-like receptors. The present study provides a comprehensive view of viral evolution and immune escape in a DNA virus.

Highlights

Viral evolutionary rates can vary strongly depending on the method used to estimate them [1, 2]
Regarding estimates based on doublestranded DNA (dsDNA) complete genomes, all of them range between 10−5 and 10−7 s/s/y [3, 5]
After complete deep genome sequencing of all 225 samples and alignment to the BK virus (BKV) Dunlop reference strain (GenBank accession number NC001538), an average of 110 ± 3 polymorphisms per sample was observed with an average median coverage of 3043 ± 78 reads/position (S1 Table, GenBank accession numbers KT896230-KT896454; see Methods)

Summary

Introduction

Viral evolutionary rates can vary strongly depending on the method used to estimate them [1, 2]. Regarding estimates based on dsDNA complete genomes, all of them range between 10−5 and 10−7 s/s/y [3, 5]. This finding confirms that viruses are fast evolving entities whereas humans have much lower evolutionary rates (10−8–10−9 s/s/y). The well-established co-divergence of viral populations with their hosts suggests the possibility of low evolutionary rates in viruses as well. Polyomaviruses were historically considered to be examples of human-virus co-divergence, and have been used as markers for human migration patterns, with proposed estimates ranging from 1.41 × 10−7 to 4 × 10−8 s/s/y [6, 7]. Detailed studies are needed to better understand dsDNA virus evolution in vivo, especially in viruses that can be considered as potential pathogens

Methods

Results

Conclusion