Skip to main content

Advertisement

SpringerLink
Log in

Natural History of Human Papillomavirus Infection

  • Management of HPV and Associated Cervical Lesions (C-H Lai, Section Editor)
  • Published:
Current Obstetrics and Gynecology Reports Aims and scope Submit manuscript

Abstract

Human papillomavirus (HPV) is strongly associated with cervical precancerous lesions and invasive cervical cancers. HPVs are classified as high-risk, low-risk, and intermediated-risk groups. Cervical precancerous lesions and invasive cervical cancers are caused by the high-risk group. Cancer progression is associated with persistent high-risk HPV infection and deregulated viral gene expression, which leads to excessive cell proliferation, deficient DNA repair, and genetic damage to infected cells. The life cycle of the high- or low-risk groups is similar; however, in the high-risk group, E6 and E7 proteins interact with p53, PDZ domain protein, and retinoblastoma protein. In this article, we reviewed the natural life cycle of carcinogenic HPVs to help understand cervical disease.

This is a preview of subscription content, log in via an institution to check access.

Access this article

Log in via an institution

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Institutional subscriptions

Similar content being viewed by others

References

Papers of particular interest, published recently, have been highlighted as: • Of importance

  1. Ferlay J et al. Estimates of worldwide burden of cancer in 2008: GLOBOCAN 2008. Int J Cancer. 2010;127(12):2893–917.

    Article  CAS  PubMed  Google Scholar 

  2. Arbyn M et al. Worldwide burden of cervical cancer in 2008. Ann Oncol. 2011;22(12):2675–86.

    Article  CAS  PubMed  Google Scholar 

  3. Berger JL, Ramirez PT. Surgical management of cervical carcinoma. Hematol Oncol Clin North Am. 2012;26(1):63–78.

    Article  PubMed  Google Scholar 

  4. Hausen HZ. Yosei Ito Memorial Lecture: Papillomvirus in human cancers. Leukemia. 1999;13:1–5.

    Article  PubMed  Google Scholar 

  5. Hariri S et al. Prevalence of genital human papillomavirus among females in the United States, the National Health And Nutrition Examination Survey, 2003-2006. J Infect Dis. 2011;204(4):566–73.

    Article  PubMed  Google Scholar 

  6. Stanley M. Chapter 17: Genital human papillomavirus infections- current and prospective therapies. J Natl Cancer Inst Monogr. 2003;31:117–24.

    Article  PubMed  Google Scholar 

  7. Rousseau MC, Villa LL, Costa MC, Abrahamowicz M, Rohan TE, Franco E. Occurence of cervical infection with multiple human papillomavirus types is associated with age and cytologic abnirmalities. Sex Transm Dis. 2003;30(7):581–7.

    Article  PubMed  Google Scholar 

  8. Partridge JM et al. Genital human papillomavirus infection in men: incidence and risk factors in a cohort of university students. J Infect Dis. 2007;196(8):1128–36.

    Article  PubMed  Google Scholar 

  9. Smith JS et al. Human papillomavirus type distribution in invasive cervical cancer and high-grade cervical lesions: a meta-analysis update. Int J Cancer. 2007;121(3):621–32.

    Article  CAS  PubMed  Google Scholar 

  10. Khan MJ et al. The elevated 10-year risk of cervical precancer and cancer in women with human papillomavirus (HPV) type 16 or 18 and the possible utility of type-specific HPV testing in clinical practice. J Natl Cancer Inst. 2005;97(14):1072–9.

    Article  PubMed  Google Scholar 

  11. Bernard HU et al. Classification of papillomaviruses (PVs) based on 189 PV types and proposal of taxonomic amendments. Virology. 2010;401(1):70–9.

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  12. Bosch FX et al. Epidemiology and natural history of human papillomavirus infections and type-specific implications in cervical neoplasia. Vaccine. 2008;26 Suppl 10:K1–16.

    Article  PubMed  Google Scholar 

  13. zur Hausen H. Papillomaviruses in the causation of human cancers - a brief historical account. Virology. 2009;384(2):260–5.

    Article  PubMed  Google Scholar 

  14. Munoz N et al. Chapter 1: HPV in the etiology of human cancer. Vaccine. 2006;24 Suppl 3:S3/1–10.

    CAS  Google Scholar 

  15. Bouvard V, Baan R, Straif K, Grosse Y, Secretan B, El G. A review of human carcinogen s- Part B: biologic agents. Lancet Oncol. 2009;10(4):321–2.

    Article  PubMed  Google Scholar 

  16. Schiffman M, Clifford G, Buonaguro FM. Classification of weakly carcinogenic human papillomavirus types: addressing the limits of epidemiology at the borderline. Infect Agent Cancer. 2009;4:8.

    Article  PubMed Central  PubMed  Google Scholar 

  17. Doorbar J. Molecular biology of human papillomavirus infection and cervical cancer. Clin Sci (Lond). 2006;110(5):525–41.

    Article  CAS  Google Scholar 

  18. Middleton K et al. Organization of Human Papillomavirus Productive Cycle during Neoplastic Progression Provides a Basis for Selection of Diagnostic Markers. J Virol. 2003;77(19):10186–201.

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  19. Melsheimer P, Vinokurova S, Wentzensen N, et al. DNA aneuploidy and integration of human papillomavirus type 15 E6/E7 oncogenes in intraepithelial neoplasia and invasive squamous cell carcinoma of the cervix uteri. Clin Cancer Res. 2004;10:3059–63.

    Article  CAS  PubMed  Google Scholar 

  20. Schiller JT, Day PM, Kines RC. Current understanding of the mechanism of HPV infection. Gynecol Oncol. 2010;118(1 Suppl):S12–7.

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  21. Buck CB et al. Arrangement of L2 within the papillomavirus capsid. J Virol. 2008;82(11):5190–7.

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  22. Finnen RL et al. Interactions between Papillomavirus L1 and L2 Capsid Proteins. J Virol. 2003;77(8):4818–26.

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  23. Doorbar J. The papillomavirus life cycle. J Clin Virol. 2005;32 Suppl 1:S7–15.

    Article  CAS  PubMed  Google Scholar 

  24. Kines RC et al. The initial steps leading to papillomavirus infection occur on the basement membrane prior to cell surface binding. Proc Natl Acad Sci U S A. 2009;106(48):20458–63.

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  25. Bienkowska-Haba M, Patel HD, Sapp M. Target cell cyclophilins facilitate human papillomavirus type 16 infection. PLoS Pathog. 2009;5(7):e1000524.

    Article  PubMed Central  PubMed  Google Scholar 

  26. Bergant Marusic M, Ozbun MA, Campos SK, Myers MP, Banks L. Human papillomavirus L2 facilitates viral escape from late endosomes via sorting nexin 17. Traffic. 2012;13(3):455–67.

    Article  PubMed  Google Scholar 

  27. Schelhaas M et al. Entry of human papillomavirus type 16 by actin-dependent, clathrin- and lipid raft-independent endocytosis. PLoS Pathog. 2012;8(4):e1002657.

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  28. Kim K, Lambert PF. E1 protein of bovine papillomavirus 1 is not required for the maintenance of viral plasmid DNA replication. Virology. 2002;293(1):10–4.

    Article  CAS  PubMed  Google Scholar 

  29. Angeletti PC et al. Stable Replication of Papillomavirus Genomes in Saccharomyces cerevisiae. J Virol. 2002;76(7):3350–8.

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  30. McBride AA. Chapter 4 Replication and Partitioning of Papillomavirus Genomes. 2008; 72: 155-205

  31. Valencia C et al. Human papillomavirus E6/E7 oncogenes promote mouse ear regeneration by increasing the rate of wound re-epithelization and epidermal growth. J Invest Dermatol. 2008;128(12):2894–903.

    Article  CAS  PubMed  Google Scholar 

  32. Isaacson Wechsler E et al. Reconstruction of human papillomavirus type 16-mediated early-stage neoplasia implicates E6/E7 deregulation and the loss of contact inhibition in neoplastic progression. J Virol. 2012;86(11):6358–64.

    Article  PubMed Central  PubMed  Google Scholar 

  33. Barrow-Laing L, Chen W, Roman A. Low- and high-risk human papillomavirus E7 proteins regulate p130 differently. Virology. 2010;400(2):233–9.

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  34. Roman A. The human papillomavirus E7 protein shines a spotlight on the pRB family member, p130. Cell Cycle. 2006;5(6):567–8.

    Article  CAS  PubMed  Google Scholar 

  35. Javier RT. Cell polarity proteins: common targets for tumorigenic human viruses. Oncogene. 2008;27(55):7031–46.

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  36. Culp TD et al. Papillomavirus particles assembled in 293TT cells are infectious in vivo. J Virol. 2006;80(22):11381–4.

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  37. Galloway DA et al. Regulation of telomerase by human papillomaviruses. Cold Spring Harb Symp Quant Biol. 2005;70:209–15.

    Article  CAS  PubMed  Google Scholar 

  38. Klingelhutz AJ, Foster SA, McDougall JK. Telomerase activation by the E6 gene product of human papillomavirus type 16. Nature. 1996;380:79–82.

    Article  CAS  PubMed  Google Scholar 

  39. Fu L, et al. Degradation of p53 by human Alphapapillomavirus E6 proteins shows a stronger correlation with phylogeny than oncogenicity. PLoS One. 2010; 5(9).

  40. Zanier K et al. Solution structure analysis of the HPV16 E6 oncoprotein reveals a self-association mechanism required for E6-mediated degradation of p53. Structure. 2012;20(4):604–17.

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  41. Pim D, Banks L. Interaction of viral oncoproteins with cellular target molecules: infection with high-risk vs low-risk human papillomaviruses. APMIS. 2010;118(6–7):471–93.

    Article  CAS  PubMed  Google Scholar 

  42. Krawczyk E et al. Koilocytosis: a cooperative interaction between the human papillomavirus E5 and E6 oncoproteins. Am J Pathol. 2008;173(3):682–8.

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  43. Paavonen J et al. Efficacy of a prophylactic adjuvanted bivalent L1 virus-like-particle vaccine against infection with human papillomavirus types 16 and 18 in young women: an interim analysis of a phase III double-blind, randomised controlled trial. Lancet. 2007;369(9580):2161–70.

    Article  CAS  PubMed  Google Scholar 

  44. Jeon S, Allen-Hoffmann BL, Lambert PF. Integration of human papillomavirus type 16 into the human genome correlates with a selective growth advantage of cells. J Virol. 1995;69(5):2989–97.

    CAS  PubMed Central  PubMed  Google Scholar 

  45. Jeon S, Lambert PF. Integration of human papillomavirus type 16 DNA into the human genome leads to increased stability of E6 and E7 mRNAs: Implications for cervical carcinogenesis. Proc Natl Acad Sci U S A. 1995;92:1654–8.

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  46. Pett M, Coleman N. Integration of high-risk human papillomavirus: a key event in cervical carcinogenesis? J Pathol. 2007;212:356–67.

    Article  CAS  PubMed  Google Scholar 

  47. Wang Q et al. Functional Analysis of the Human Papillomavirus Type 16 E1 E4 Protein Provides a Mechanism for In Vivo and In Vitro Keratin Filament Reorganization. J Virol. 2003;78(2):821–33.

    Article  Google Scholar 

  48. Matsukura T, Koi S, Sugase M. Both episomal and integrated forms of human papillomavirus type 16 are involved in invasive cervical cancers. Virology. 1989;172:63–72.

    Article  CAS  PubMed  Google Scholar 

  49. Hanahan D, Weinberg RA. Hallmarks of cancer: the next generation. Cell. 2011;144(5):646–74.

    Article  CAS  PubMed  Google Scholar 

  50. Stanley M, Pinto LA, Trimble C. Human papillomavirus vaccines–immune responses. Vaccine. 2012;30 Suppl 5:F83–7.

    Article  CAS  PubMed  Google Scholar 

  51. Ressing ME, van Driel WJ, Brandt RMP, Kenter GG, Jong JH, Bauknecht T, et al. Detection of T helper responses, but not of human papillomavirus-specific cytologic T Lymphocyte responses, after peptide vaccination of patients with cervical carcinoma. J Immunother. 2000;23(2):255–66.

    Article  CAS  PubMed  Google Scholar 

  52. Baldwin PJ, van der Burg SH, Boswell CM, et al. Vaccinia-expressed human papillomavirus 16 and 18 E6 and E7 as a therapeutic vaccination for vulval and vaginal intraepithelial neoplasia. Clin Cancer Res. 2003;9:5205–13.

    CAS  PubMed  Google Scholar 

  53. Trimble CL et al. A phase I trial of a human papillomavirus DNA vaccine for HPV16+ cervical intraepithelial neoplasia 2/3. Clin Cancer Res. 2009;15(1):361–7.

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  54. Matijevic M et al. Immunization with a poly (lactide co-glycolide) encapsulated plasmid DNA expressing antigenic regions of HPV 16 and 18 results in an increase in the precursor frequency of T cells that respond to epitopes from HPV 16, 18, 6 and 11. Cell Immunol. 2011;270(1):62–9.

    Article  CAS  PubMed  Google Scholar 

  55. Maciag PC, Radulovic S, Rothman J. The first clinical use of a live-attenuated Listeria monocytogenes vaccine: a Phase I safety study of Lm-LLO-E7 in patients with advanced carcinoma of the cervix. Vaccine. 2009;27(30):3975–83.

    Article  CAS  PubMed  Google Scholar 

  56. Safaeian M et al. Epidemiological study of anti-HPV16/18 seropositivity and subsequent risk of HPV16 and -18 infections. J Natl Cancer Inst. 2010;102(21):1653–62.

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  57. Ho GYF, Studenstov Y, Hall CB, Bierman R, Beardsley L, Lempa M, et al. Rsik factor for subseqwunt cervicovaginal human papillomavirus(HPV) infection and the protective role of antibodies to HPV 16 virus like particles. J Infect Dis. 2002;186(6):737–42.

    Article  PubMed  Google Scholar 

  58. Malik ZA, Hailpern SM, Burk RD. Persistent antibodies to HPV virus like particles following natural infection are protective against subseqeunt cervicovaginal infection with related and unrelated HPV. Viral Immunol. 2009;22(6):445–9.

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  59. Theiler RN, Farr SL, Karona JM, PAramsothy P, Viscidi R, Duerr A, et al. High-risk human papillomavirus reactivation in human immunodeficiency virus-infected women: risk factors for cervical viral shedding. Obstet Gynecol. 2010;115(6):1150–8.

    Article  PubMed  Google Scholar 

  60. Strickler HD et al. Natural history and possible reactivation of human papillomavirus in human immunodeficiency virus-positive women. J Natl Cancer Inst. 2005;97(8):577–86.

    Article  PubMed  Google Scholar 

  61. Winer TRL, Kiviat NB, Hughes JP, Adam DE, Lee SK, Kuypers JM. Develpoment and duration of human papillomavirus lesions, after initial infection. J Infect Dis. 2005;191(5):731–8.

    Article  PubMed  Google Scholar 

  62. Moscicki AB. Management of adolescents who have abnormal cytology and histology. Obstet Gynecol Clin North Am. 2008;35(4):633–43.

    Article  PubMed Central  PubMed  Google Scholar 

  63. Oster AG. Natural history of cervical intraepithelial neoplasia: a critical review. Int J Gynecol Pathol. 1993;12(2):186–92.

    Article  Google Scholar 

  64. Castle PE, Schiffman M, Wheeler CM, Solomon D. Evidence for frequent regression of cervical intraepthelial neoplasia-grade2. Obstet Gynecol Clin North Am. 2009;113(1):18–24.

    Google Scholar 

  65. Jaisamrarn U et al. Natural History of Progression of HPV Infection to Cervical Lesion or Clearance: Analysis of the Control Arm of the Large. Randomised PATRICIA Study. PLoS One. 2013;8(11):e79260.

    Article  PubMed Central  PubMed  Google Scholar 

Download references

Acknowledgments

This research was supported by a fund (No.2013-E51005-01) by Research of Korea Center for Disease Control and Prevention.

Compliance with Ethics Guidelines

ᅟ

Conflict of Interest

Eun Young Ki and Jong Sup Park declare that they have no conflict of interest

Human and Animal Rights and Informed Consent

This article does not contain any studies with human or animal subjects performed by any of the authors.

Author information

Authors and Affiliations

  1. Department of Obstetrics and Gynecology, Seoul St. Mary’s Hospital, The Catholic University of Korea, Seoul St. Mary’s hospital Banpo dong #505, Seochogu, Seoul, South Korea, 137-040

    Eun Young Ki & Jong Sup Park

Authors
  1. Eun Young Ki
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Jong Sup Park
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Jong Sup Park.

Rights and permissions

Reprints and permissions

About this article

Cite this article

Ki, E.Y., Park, J.S. Natural History of Human Papillomavirus Infection. Curr Obstet Gynecol Rep 3, 123–127 (2014). https://doi.org/10.1007/s13669-014-0082-y

Download citation

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s13669-014-0082-y

Keywords

Search

Navigation