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The life cycle, natural history, and immunology of human papillomaviruses

Philip E Castle, PhD, MPH
Section Editor
Martin S Hirsch, MD
Deputy Editor
Allyson Bloom, MD


Human papillomaviruses (HPV) are highly prevalent, species- and tissue-specific DNA viruses that infect epithelial cells [1,2]. Persistent viral infection with carcinogenic HPV genotypes causes virtually all cancer of the cervix [3-5]. Carcinogenic HPV infections also cause many cancers of the anus, vagina, vulva, penis, and oropharynx [6-8].

Cervical cancer is the third most common cancer in women worldwide [5,9]. Although Pap testing/cytologic screening has reduced the incidence of cervical cancer by 70 percent or more where it has been effectively implemented, cervical cancer remains a leading cause of death in countries without effective screening programs [10]. (See "Invasive cervical cancer: Epidemiology, risk factors, clinical manifestations, and diagnosis".)

Based on the etiologic link between persistent carcinogenic HPV infection of the cervix and cervical cancer [3,4,11] and its immediate precursor lesions [12], one approach for the prevention of cervical disease is HPV vaccination [13]. This topic will review the life cycle, natural history, and immune response to HPV. (See "Epidemiology of human papillomavirus infections" and "Virology of human papillomavirus infections and the link to cancer".)


Over 40 mucosal HPV genotypes infect the lower female genital tract. Approximately 15 HPV types can cause all cervical cancer worldwide and are known as carcinogenic, high-risk, or cancer-associated HPV types [5]. The carcinogenic genotypes of HPV16 and HPV18, which are targeted by the current versions of the HPV vaccine, cause approximately 70 percent of all cervical cancers worldwide [14].

Productive viral infections lead to cervical abnormalities that are classified according to specimen (eg, cytology or histology) and by severity (eg, mild, moderate, or severe). Mild and morphologic changes that are the result of production HPV infections are classified as cytologic low-grade squamous intraepithelial lesion [LSIL] or histologic cervical intraepithelial neoplasia grade 1 [CIN1], whereas cervical precancerous lesions are classified as cytologic high-grade squamous intraepithelial lesion [HSIL] or histologic CIN2 or CIN3 [CIN2/3]. (See "Cervical intraepithelial neoplasia: Terminology, incidence, pathogenesis, and prevention".)


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Literature review current through: Dec 2016. | This topic last updated: Fri Apr 17 00:00:00 GMT+00:00 2015.
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  1. Doorbar J. Molecular biology of human papillomavirus infection and cervical cancer. Clin Sci (Lond) 2006; 110:525.
  2. de Villiers EM, Fauquet C, Broker TR, et al. Classification of papillomaviruses. Virology 2004; 324:17.
  3. Muñoz N, Bosch FX, de Sanjosé S, et al. Epidemiologic classification of human papillomavirus types associated with cervical cancer. N Engl J Med 2003; 348:518.
  4. Walboomers JM, Jacobs MV, Manos MM, et al. Human papillomavirus is a necessary cause of invasive cervical cancer worldwide. J Pathol 1999; 189:12.
  5. Schiffman M, Castle PE, Jeronimo J, et al. Human papillomavirus and cervical cancer. Lancet 2007; 370:890.
  6. Parkin DM, Bray F, Ferlay J, Pisani P. Global cancer statistics, 2002. CA Cancer J Clin 2005; 55:74.
  7. D'Souza G, Kreimer AR, Viscidi R, et al. Case-control study of human papillomavirus and oropharyngeal cancer. N Engl J Med 2007; 356:1944.
  8. Kreimer AR, Clifford GM, Boyle P, Franceschi S. Human papillomavirus types in head and neck squamous cell carcinomas worldwide: a systematic review. Cancer Epidemiol Biomarkers Prev 2005; 14:467.
  9. Ferlay J, Shin HR, Bray F, et al. GLOBOCAN 2008 v1.2, Cancer Incidence and Mortality Worldwide: IARC CancerBase No. 10 [Internet]. Lyon, France: International Agency for Research on Cancer; 2010. http://globocan.iarc.fr (Accessed on April 27, 2012).
  10. Cervix Cancer Screening. IARC Press, 2005.
  11. Wright TC Jr, Schiffman M. Adding a test for human papillomavirus DNA to cervical-cancer screening. N Engl J Med 2003; 348:489.
  12. Schiffman MH, Bauer HM, Hoover RN, et al. Epidemiologic evidence showing that human papillomavirus infection causes most cervical intraepithelial neoplasia. J Natl Cancer Inst 1993; 85:958.
  13. Schiffman M, Castle PE. The promise of global cervical-cancer prevention. N Engl J Med 2005; 353:2101.
  14. de Sanjose S, Quint WG, Alemany L, et al. Human papillomavirus genotype attribution in invasive cervical cancer: a retrospective cross-sectional worldwide study. Lancet Oncol 2010; 11:1048.
  15. Greer CE, Wheeler CM, Ladner MB, et al. Human papillomavirus (HPV) type distribution and serological response to HPV type 6 virus-like particles in patients with genital warts. J Clin Microbiol 1995; 33:2058.
  16. Yang R, Yutzy WH 4th, Viscidi RP, Roden RB. Interaction of L2 with beta-actin directs intracellular transport of papillomavirus and infection. J Biol Chem 2003; 278:12546.
  17. Yang R, Day PM, Yutzy WH 4th, et al. Cell surface-binding motifs of L2 that facilitate papillomavirus infection. J Virol 2003; 77:3531.
  18. Lowy DR, Schiller JT. Prophylactic human papillomavirus vaccines. J Clin Invest 2006; 116:1167.
  19. Johnson KM, Kines RC, Roberts JN, et al. Role of heparan sulfate in attachment to and infection of the murine female genital tract by human papillomavirus. J Virol 2009; 83:2067.
  20. Selinka HC, Florin L, Patel HD, et al. Inhibition of transfer to secondary receptors by heparan sulfate-binding drug or antibody induces noninfectious uptake of human papillomavirus. J Virol 2007; 81:10970.
  21. Shafti-Keramat S, Handisurya A, Kriehuber E, et al. Different heparan sulfate proteoglycans serve as cellular receptors for human papillomaviruses. J Virol 2003; 77:13125.
  22. Herrero R, Castle PE, Schiffman M, et al. Epidemiologic profile of type-specific human papillomavirus infection and cervical neoplasia in Guanacaste, Costa Rica. J Infect Dis 2005; 191:1796.
  23. Zhao FH, Lewkowitz AK, Hu SY, et al. Prevalence of human papillomavirus and cervical intraepithelial neoplasia in China: a pooled analysis of 17 population-based studies. Int J Cancer 2012; 131:2929.
  24. http://www.cdc.gov/std/HPV/STDFact-HPV.htm (Accessed on April 27, 2012).
  25. Plummer M, Schiffman M, Castle PE, et al. A 2-year prospective study of human papillomavirus persistence among women with a cytological diagnosis of atypical squamous cells of undetermined significance or low-grade squamous intraepithelial lesion. J Infect Dis 2007; 195:1582.
  26. Wang SS, Hildesheim A. Chapter 5: Viral and host factors in human papillomavirus persistence and progression. J Natl Cancer Inst Monogr 2003; :35.
  27. Carrington M, Wang S, Martin MP, et al. Hierarchy of resistance to cervical neoplasia mediated by combinations of killer immunoglobulin-like receptor and human leukocyte antigen loci. J Exp Med 2005; 201:1069.
  28. Rodríguez AC, Schiffman M, Herrero R, et al. Rapid clearance of human papillomavirus and implications for clinical focus on persistent infections. J Natl Cancer Inst 2008; 100:513.
  29. Castle PE, Fetterman B, Akhtar I, et al. Age-appropriate use of human papillomavirus vaccines in the U.S. Gynecol Oncol 2009; 114:365.
  30. Rositch AF, Burke AE, Viscidi RP, et al. Contributions of recent and past sexual partnerships on incident human papillomavirus detection: acquisition and reactivation in older women. Cancer Res 2012; 72:6183.
  31. Maglennon GA, Doorbar J. The biology of papillomavirus latency. Open Virol J 2012; 6:190.
  32. Theiler RN, Farr SL, Karon JM, et al. High-risk human papillomavirus reactivation in human immunodeficiency virus-infected women: risk factors for cervical viral shedding. Obstet Gynecol 2010; 115:1150.
  33. Einstein MH, Schiller JT, Viscidi RP, et al. Clinician's guide to human papillomavirus immunology: knowns and unknowns. Lancet Infect Dis 2009; 9:347.
  34. Grulich AE, van Leeuwen MT, Falster MO, Vajdic CM. Incidence of cancers in people with HIV/AIDS compared with immunosuppressed transplant recipients: a meta-analysis. Lancet 2007; 370:59.
  35. Stanley M. Immune responses to human papillomavirus. Vaccine 2006; 24 Suppl 1:S16.