Fundamental Biology of Human Papillomaviruses

  • Meghan Lambie
  • Scott V. Bratman


The human papillomavirus (HPV) is the cause of multiple neoplastic conditions including recurrent respiratory papillomatosis and invasive cervical carcinoma. Despite the extremely high incidence rate of infection with HPV, the virus is normally cleared from the body, and disease states are only seen in a small subset of exposed individuals. There are over 120 different HPV types, each with distinct characteristics. The HPV genome encodes for seven early-expressed proteins (E1–7) and two late-expressed proteins (L1–2). The viral life cycle is tightly linked with normal physiology of cutaneous and mucosal stratified squamous epithelial tissues. In HPV-infected cells, progression toward neoplasia requires that the virus evades immune detection and clearance. Viral factors are able to co-opt normal homeostatic processes within infected squamous epithelial tissues to establish persistent infections, evade host immune detection, and activate neoplastic pathways. Key oncoproteins E6 and E7 exert their function through multiple mechanisms to drive neoplastic processes in both benign and malignant lesions. This chapter provides an overview of the key molecular features of the HPV family of viruses and their pathogenic mechanisms.


Human papillomavirus HPV Recurrent respiratory papillomatosis E6 E7 Neoplasia Cancer Transformation Oncoproteins Viral life cycle 


  1. Antonsson A, Forslund O, Ekberg H, et al. The ubiquity and impressive genomic diversity of human skin papillomaviruses suggest a commensalic nature of these viruses. J Virol. 2000;74:11636–41. doi: 10.1128/JVI.74.24.11636-11641.2000.CrossRefPubMedPubMedCentralGoogle Scholar
  2. Bernard BA, Bailly C, Lenoir MC, et al. The human papillomavirus type 18 (HPV18) E2 gene product is a repressor of the HPV18 regulatory region in human keratinocytes. J Virol. 1989;63:4317–24.PubMedPubMedCentralGoogle Scholar
  3. Bonagura VR, Hatam LJ, Rosenthal DW, et al. Recurrent Respiratory Papillomatosis: A Complex Defect in Immune Responsiveness to Human Papillomavirus-6 and -11. J Pediatr. 2010;48:1–6. doi: 10.1097/MPG.0b013e3181a15ae8.Screening.Google Scholar
  4. Brehm A, Nielsen SJ, Miska EA, et al. The E7 oncoprotein associates with Mi2 and histone deacetylase activity to promote cell growth. EMBO J. 1999;18:2449–58. doi: 10.1093/emboj/18.9.2449.CrossRefPubMedPubMedCentralGoogle Scholar
  5. Brimer N, Lyons C, Vande Pol SB. Association of E6AP (UBE3A) with human papillomavirus type 11 E6 protein. Virology. 2007;358:303–10. doi: 10.1016/j.virol.2006.08.038.CrossRefPubMedGoogle Scholar
  6. Bryan JT, Brown DR. Transmission of human papillomavirus type 11 infection by desquamated cornified cells. Virology. 2001;281:35–42. doi: 10.1006/viro.2000.0777.CrossRefPubMedGoogle Scholar
  7. Buck CB, Thompson CD, Pang Y-YS, et al. Maturation of papillomavirus capsids. J Virol. 2005;79:2839–46. doi: 10.1128/JVI.79.5.2839-2846.2005.CrossRefPubMedPubMedCentralGoogle Scholar
  8. de Villiers EM. Cross-roads in the classification of papillomaviruses. Virology. 2013;445:2–10.CrossRefPubMedGoogle Scholar
  9. De Villiers EM, Fauquet C, Broker TR, et al. Classification of papillomaviruses. Virology. 2004;324:17–27.CrossRefPubMedGoogle Scholar
  10. Dochez C, Bogers JJ, Verhelst R, Rees H. HPV vaccines to prevent cervical cancer and genital warts: An update. Vaccine. 2014;32:1595–601. doi: 10.1016/j.vaccine.2013.10.081.CrossRefPubMedGoogle Scholar
  11. Donne AJ, Hampson L, Homer JJ, Hampson IN. The role of HPV type in Recurrent Respiratory Papillomatosis. Int J Pediatr Otorhinolaryngol. 2010;74:7–14.CrossRefPubMedGoogle Scholar
  12. Doorbar J. The papillomavirus life cycle. J Clin Virol. 2005;32:7–15.CrossRefGoogle Scholar
  13. Doorbar J, Quint W, Banks L, et al. The biology and life-cycle of human papillomaviruses. Vaccine. 2012;30:19–32.CrossRefGoogle Scholar
  14. Doorbar J, Egawa N, Griffin H, et al. Human papillomavirus molecular biology and disease association. Rev Med Virol. 2015;25(Suppl 1):2–23. doi: 10.1002/rmv.1822.CrossRefPubMedPubMedCentralGoogle Scholar
  15. Draganov P, Todorov S, Todorov I, et al. Identification of HPV DNA in patients with juvenile-onset recurrent respiratory papillomatosis using SYBR?? Green real-time PCR. Int J Pediatr Otorhinolaryngol. 2006;70:469–73.CrossRefPubMedGoogle Scholar
  16. Duensing S, Münger K. The human papillomavirus type 16 E6 and E7 oncoproteins independently induce numerical and structural chromosome instability. Cancer Res. 2002;62:7075–82.PubMedGoogle Scholar
  17. Dyson N, Howley PM, Münger K, Harlow E. The human papilloma virus-16 E7 oncoprotein is able to bind to the retinoblastoma gene product. Science. 1989;243:934–7. doi: 10.1126/science.2537532.CrossRefPubMedGoogle Scholar
  18. Fernandes J. Biology and natural history of human papillomavirus infection. Open Access J. 2013;5:1–12. doi: 10.2147/OAJCT.S37741.Google Scholar
  19. Forman D, de Martel C, Lacey CJ, et al. Global burden of human papillomavirus and related diseases. Vaccine. 2012;30(Suppl 5):F12–23. doi: 10.1016/j.vaccine.2012.07.055.CrossRefPubMedGoogle Scholar
  20. Giroglou T, Florin L, Schäfer F, et al. Human papillomavirus infection requires cell surface heparan sulfate. J Virol. 2001;75:1565–70. doi: 10.1128/JVI.75.3.1565-1570.2001.CrossRefPubMedPubMedCentralGoogle Scholar
  21. Groves IJ, Coleman N. Pathogenesis of human papillomavirus-associated mucosal disease. J Pathol. 2015;235:527–38. doi: 10.1002/path.4496.CrossRefPubMedGoogle Scholar
  22. Hanahan D. The Hallmarks of Cancer. Cell. 2000;100:57–70. doi: 10.1016/S0092-8674(00)81683-9.CrossRefPubMedGoogle Scholar
  23. Hanahan D, Weinberg RA. Hallmarks of cancer: the next generation. Cell. 2011;144:646–74. doi: 10.1016/j.cell.2011.02.013.CrossRefPubMedGoogle Scholar
  24. zur Hausen H. Condylomata acuminata and human genital cancer. Cancer Res. 1976;36:794.PubMedGoogle Scholar
  25. zur Hausen H. Papillomavirus infections — a major cause of human cancers. Biochim Biophys Acta - Rev Cancer. 1996;1288:F55–78. doi: 10.1016/0304-419X(96)00020-0.CrossRefGoogle Scholar
  26. Hu Z, Zhu D, Wang W, et al. Genome-wide profiling of HPV integration in cervical cancer identifies clustered genomic hot spots and a potential microhomology-mediated integration mechanism. Nat Genet. 2015;47:158–63. doi: 10.1038/ng.3178.CrossRefPubMedGoogle Scholar
  27. Kajitani N, Satsuka A, Kawate A, Sakai H. Productive lifecycle of human papillomaviruses that depends upon squamous epithelial differentiation. Front Microbiol. 2012;3:00152. doi: 10.3389/fmicb.2012.00152.CrossRefGoogle Scholar
  28. Kanodia S, Fahey LM, Kast WM. Mechanisms used by human papillomaviruses to escape the host immune response. Curr Cancer Drug Targets. 2007;7:79–89. doi: 10.2174/156800907780006869.CrossRefPubMedGoogle Scholar
  29. Klingelhutz AJ, Roman A. Cellular transformation by human papillomaviruses: Lessons learned by comparing high- and low-risk viruses. Virology. 2012;424:77–98.CrossRefPubMedPubMedCentralGoogle Scholar
  30. Lechner MS, Laimins LA. Inhibition of p53 DNA binding by human papillomavirus E6 proteins. J Virol. 1994;68:4262–73.PubMedPubMedCentralGoogle Scholar
  31. Lucs A, DeVoti J, Hatam L, et al. Immune Dysregulation in patients persistently infected with human papillomaviruses 6 and 11. J Clin Med. 2015;4:375–88. doi: 10.3390/jcm4030375.CrossRefPubMedPubMedCentralGoogle Scholar
  32. Major T, Szarka K, Sziklai I, et al. The characteristics of human papillomavirus DNA in head and neck cancers and papillomas. J Clin Pathol. 2005;58:51–5. doi: 10.1136/jcp.2004.016634.CrossRefPubMedPubMedCentralGoogle Scholar
  33. Major T, Sziklai I, Czegledy J, et al. Follow-up of HPV DNA copy number in cidofovir therapy of recurrent respiratory papillomatosis. Anticancer Res. 2008;28:2169–74.PubMedGoogle Scholar
  34. McLaughlin-Drubin ME, Munger K. The human papillomavirus E7 oncoprotein. Virology. 2009;384:335–44.CrossRefPubMedGoogle Scholar
  35. Moody CA, Laimins LA. Human papillomavirus oncoproteins: pathways to transformation. Nat Rev Cancer. 2010;10:550–60. doi: 10.1038/nrc2886.CrossRefPubMedGoogle Scholar
  36. Nicolaides L, Davy C, Raj K, et al. Stabilization of HPV16 E6 protein by PDZ proteins, and potential implications for genome maintenance. Virology. 2011;414:137–45. doi: 10.1016/j.virol.2011.03.017.CrossRefPubMedGoogle Scholar
  37. Oh ST, Longworth MS, Laimins LA. Roles of the E6 and E7 proteins in the life cycle of low-risk human papillomavirus type 11. J Virol. 2004;78:2620–6. doi: 10.1128/JVI.78.5.2620.CrossRefPubMedPubMedCentralGoogle Scholar
  38. Patel D, Huang SM, Baglia LA, McCance DJ. The E6 protein of human papillomavirus type 16 binds to and inhibits co-activation by CBP and p300. EMBO J. 1999;18:5061–72. doi: 10.1093/emboj/18.18.5061.CrossRefPubMedPubMedCentralGoogle Scholar
  39. Pim D, Banks L. Interaction of viral oncoproteins with cellular target molecules: Infection with high-risk vs low-risk human papillomaviruses. APMIS. 2010;118:471–93.CrossRefPubMedGoogle Scholar
  40. Pim D, Thomas M, Javier R, et al. HPV E6 targeted degradation of the discs large protein: evidence for the involvement of a novel ubiquitin ligase. Oncogene. 2000;19:719–25. doi: 10.1038/sj.onc.1203374.CrossRefPubMedGoogle Scholar
  41. Rebhandl S, Huemer M, Greil R, Geisberger R. AID/APOBEC deaminases and cancer. Oncoscience. 2015;2:320–33. doi: 10.18632/oncoscience.155.CrossRefPubMedPubMedCentralGoogle Scholar
  42. Roden RB, Lowy DR, Schiller JT. Papillomavirus is resistant to desiccation. J Infect Dis. 1997;176:1076–9. doi: 10.1086/516515.CrossRefPubMedGoogle Scholar
  43. Satsuka A, Mehta K, Laimins L. p38MAPK and MK2 pathways are important for the differentiation-dependent human papillomavirus life cycle. J Virol. 2015;89:1919–24. doi: 10.1128/JVI.02712-14.CrossRefPubMedGoogle Scholar
  44. Scheffner M, Huibregtse JM, Vierstra RD, Howley PM. The HPV-16 E6 and E6-AP complex functions as a ubiquitin-protein ligase in the ubiquitination of p53. Cell. 1993;75:495–505. doi: 10.1016/0092-8674(93)90384-3.CrossRefPubMedGoogle Scholar
  45. Stanley MA. Epithelial cell responses to infection with human papillomavirus. Clin Microbiol Rev. 2012;25:215–22.CrossRefPubMedPubMedCentralGoogle Scholar
  46. Stern Y, Felipovich A, Cotton RT, Segal K. Immunocompetency in children with recurrent respiratory papillomatosis : prospective study. Ann Otol Rhinol Laryngol. 2007;116:169–71.CrossRefPubMedGoogle Scholar
  47. Tommasino M. The human papillomavirus family and its role in carcinogenesis. Semin Cancer Biol. 2014;26:13–21.CrossRefPubMedGoogle Scholar
  48. Tsakogiannis D, Ruether IGA, Kyriakopoulou Z, et al. Molecular and phylogenetic analysis of the HPV 16 E4 gene in cervical lesions from women in Greece. Arch Virol. 2012;157:1729–39. doi: 10.1007/s00705-012-1356-1.CrossRefPubMedGoogle Scholar
  49. Walboomers JMM, Jacobs MV, Manos MM, et al. Human papillomavirus is a necessary cause of invasive cervical cancer worldwide. J Pathol. 1999;189:12–9. doi:10.1002/(SICI)1096-9896(199909)189:1<12::AID-PATH431>3.0.CO;2-F.CrossRefPubMedGoogle Scholar
  50. Weissenborn SJ, Nindl I, Purdie K, et al. Human papillomavirus-DNA loads in actinic keratoses exceed those in non-melanoma skin cancers. J Invest Dermatol. 2005;125:93–7. doi: 10.1111/j.0022-202X.2005.23733.x.CrossRefPubMedGoogle Scholar
  51. White AE, Livanos EM, Tlsty TD. Differential disruption of genomic integrity and cell cycle regulation in normal human fibroblasts by the HPV oncoproteins. Genes Dev. 1994;8:666–77.CrossRefPubMedGoogle Scholar
  52. Zhou Q, Zhu K, Cheng H. Toll-like receptors in human papillomavirus infection. Arch Immunol Ther Exp. 2013;61:203–15.CrossRefGoogle Scholar

Copyright information

© Springer International Publishing AG 2018

Authors and Affiliations

  1. 1.Medical BiophysicsPrincess Margaret Cancer CentreTorontoCanada
  2. 2.Radiation OncologyPrincess Margaret Cancer CentreTorontoCanada

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