Within-host variations of human papillomavirus reveal APOBEC signature mutagenesis in the viral genome

Yusuke Hirose, Mamiko Onuki, Yuri Tenjimbayashi, Seiichiro Mori, Yoshiyuki Ishii, Takamasa Takeuchi, Nobutaka Tasaka, Toyomi Satoh, Tohru Morisada, Takashi Iwata, Shingo Miyamoto, Koji Matsumoto, Akihiko Sekizawa, Iwao Kukimoto

Research output: Contribution to journalArticle

15 Citations (Scopus)

Abstract

Persistent infection with oncogenic human papillomaviruses (HPVs) causes cervical cancer, accompanied by the accumulation of somatic mutations into the host genome. There are concomitant genetic changes in the HPV genome during viral infection; however, their relevance to cervical carcinogenesis is poorly understood. Here, we explored within-host genetic diversity of HPV by performing deepsequencing analyses of viral whole-genome sequences in clinical specimens. The whole genomes of HPV types 16, 52, and 58 were amplified by type-specific PCR from total cellular DNA of cervical exfoliated cells collected from patients with cervical intraepithelial neoplasia (CIN) and invasive cervical cancer (ICC) and were deep sequenced. After constructing a reference viral genome sequence for each specimen, nucleotide positions showing changes with > 0.5% frequencies compared to the reference sequence were determined for individual samples. In total, 1,052 positions of nucleotide variations were detected in HPV genomes from 151 samples (CIN1, n = 56; CIN2/3, n = 68; ICC, n = 27), with various numbers per sample. Overall, C-to-T and C-to-A substitutions were the dominant changes observed across all histological grades. While C-to-T transitions were predominantly detected in CIN1, their prevalence was decreased in CIN2/3 and fell below that of C-to-A transversions in ICC. Analysis of the trinucleotide context encompassing substituted bases revealed that TpCpN, a preferred target sequence for cellular APOBEC cytosine deaminases, was a primary site for C-to-T substitutions in the HPV genome. These results strongly imply that the APOBEC proteins are drivers of HPV genome mutation, particularly in CIN1 lesions.

Original languageEnglish
Article numbere00017-18
JournalJournal of Virology
Volume92
Issue number12
DOIs
Publication statusPublished - 2018 Jun 1

Keywords

  • APOBEC
  • Genetic diversity
  • Human papillomavirus
  • Nextgeneration sequencing
  • Quasispecies

ASJC Scopus subject areas

  • Microbiology
  • Immunology
  • Insect Science
  • Virology

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  • Cite this

    Hirose, Y., Onuki, M., Tenjimbayashi, Y., Mori, S., Ishii, Y., Takeuchi, T., Tasaka, N., Satoh, T., Morisada, T., Iwata, T., Miyamoto, S., Matsumoto, K., Sekizawa, A., & Kukimoto, I. (2018). Within-host variations of human papillomavirus reveal APOBEC signature mutagenesis in the viral genome. Journal of Virology, 92(12), [e00017-18]. https://doi.org/10.1128/JVI.00017-18