High Levels of Within-Host Variations of Human Papillomavirus 16 E1/E2 Genes in Invasive Cervical Cancer

Yusuke Hirose, Mayuko Yamaguchi-Naka, Mamiko Onuki, Yuri Tenjimbayashi, Nobutaka Tasaka, Toyomi Satoh, Kohsei Tanaka, Takashi Iwata, Akihiko Sekizawa, Koji Matsumoto, Iwao Kukimoto

Research output: Contribution to journalArticlepeer-review

Abstract

Human papillomavirus type 16 (HPV16) is the most common HPV genotype found in invasive cervical cancer (ICC). Recent comprehensive genomics studies of HPV16 have revealed that a large number of minor nucleotide variations in the viral genome are present in each infected woman; however, it remains unclear whether such within-host variations of HPV16 are linked to cervical carcinogenesis. Here, by employing next-generation sequencing approaches, we explored the mutational profiles of the HPV16 genome within individual clinical specimens from ICC (n = 31) and normal cervix (n = 21) in greater detail. A total of 367 minor nucleotide variations (167 from ICC and 200 from the normal cervix) were detected throughout the viral genome in both groups, while nucleotide variations at high frequencies (>10% abundance in relative read counts in a single sample) were more prevalent in ICC (10 in ICC versus 1 in normal). Among the high-level variations found in ICC, six were located in the E1/E2 genes, and all of them were non-synonymous substitutions (Q142K, M207I, and L262V for E1; D153Y, R302T, and T357A for E2). In vitro functional analyses of these E1/E2 variants revealed that E1/M207I, E2/D153Y, and E2/R302T had reduced abilities to support viral replication, and that E2/D153Y and E2/R302T failed to suppress the viral early promoter. These results imply that some within-host variations of E1/E2 present at high levels in ICC may be positively selected for and contribute to cervical cancer development through dysfunction or de-stabilization of viral replication/transcription proteins.

Original languageEnglish
Article number596334
JournalFrontiers in Microbiology
Volume11
DOIs
Publication statusPublished - 2020 Nov 24

Keywords

  • APOBEC
  • E1/E2
  • human papillomavirus
  • positive selection
  • within-host variation

ASJC Scopus subject areas

  • Microbiology
  • Microbiology (medical)

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