Mutations in the HPV16 genome induced by APOBEC3 are associated with viral clearance

Nat Commun. 2020 Feb 14;11(1):886. doi: 10.1038/s41467-020-14730-1.

Abstract

HPV16 causes half of cervical cancers worldwide; for unknown reasons, most infections resolve within two years. Here, we analyze the viral genomes of 5,328 HPV16-positive case-control samples to investigate mutational signatures and the role of human APOBEC3-induced mutations in viral clearance and cervical carcinogenesis. We identify four de novo mutational signatures, one of which matches the COSMIC APOBEC-associated signature 2. The viral genomes of the precancer/cancer cases are less likely to contain within-host somatic HPV16 APOBEC3-induced mutations (Fisher's exact test, P = 6.2 x 10-14), and have a 30% lower nonsynonymous APOBEC3 mutation burden compared to controls. We replicate the low prevalence of HPV16 APOBEC3-induced mutations in 1,749 additional cases. APOBEC3 mutations also historically contribute to the evolution of HPV16 lineages. We demonstrate that cervical infections with a greater burden of somatic HPV16 APOBEC3-induced mutations are more likely to be benign or subsequently clear, suggesting they may reduce persistence, and thus progression, within the host.

Publication types

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

MeSH terms

  • APOBEC Deaminases
  • Adult
  • Case-Control Studies
  • Cervix Uteri / virology
  • Cytidine Deaminase / genetics
  • Cytidine Deaminase / metabolism*
  • Female
  • Genome, Viral*
  • Host-Pathogen Interactions
  • Human papillomavirus 16 / genetics*
  • Human papillomavirus 16 / physiology
  • Humans
  • Middle Aged
  • Mutation
  • Papillomavirus Infections / enzymology*
  • Papillomavirus Infections / genetics
  • Papillomavirus Infections / virology
  • Uterine Cervical Neoplasms / enzymology
  • Uterine Cervical Neoplasms / genetics
  • Uterine Cervical Neoplasms / virology

Substances

  • APOBEC Deaminases
  • APOBEC3 proteins, human
  • Cytidine Deaminase