Human papillomaviruses (HPVs) are the etiologic agents of cervical cancer, the unique human neoplasia that has one single necessary cause. The diversity of HPVs is well described, with 200 HPV types existing as distinct taxonomic units and each receiving an Arabic number. On a clinical basis, they are usually grouped by their site of occurrence and disease associations. Those types inhabiting the anogenital mucosa are more intensively studied and further divided into cancer-associated HPVs, which are termed ‘high risk', while those linked to benign proliferative lesions are assigned as ‘low risk'. HPV16 is responsible for approximately 50% of all ICC cases, and paradoxically is one of the most prevalent types among healthy women. Longitudinal studies have shown that when an incidental HPV16 infection becomes persistent it will result in an enhanced risk for the development of high-grade lesions. However, it is unknown why some persistent, HPV16 infections (or infections by other HR-HPV types) progress to CIN3+ while most clear spontaneously. Several epidemiological investigations have focused on cofactors, from the most obvious such as cigarette and other carcinogenic exposures, to coinfections by other STDs such as chlamydia, with no significant findings. Thus, the current focus is on genomic variation from both virus and host. Such studies have been potentialized by the enormous technical advances in nucleic acid sequencing, allowing this relationship to be broadly interrogated. Corroborating subgenomic data from decades ago, an association between HPV16 lineages and carcinogenesis is being revealed. However, this effect does not seem to apply across female populations from different continents/ethnicities, again highlighting a role played by HPV16 adaptation and evasion from the host over time.

Keywords:
Human papillomavirus, Cervical cancer, Genetic diversity
1.
Bravo IG, Felez-Sanchez M: Papillomaviruses: viral evolution, cancer and evolutionary medicine. Evol Med Public Health 2015;2015:32-51.
2.
Doorbar J, et al: Human papillomavirus molecular biology and disease association. Rev Med Virol 2015;25(suppl 1):2-23.
3.
Cubie HA: Diseases associated with human papillomavirus infection. Virology 2013;445:21-34.
4.
Bernard HU, et al: Classification of papillomaviruses (PVs) based on 189 PV types and proposal of taxonomic amendments. Virology 2010;401:70-79.
5.
Bravo IG, de Sanjose S, Gottschling M: The clinical importance of understanding the evolution of papillomaviruses. Trends Microbiol 2010;18:432-438.
6.
de Villiers EM: Cross-roads in the classification of papillomaviruses. Virology 2013;445:2-10.
7.
Marin A, et al: Variation in G + C-content and codon choice: differences among synonymous codon groups in vertebrate genes. Nucleic Acids Res 1989;17:6181-6189.
8.
Zhao KN, Liu WJ, Frazer IH: Codon usage bias and A+T content variation in human papillomavirus genomes. Virus Res 2003;98:95-104.
9.
Cladel NM, Bertotto A, Christensen ND: Human alpha and beta papillomaviruses use different synonymous codon profiles. Virus Genes 2010;40:329-340.
10.
Felez-Sanchez M, et al: Cancer, warts, or asymptomatic infections: clinical presentation matches codon usage preferences in human papillomaviruses. Genome Biol Evol 2015;7:2117-2135.
11.
Vartanian JP, et al: Evidence for editing of human papillomavirus DNA by APOBEC3 in benign and precancerous lesions. Science 2008;320:230-233.
12.
Wang Z, et al: APOBEC3 deaminases induce hypermutation in human papillomavirus 16 DNA upon beta interferon stimulation. J Virol 2014;88:1308-1317.
13.
Munk C, Willemsen A, Bravo IG: An ancient history of gene duplications, fusions and losses in the evolution of APOBEC3 mutators in mammals. BMC Evol Biol 2012;12:71.
14.
Rector A, et al: Ancient papillomavirus-host co-speciation in Felidae. Genome Biol 2007;8:R57.
15.
Shah SD, Doorbar J, Goldstein RA: Analysis of host-parasite incongruence in papillomavirus evolution using importance sampling. Mol Biol Evol 2010;27:1301-1314.
16.
Chen Z, et al: Evolution and taxonomic classification of human papillomavirus 16 (HPV16)-related variant genomes: HPV31, HPV33, HPV35, HPV52, HPV58 and HPV67. PLoS One 2011;6:e20183.
17.
Antonsson A, et al: The ubiquity and impressive genomic diversity of human skin papillomaviruses suggest a commensalic nature of these viruses. J Virol 2000;74:11636-11641.
18.
Bouvard V, et al: A review of human carcinogens - part B: biological agents. Lancet Oncol 2009;10:321-322.
19.
de Sanjose S, et al: Human papillomavirus genotype attribution in invasive cervical cancer: a retrospective cross-sectional worldwide study. Lancet Oncol 2010;11:1048-1056.
20.
Li N, et al: Human papillomavirus type distribution in 30,848 invasive cervical cancers worldwide: variation by geographical region, histological type and year of publication. Int J Cancer 2011;128:927-935.
21.
Ho L, et al: Sequence variants of human papillomavirus type 16 in clinical samples permit verification and extension of epidemiological studies and construction of a phylogenetic tree. J Clin Microbiol 1991;29:1765-1772.
22.
Yamada T, et al: Human papillomavirus type 16 variant lineages in United States populations characterized by nucleotide sequence analysis of the E6, L2, and L1 coding segments. J Virol 1995;69:7743-7753.
23.
Arias-Pulido H, et al: Human papillomavirus type 18 variant lineages in United States populations characterized by sequence analysis of LCR-E6, E2, and L1 regions. Virology 2005;338:22-34.
24.
Calleja-Macias IE, et al: Genomic diversity of human papillomavirus-16, 18, 31, and 35 isolates in a Mexican population and relationship to European, African, and Native American variants. Virology 2004;319:315-323.
25.
Cornet I, et al: Human papillomavirus type 16 genetic variants: phylogeny and classification based on E6 and LCR. J Virol 2012;86:6855-6861.
26.
Chen Z, et al: Diversifying selection in human papillomavirus type 16 lineages based on complete genome analyses. J Virol 2005;79:7014-7023.
27.
Smith B, et al: Sequence imputation of HPV16 genomes for genetic association studies. PLoS One 2011;6:e21375.
28.
Chen Z, et al: Evolutionary dynamics of variant genomes of human papillomavirus types 18, 45, and 97. J Virol 2009;83:1443-1455.
29.
Chen Z, et al: Evolution and taxonomic classification of Alphapapillomavirus 7 complete genomes: HPV18, HPV39, HPV45, HPV59, HPV68 and HPV70. PLoS One 2013;8:e72565.
30.
Berumen J, et al: Asian-American variants of human papillomavirus 16 and risk for cervical cancer: a case-control study. J Natl Cancer Inst 2001;93:1325-1330.
31.
Hildesheim A, et al: Human papillomavirus type 16 variants and risk of cervical cancer. J Natl Cancer Inst 2001;93:315-318.
32.
Villa LL, et al: Molecular variants of human papillomavirus types 16 and 18 preferentially associated with cervical neoplasia. J Gen Virol 2000;81(pt 12):2959-2968.
33.
Cornet I, et al: HPV16 genetic variation and the development of cervical cancer worldwide. Br J Cancer 2013;108:240-244.
34.
Xi LF, et al: Human papillomavirus type 16 and 18 variants: race-related distribution and persistence. J Natl Cancer Inst 2006;98:1045-1052.
35.
Sichero L, et al: High grade cervical lesions are caused preferentially by non-European variants of HPVs 16 and 18. Int J Cancer 2007;120:1763-1768.
36.
Mirabello L, et al: HPV16 sublineage associations with histology-specific cancer risk using HPV whole-genome sequences in 3,200 women. J Natl Cancer Inst 2016;108.
37.
Chan PK, et al: Association of human papillomavirus type 58 variant with the risk of cervical cancer. J Natl Cancer Inst 2002;94:1249-1253.
38.
Khouadri S, et al: Human papillomavirus type 33 polymorphisms and high-grade squamous intraepithelial lesions of the uterine cervix. J Infect Dis 2006;194:886-894.
39.
de Oliveira CM, et al: High-level of viral genomic diversity in cervical cancers: a Brazilian study on human papillomavirus type 16. Infect Genet Evol 2015;34:44-51.
40.
de Oliveira CM, Aquiar LS, Genta ML, Alves VA, Levi JE: HPV-11 associated metastatic cervical cancer. Gynecol Oncol Case Rep 2012;2:18-19.
41.
Villa LL, Schlegel R: Differences in transformation activity between HPV-18 and HPV-16 map to the viral LCR-E6-E7 region. Virology 1991;181:374-377.
42.
O'Connor M, Chan S-Y, Bernard HU: Transcription factor binding sites in the long control region of genital HPVs; in Meyers G, Bernard HU, Delius, et al. (eds): Human Papillomaviruses, 1995 Compendium. Los Alamos, Los Alamos National Laboratory, 1995.
43.
Garcia-Vallve S, et al: Different papillomaviruses have different repertoires of transcription factor binding sites: convergence and divergence in the upstream regulatory region. BMC Evol Biol 2006;6:20.
44.
Rose B, et al: Point mutations in SP1 motifs in the upstream regulatory region of human papillomavirus type 18 isolates from cervical cancers increase promoter activity. J Gen Virol 1998;79(pt 7):1659-1663.
45.
Hubert WG: Variant upstream regulatory region sequences differentially regulate human papillomavirus type 16 DNA replication throughout the viral life cycle. J Virol 2005;79:5914-5922.
46.
Bravo IG, Alonso A: Mucosal human papillomaviruses encode four different E5 proteins whose chemistry and phylogeny correlate with malignant or benign growth. J Virol 2004;78:13613-13626.
47.
Liu L, et al: Comparison of next-generation sequencing systems. J Biomed Biotechnol 2012;2012:251364.
48.
Kukimoto I, et al: Genetic variation of human papillomavirus type 16 in individual clinical specimens revealed by deep sequencing. PLoS One 2013;8:e80583.
49.
DiLorenzo TP, et al: Human papillomavirus type 6a DNA in the lung carcinoma of a patient with recurrent laryngeal papillomatosis is characterized by a partial duplication. J Gen Virol 1992;73(pt 2):423-428.
50.
Yuan H, et al: Use of reprogrammed cells to identify therapy for respiratory papillomatosis. N Engl J Med 2012;367:1220-1227.
51.
Murray RF, Hobbs J, Payne B: Possible clonal origin of common warts (Verruca vulgaris). Nature 1971;232:51-52.
52.
Quint W, et al: One virus, one lesion - individual components of CIN lesions contain a specific HPV type. J Pathol 2012;227:62-71.
53.
Dillner J: Mapping of linear epitopes of human papillomavirus type 16: the E1, E2, E4, E5, E6 and E7 open reading frames. Int J Cancer 1990;46:703-711.
54.
Watts KJ, et al: Sequence variation and physical state of human papillomavirus type 16 cervical cancer isolates from Australia and New Caledonia. Int J Cancer 2002;97:868-874.
55.
Beckman G, et al: Is p53 polymorphism maintained by natural selection? Hum Hered 1994;44:266-270.
56.
Zoodsma M, et al: Analysis of the entire HLA region in susceptibility for cervical cancer: a comprehensive study. J Med Genet 2005;42:e49.
57.
Engelmark M, et al: Affected sib-pair analysis of the contribution of HLA class I and class II loci to development of cervical cancer. Hum Mol Genet 2004;13:1951-1958.
58.
de Araujo Souza PS, Sichero L, Maciag PC: HPV variants and HLA polymorphisms: the role of variability on the risk of cervical cancer. Future Oncol 2009;5:359-370.
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