Within-Host Variations of Human Papillomavirus Reveal APOBEC Signature Mutagenesis in the Viral Genome

• DOI: 10.1128/jvi.00017-18
• Publication Date: 2018-03-27T10:08:05Z
• Authors: 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
• Keywords: APOBEC

ABSTRACT Persistent infection with oncogenic human papillomaviruses (HPVs) causes cervical cancer, accompanied by the accumulation of somatic mutations into host genome. There are concomitant genetic changes in HPV genome during viral infection; however, their relevance to carcinogenesis is poorly understood. Here, we explored within-host diversity performing deep-sequencing analyses whole-genome sequences clinical specimens. The whole genomes types 16, 52, and 58 were amplified type-specific PCR from total cellular DNA exfoliated cells collected patients intraepithelial neoplasia (CIN) invasive cancer (ICC) deep sequenced. After constructing a reference sequence for each specimen, nucleotide positions showing >0.5% frequencies compared determined individual samples. In total, 1,052 variations detected 151 samples (CIN1, n = 56; CIN2/3, 68; ICC, 27), various numbers per sample. Overall, C-to-T C-to-A substitutions dominant observed across all histological grades. While transitions predominantly CIN1, prevalence was decreased CIN2/3 fell below that transversions ICC. Analysis trinucleotide context encompassing substituted bases revealed TpCpN, preferred target APOBEC cytosine deaminases, primary site These results strongly imply proteins drivers mutation, particularly CIN1 lesions. IMPORTANCE HPVs exhibit surprisingly high levels diversity, including large repertoire minor genomic variants genotype. conducting analyses, show first time comprehensive snapshot high-risk carcinogenesis. Quasispecies harboring extensively different grades CIN cancer. Among variations, transitions, characteristic change mediated throughout genome, most strikingly low-grade suggest primarily generated through interaction cell DNA-editing enzymes such variability an evolutionary source HPVs.