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Human papillomavirus type 31 (HPV31) is detected less frequently in cervical cancer than two major causative types, HPV16 and HPV18. Here, we report a comprehensive analysis of HPV31 genome sequences in cervical lesions collected from Japanese women. Of 52 HPV31-positive cervical specimens analyzed by deep sequencing, 43 samples yielded complete genome sequences of around 7900 base pairs and 9 samples yielded partially deleted genome sequences. Phylogenetic analysis showed that HPV31 variant distribution was lineage A in 19 samples (36.5%), lineage B in 28 samples (53.8%), and lineage C in 5 samples (9.6%), indicating that lineage B variants are dominant among HPV31 infections in Japan. Deletions in the viral genome were found in the region from the E1 to L1 genes, but all the deleted genomes retained the E6/E7 genes. Among intra-patient nucleotide variations relative to a consensus genome sequence in each sample, C-to-T substitutions were most frequently detected, followed by T-to-C and C-to-A substitutions. High-frequency, intra-patient mutations (>10%) in cervical cancer samples were found in the E1, E2, and E7 genes, and all of them were nonsynonymous substitutions. The enrichment of high-frequency nonsynonymous substitutions strongly suggests that these intra-patient mutations are positively selected during the development of cervical cancer/precancer.

Human papillomavirus (HPV) is a sexually transmitted virus with an approximately 8-kilo base DNA genome, which establishes long-term persistent infection in anogenital tissues. High levels of genetic variations, including viral genotypes and intra-type variants, have been described for HPV genomes, together with geographical differences in the distribution of genotypes and variants. Here, by employing a maximum likelihood method, we performed phylogenetic analyses of the complete genome sequences of HPV16, HPV18 and HPV58 available from GenBank (n = 627, 146 and 157, respectively). We found several characteristic clusters that exclusively contain HPV genomes from Japan: two for HPV16 (sublineages A4 and A5), one for HPV18 (sublineage A1) and two for HPV58 (sublineages A1 and A2). Bayesian phylogenetic analyses of concatenated viral gene sequences showed that divergence of the most recent common ancestor of these Japan-specific clades was estimated to have occurred ~98,000 years before present (YBP) for HPV16 A4, ~39,000 YBP for HPV16 A5, ~38,000 YBP for HPV18 A1, ~26,000 for HPV58 A1 and ~25,000 YBP for HPV58 A2. This estimated timeframe for the divergence of the Japan-specific clades suggests that the introduction of these HPV variants into the Japanese archipelago dates back to at least ~25,000 YBP and provides a scenario of virus co-migration with ancestral Japanese populations from continental Asia during the Upper Paleolithic period.

Since the human papillomavirus (HPV) vaccination program for Japanese girls aged 12–16 years began in 2010, vaccination uptake has been low in women born before 1993 but high (approximately 70%) in those born during 1994–1999. We previously compared the prevalence of vaccine types HPV16 and HPV18 in cervical intraepithelial neoplasia grade 1–3 (CIN1–3) or adenocarcinoma in situ (AIS) between vaccinated and unvaccinated cohorts and found direct protection effects among vaccinated women in Japan. In this study, we focused on changes in HPV16/18 prevalence among “unvaccinated” cohorts with CIN/AIS. We analyzed HPV16/18 prevalence among 5051 unvaccinated women aged trend = 0.03) and CIN2–3/AIS (62.5–36.4%, Ptrend = 0.07) among women aged p = 0.04). Significant reduction in HPV16/18 prevalence among young unvaccinated women with CIN1 and CIN2–3/AIS suggests herd effects of HPV vaccination in Japan.

Recent large-scale genomics studies of human papillomaviruses (HPVs) have shown a high level of genomic variability of HPV16, the most prevalent genotype in HPV-associated malignancies, and provided new insights into the biological and clinical relevance of its genetic variations in cervical cancer development. Here, we performed deep sequencing analyses of the viral genome to explore genetic variations of HPV16 that are prevalent in Japan. A total of 100 complete genome sequences of HPV16 were determined from cervical specimens collected from Japanese women with cervical intraepithelial neoplasia and invasive cervical cancer, or without cervical malignancies. Phylogenetic analyses revealed the variant distribution in the Japanese HPV16 isolates; overall, lineage A was the most prevalent (94.0%), in which sublineage A4 was dominant (52.0%), followed by sublineage A1 (21.0%). The relative risk of sublineage A4 for cervical cancer development was significantly higher compared to sublineages A1/A2/A3 (odds ratio = 6.72, 95% confidence interval = 1.78–28.9). Interestingly, a novel cluster of variants that branched from A1/A2/A3 was observed for the Japanese HPV16 isolates, indicating that unique HPV16 variants are prevalent among Japanese women.