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

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

doi:10.1371/journal.ppat.1007368

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

PLoS Pathog. 2018 Oct 18;14(10):e1007368. doi: 10.1371/journal.ppat.1007368. eCollection 2018 Oct.

Authors

Pilar Domingo-Calap^{1

2}, Benjamin Schubert^{3

4}, Mélanie Joly^{1

2

5}, Morgane Solis^{1

2

6}, Meiggie Untrau^{1

2}, Raphael Carapito^{1

2

7}, Philippe Georgel^{1

2}, Sophie Caillard^{1

2

5}, Samira Fafi-Kremer^{1

2

6}, Nicodème Paul^{1

2}, Oliver Kohlbacher^{3

4

8

9

10

11}, Fernando González-Candelas¹², Seiamak Bahram^{1

2

7}

Affiliations

¹ Plateforme GENOMAX, Laboratoire d'ImmunoRhumatologie Moléculaire, INSERM UMR_S1109, LabEx Transplantex, Centre de Recherche d'Immunologie et d'Hématologie, Faculté de Médecine, Fédération de Médecine Translationnelle de Strasbourg (FMTS), Université de Strasbourg, Strasbourg, France.
² Fédération Hospitalo-Universitaire, OMICARE, Centre de Recherche d'Immunologie et d'Hématologie, Strasbourg, France.
³ Center for Bioinformatics, University of Tübingen, Tübingen, Germany.
⁴ Applied Bioinformatics, Department of Computer Science, Tübingen, Germany.
⁵ Service de Néphrologie et Transplantation Rénale, Hôpitaux Universitaires de Strasbourg, France.
⁶ Laboratoire de Virologie, Plateau Technique de Microbiologie, Pôle de Biologie, Hôpitaux Universitaires de Strasbourg, France.
⁷ Laboratoire Central d'Immunologie, Plateau Technique de Biologie, Nouvel Hôpital Civil, France.
⁸ Quantitative Biology Center, Tübingen, Germany.
⁹ Faculty of Medicine, University of Tübingen, Tübingen, Germany.
¹⁰ Biomolecular Interactions, Max Planck Institute for Developmental Biology, Tübingen, Germany.
¹¹ Institute for Translational Bioinformatics, University Hospital Tübingen, Tübingen, Germany.
¹² Unidad Mixta Infección y Salud Pública FISABIO/Universitat de València, Institute for Integrative Systems Biology I2SysBio (CSIC-UV) and CIBER en Epidemiología y Salud Pública, Valencia, Spain.

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.

Publication types

Research Support, Non-U.S. Gov't

MeSH terms

Amino Acid Substitution
BK Virus / genetics*
BK Virus / immunology
Genome, Viral
HLA-C Antigens / genetics
HLA-C Antigens / immunology
HLA-C Antigens / metabolism*
High-Throughput Nucleotide Sequencing
Humans
Mutation*
Organ Transplantation*
Peptide Fragments / genetics
Peptide Fragments / immunology
Peptide Fragments / metabolism*
Phylogeny
Polyomavirus Infections / genetics
Polyomavirus Infections / immunology
Polyomavirus Infections / virology*

Substances

HLA-C Antigens
Peptide Fragments

Grants and funding

This work has been published under the framework of the Laboratoire d’Excellence (LABEX) TRANSPLANTEX [ANR-11-LABX-0070_TRANSPLANTEX] and benefits from a funding from the French government, managed by the French National Research Agency (ANR) as part of the « Investments for the future » program (SB)(http://www.agence-nationale-recherche.fr/investissementsdavenir/). Additional support was received from the Strasbourg High Throughput Next Generation Sequencing facility (GENOMAX)(SB)(no URL available), the Institut National de la Santé et de la Recherche Médicale (INSERM)(SB)(www.inserm.fr), Initiative d'Excellence (IDEX) fund of the University of Strasbourg (UNISTRA)(SB)(www.unistra.fr), the Institut Universitaire de France (IUF)(SB)(http://www.iufrance.fr), projects BFU2014-58656R and BFU2017-89594R from Ministry of Economy and Competitiveness (MINECO; Spanish Government) (http://www.idi.mineco.gob.es)(FGC) and the project PROMETEO/2016/122 from the Generalitat Valenciana (FGC)(www.gva.es/). The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.