Papillomaviridae: HPV

Human papillomavirus (HPV) is a nonenveloped, circular, double-stranded DNA virus belonging to the Papillomaviridae family. Humans are the only reservoir, and transmission occurs through close skin-to-skin or sexual contact. Human papillomaviruses infect basal epithelial cells and can affect cell-regulatory proteins to result in cell proliferation. There are > 200 serotypes that can cause several conditions, including cutaneous warts, anogenital warts, and neoplasms.

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Classification

DNA virus classification flowchart

DNA virus identification:
Viruses can be classified in many ways. Most viruses, however, will either have a genome formed by DNA or RNA. Viruses with a DNA genome can be further characterized by whether that DNA is single or double stranded. If the viruses are covered by a thin coat of cell membrane (usually taken from the host cell), they are called “enveloped” viruses. If that coat is absent, the viruses are called “naked” viruses. Some of the enveloped viruses translate their DNA into RNA before it is incorporated into the host cell’s genome.

Image by Lecturio.

General Characteristics

Basic features of human papillomavirus (HPV)

  • Taxonomy:
    • Family: Papillomaviridae
    • Genera:
      • Alphapapillomavirus
      • Betapapillomavirus
      • Gammapapillomavirus
      • Mupapillomavirus
      • Nupapillomavirus
  • DNA virus:
    • Double stranded
    • Circular genome
  • Structure:
    • Nonenveloped 
    • Icosahedral capsid
A scanning electron microscope model of human papillomavirus

A scanning electron microscope model of the human papillomavirus

Image: “An atomic model of human papillomavirus” by Zhao et al; BioMed Central Ltd. License: CC BY 2.0

Clinically relevant species

There are > 200 HPV serotypes. The notable serotypes include:

  • Low-risk subtypes (causative agents for genital warts):
    • HPV 6 
    • HPV 11
  • High-risk subtypes (associated with cervical cancer):
    • HPV 16
    • HPV 18

Associated diseases

  • Nongenital cutaneous warts:
    • Common warts (verruca vulgaris)
    • Plantar warts (verruca plantaris)
    • Flat warts (verruca plana)
  • Anogenital warts (condyloma acuminata)
  • Neoplasms:
    • Laryngeal papillomatosis
    • Cervical cancer
    • Vulvar and vaginal cancer
    • Anal cancer
    • Oropharyngeal cancer
    • Penile cancer

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Pathogenesis

Reservoir

Humans are the only reservoir.

Transmission

  • Direct transmission via skin-to-skin contact
  • Sexual activity
  • Contact with fomites

Host risk factors

  • High number of sexual partners and sexual activity at a young age
  • Use of oral contraceptives
  • Chewing betel nut
  • Cigarette smoking
  • Radiation/UV exposure

Pathophysiology

  • The virus enters the epithelium through disruption of the skin or mucosa.
  • Infects basal cells → may enter a latent phase
  • Viral DNA may: 
    • Integrate into host DNA
    • Remain as an independent episome 
  • Viral proteins (e.g., E6 and E7) degrade p53 and RB protein → leads to:
    • Basal epithelial cell proliferation → warts
  • ↓ Ability to keep cells with damaged DNA in G1 phase and ↓ ability to initiate apoptosis → more mutations are likely → ↑ likelihood of neoplasia
pathophysiology of human papillomavirus infection

Diagram summarizing the pathophysiology of a human papillomavirus infection

Image by Lecturio. License: CC BY-NC-SA 4.0

Diseases Caused by HPV

Table: Diseases caused by HPV
Notable serotypesDiseaseClinical features
1, 2, 3, 4, 10, 27, 57Cutaneous warts:
  • Common
  • Plantar
  • Flat
  • Benign
  • Soft, tan-colored, cauliflower-like papules
  • Usually on hands and feet
  • Can be single or grouped
6 and 11Anogenital warts (condylomata acuminata)
  • Benign eyophytic lesions
  • Found on external genitalia and perianal region
Laryngeal papillomatosis
  • Benign laryngeal tumors
  • Could lead to airway obstruction
16 and 18Neoplasia:
  • Cervical cancer
  • Vulvar and vaginal cancer
  • Penile cancer
  • Anal cancer
  • Oropharyngeal cancer
  • Mutations in mucosal cells lead to dysplasia.
  • Progresses to carcinoma in situ and invasive carcinoma

Comparisons of Similar DNA Viruses

The following table compares 2 clinically similar double-stranded DNA viruses:

OrganismHuman papillomavirusHerpes simplex virus
Characteristics
  • Nonenveloped
  • Circular
  • Double-stranded DNA
  • > 200 serotypes
  • Enveloped
  • Linear
  • Double-stranded DNA
  • 2 serotypes
Transmission
  • Direct skin contact
  • Sexual activity
  • Contact with saliva
  • Contact with lesions
Clinical
  • Cutaneous warts
  • Anogenital warts
  • Neoplasms
  • Gingivostomatitis
  • Genital herpes
  • Herpetic whitlow
  • Proctitis
  • Hepatitis
  • Esophagitis
  • Encephalitis and aseptic meningitis
  • Pneumonitis
Diagnosis
  • Clinical
  • Biopsy
  • HPV DNA testing
  • Clinical
  • PCR
  • Viral culture
  • Biopsy
  • Antibody testing

References

  1. Nunes, E.M., Talpe-Nunes, V., Sichero, L. (2018) Epidemiology and biology of cutaneous human papillomavirus. Clinics (Sao Paulo); 73(suppl 1):e489s. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6097087/
  2. Araldi, R.P., Sant’Ana, T.A., Módolo, D.G., de Melo, T.C., Spadacci-Morena, D.D., de Cassia Stocco, R., Cerutti, J.M., de Souza, E.B. (2018). The human papillomavirus (HPV)-related cancer biology: An overview. Biomed Pharmacother. 106, 1537-1556. https://pubmed.ncbi.nlm.nih.gov/30119229/
  3. Van Dyne, E.A., Henley, S.J., Saraiya, M., Thomas, C.C., Markowitz, L.E., Benard, V.B. (2018). Trends in human papillomavirus-associated cancers – United States, 1999-2015. MMWR Morb Mortal Wkly Rep. 67(33), 918-924. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6107321/
  4. Arrossi, S., Temin, S., Garland, S., Eckert, L.O., Bhatla, N., Castellsagué, X., Alkaff, S.E., Felder, T., Hammouda, D., Konno, R., Lopes, G., Mugisha, E., Murillo, R., Scarinci, I.C., Stanley, M., Tsu, V., Wheeler, C.M., Adewole, I.F., de Sanjosé, S. (2017). Primary Prevention of Cervical Cancer: American Society of Clinical Oncology Resource-Stratified Guideline. J Glob Oncol. 3(5), 611-634. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5646902/
  5. Khan, M.J., Castle, P.E., Lorincz, A.T., Wacholder, S., Sherman, M., Scott, D.R., Rush, B.B., Glass, A.G., Schiffman, M. (2005) 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. 97(14), 1072-1079. https://pubmed.ncbi.nlm.nih.gov/16030305/
  6. Palefsky, J.M. (2020). Human papillomavirus infections: Epidemiology and disease associations. In Bloom, A. (Ed.), UpToDate. Retrieved May 25, 2021, from https://www.uptodate.com/contents/human-papillomavirus-infections-epidemiology-and-disease-associations
  7. Palefsky, J.M. (2019). Virology of human papillomavirus infections and the link to cancer. In Bloom, A. (Ed.), UpToDate. Retrieved May 25, 2021, from https://www.uptodate.com/contents/virology-of-human-papillomavirus-infections-and-the-link-to-cancer
  8. Morris, S.R. (2020). Human papillomavirus (HPV) infection. [online] MSD Manual Professional Version. Retrieved May 25, 2021, from https://www.msdmanuals.com/professional/infectious-diseases/sexually-transmitted-diseases-stds/human-papillomavirus-hpv-infection
  9. Luria, L., Cardoza-Favarato, G. (2021). Human papillomavirus. [online] StatPearls. Retrieved May 25, 2021, from https://www.ncbi.nlm.nih.gov/books/NBK448132/
  10. Gearhart, P.A., Randall, T.C., Buckley, Jr., R.M., Higgins, R.V. (2020). Human papillomavirus (HPV). In Chandrasekar, P.H. (Ed.), Medscape. Retrieved May 25, 2021, from https://emedicine.medscape.com/article/219110-overview

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