Characterization of BK Polyomaviruses From Kidney Transplant Recipients Suggests a Role for APOBEC3 in Driving In-Host Virus Evolution

Cell Host Microbe. 2018 May 9;23(5):628-635.e7. doi: 10.1016/j.chom.2018.04.005.

Abstract

BK polyomavirus (BKV) frequently causes nephropathy (BKVN) in kidney transplant recipients (KTRs). BKV has also been implicated in the etiology of bladder and kidney cancers. We characterized BKV variants from two KTRs who developed BKVN followed by renal carcinoma. Both patients showed a swarm of BKV sequence variants encoding non-silent mutations in surface loops of the viral major capsid protein. The temporal appearance and disappearance of these mutations highlights the intra-patient evolution of BKV. Some of the observed mutations conferred resistance to antibody-mediated neutralization. The mutations also modified the spectrum of receptor glycans engaged by BKV during host cell entry. Intriguingly, all observed mutations were consistent with DNA damage caused by antiviral APOBEC3 cytosine deaminases. Moreover, APOBEC3 expression was evident upon immunohistochemical analysis of renal biopsies from KTRs. These results provide a snapshot of in-host BKV evolution and suggest that APOBEC3 may drive BKV mutagenesis in vivo.

Keywords: APOBEC; APOBEC3; BKPyV; JCPyV; JCV; bladder; carcinoma; human polyomavirus; urothelial.

Publication types

  • Research Support, N.I.H., Intramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Adult
  • Amino Acid Substitution
  • Animals
  • Antibodies, Neutralizing
  • Antibodies, Viral
  • BK Virus / genetics*
  • BK Virus / immunology
  • Capsid Proteins / genetics
  • Cell Line
  • Chromosome Mapping
  • Cytidine Deaminase
  • Cytosine Deaminase / physiology*
  • DNA Damage
  • DNA, Viral / analysis
  • DNA, Viral / genetics
  • Female
  • HEK293 Cells
  • Humans
  • Italy
  • Kidney Diseases / pathology
  • Kidney Diseases / virology
  • Kidney Transplantation*
  • Male
  • Middle Aged
  • Mutation
  • Polyomavirus Infections / blood
  • Polyomavirus Infections / immunology
  • Polyomavirus Infections / pathology
  • Polyomavirus Infections / virology*
  • Tumor Virus Infections / blood
  • Tumor Virus Infections / immunology
  • Tumor Virus Infections / pathology
  • Tumor Virus Infections / virology*

Substances

  • Antibodies, Neutralizing
  • Antibodies, Viral
  • Capsid Proteins
  • DNA, Viral
  • VP1 protein, polyomavirus
  • Cytosine Deaminase
  • APOBEC3 protein, human
  • Cytidine Deaminase