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Papillomavirus (HPV)

Human papillomavirus (HPV) is a nonenveloped, circular, double-stranded DNA DNA A deoxyribonucleotide polymer that is the primary genetic material of all cells. Eukaryotic and prokaryotic organisms normally contain DNA in a double-stranded state, yet several important biological processes transiently involve single-stranded regions. DNA, which consists of a polysugar-phosphate backbone possessing projections of purines (adenine and guanine) and pyrimidines (thymine and cytosine), forms a double helix that is held together by hydrogen bonds between these purines and pyrimidines (adenine to thymine and guanine to cytosine). DNA Types and Structure virus Virus Viruses are infectious, obligate intracellular parasites composed of a nucleic acid core surrounded by a protein capsid. Viruses can be either naked (non-enveloped) or enveloped. The classification of viruses is complex and based on many factors, including type and structure of the nucleoid and capsid, the presence of an envelope, the replication cycle, and the host range. Virology belonging to the Papillomaviridae family. Humans are the only reservoir Reservoir Animate or inanimate sources which normally harbor disease-causing organisms and thus serve as potential sources of disease outbreaks. Reservoirs are distinguished from vectors (disease vectors) and carriers, which are agents of disease transmission rather than continuing sources of potential disease outbreaks. Humans may serve both as disease reservoirs and carriers. Escherichia coli, and transmission occurs through close skin-to-skin or sexual contact. Human papillomaviruses infect basal epithelial cells and can affect cell-regulatory proteins Proteins Linear polypeptides that are synthesized on ribosomes and may be further modified, crosslinked, cleaved, or assembled into complex proteins with several subunits. The specific sequence of amino acids determines the shape the polypeptide will take, during protein folding, and the function of the protein. Energy Homeostasis to result in cell proliferation. There are > 200 serotypes that can cause several conditions, including cutaneous warts Warts Benign epidermal proliferations or tumors; some are viral in origin. Female Genitourinary Examination, anogenital warts Warts Benign epidermal proliferations or tumors; some are viral in origin. Female Genitourinary Examination, and neoplasms Neoplasms New abnormal growth of tissue. Malignant neoplasms show a greater degree of anaplasia and have the properties of invasion and metastasis, compared to benign neoplasms. Benign Bone Tumors.

Last updated: Sep 8, 2022

Editorial responsibility: Stanley Oiseth, Lindsay Jones, Evelin Maza

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 DNA A deoxyribonucleotide polymer that is the primary genetic material of all cells. Eukaryotic and prokaryotic organisms normally contain DNA in a double-stranded state, yet several important biological processes transiently involve single-stranded regions. DNA, which consists of a polysugar-phosphate backbone possessing projections of purines (adenine and guanine) and pyrimidines (thymine and cytosine), forms a double helix that is held together by hydrogen bonds between these purines and pyrimidines (adenine to thymine and guanine to cytosine). DNA Types and Structure virus Virus Viruses are infectious, obligate intracellular parasites composed of a nucleic acid core surrounded by a protein capsid. Viruses can be either naked (non-enveloped) or enveloped. The classification of viruses is complex and based on many factors, including type and structure of the nucleoid and capsid, the presence of an envelope, the replication cycle, and the host range. Virology:
    • Double stranded
    • Circular genome Genome The complete genetic complement contained in the DNA of a set of chromosomes in a human. The length of the human genome is about 3 billion base pairs. Basic Terms of Genetics
  • Structure:
    • Nonenveloped 
    • Icosahedral capsid Capsid The outer protein protective shell of a virus, which protects the viral nucleic acid. Capsids are composed of repeating units (capsomers or capsomeres) of capsid proteins which when assembled together form either an icosahedral or helical shape. Virology
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 Warts Benign epidermal proliferations or tumors; some are viral in origin. Female Genitourinary Examination):
    • HPV 6 
    • HPV 11
  • High-risk subtypes (associated with cervical cancer Cervical cancer Cervical cancer, or invasive cervical carcinoma (ICC), is the 3rd most common cancer in women in the world, with > 50% of the cases being fatal. In the United States, ICC is the 13th most common cancer and the cause of < 3% of all cancer deaths due to the slow progression of precursor lesions and, more importantly, effective cancer screening. Cervical Cancer):
    • HPV 16
    • HPV 18

Associated diseases

  • Nongenital cutaneous warts Warts Benign epidermal proliferations or tumors; some are viral in origin. Female Genitourinary Examination:
  • Anogenital warts Warts Benign epidermal proliferations or tumors; some are viral in origin. Female Genitourinary Examination ( condyloma Condyloma Sexually transmitted form of anogenital warty growth caused by the human papillomaviruses. Male Genitourinary Examination acuminata)
  • Neoplasms Neoplasms New abnormal growth of tissue. Malignant neoplasms show a greater degree of anaplasia and have the properties of invasion and metastasis, compared to benign neoplasms. Benign Bone Tumors:
    • Laryngeal papillomatosis
    • Cervical cancer Cervical cancer Cervical cancer, or invasive cervical carcinoma (ICC), is the 3rd most common cancer in women in the world, with > 50% of the cases being fatal. In the United States, ICC is the 13th most common cancer and the cause of < 3% of all cancer deaths due to the slow progression of precursor lesions and, more importantly, effective cancer screening. Cervical Cancer
    • Vulvar and vaginal cancer Vaginal cancer Primary vaginal cancers are malignant tumors that originate from cells in the vagina. Squamous cell carcinoma (SCC) is by far the most common (80%-85%); other histologic types include adenocarcinomas, sarcomas (including sarcoma botryoides, typically seen in children), and melanomas. Vaginal Cancer
    • Anal cancer Anal cancer Anal cancer accounts for 2.7% of all gastrointestinal tract cancers. Squamous cell carcinoma is the most common type of anal cancer. The patient can present with rectal bleeding (most common), change in bowel habits, perianal pruritic mass, or perianal painful ulceration. Anal Cancer
    • Oropharyngeal cancer
    • Penile cancer Penile cancer Malignant lesions of the penis arise from the squamous epithelium of the glans, prepuce, or penile shaft. Penile cancer is rare in the United States, but there is a higher prevalence in lower socioeconomic regions. The most common histologic subtype is squamous cell carcinoma. Penile Cancer

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Pathogenesis

Reservoir Reservoir Animate or inanimate sources which normally harbor disease-causing organisms and thus serve as potential sources of disease outbreaks. Reservoirs are distinguished from vectors (disease vectors) and carriers, which are agents of disease transmission rather than continuing sources of potential disease outbreaks. Humans may serve both as disease reservoirs and carriers. Escherichia coli

Humans are the only reservoir Reservoir Animate or inanimate sources which normally harbor disease-causing organisms and thus serve as potential sources of disease outbreaks. Reservoirs are distinguished from vectors (disease vectors) and carriers, which are agents of disease transmission rather than continuing sources of potential disease outbreaks. Humans may serve both as disease reservoirs and carriers. Escherichia coli.

Transmission

  • Direct transmission via skin-to-skin contact
  • Sexual activity
  • Contact with fomites Fomites Inanimate objects that carry pathogenic microorganisms and thus can serve as the source of infection. Microorganisms typically survive on fomites for minutes or hours. Common fomites include clothing, tissue paper, hairbrushes, and cooking and eating utensils. Adenovirus
  • Vertical transmission Vertical transmission The transmission of infectious disease or pathogens from one generation to another. It includes transmission in utero or intrapartum by exposure to blood and secretions, and postpartum exposure via breastfeeding. Congenital TORCH Infections (perinatal infection)

Host risk factors

  • High number of sexual partners and sexual activity at a young age
  • Use of oral contraceptives
  • Chewing betel nut
  • Cigarette smoking Smoking Willful or deliberate act of inhaling and exhaling smoke from burning substances or agents held by hand. Interstitial Lung Diseases
  • Radiation Radiation Emission or propagation of acoustic waves (sound), electromagnetic energy waves (such as light; radio waves; gamma rays; or x-rays), or a stream of subatomic particles (such as electrons; neutrons; protons; or alpha particles). Osteosarcoma/UV exposure

Pathophysiology

  • The virus Virus Viruses are infectious, obligate intracellular parasites composed of a nucleic acid core surrounded by a protein capsid. Viruses can be either naked (non-enveloped) or enveloped. The classification of viruses is complex and based on many factors, including type and structure of the nucleoid and capsid, the presence of an envelope, the replication cycle, and the host range. Virology enters the epithelium Epithelium The epithelium is a complex of specialized cellular organizations arranged into sheets and lining cavities and covering the surfaces of the body. The cells exhibit polarity, having an apical and a basal pole. Structures important for the epithelial integrity and function involve the basement membrane, the semipermeable sheet on which the cells rest, and interdigitations, as well as cellular junctions. Surface Epithelium: Histology through disruption of the skin Skin The skin, also referred to as the integumentary system, is the largest organ of the body. The skin is primarily composed of the epidermis (outer layer) and dermis (deep layer). The epidermis is primarily composed of keratinocytes that undergo rapid turnover, while the dermis contains dense layers of connective tissue. Skin: Structure and Functions or mucosa.
  • Infects basal cells → may enter a latent phase
  • Viral DNA DNA A deoxyribonucleotide polymer that is the primary genetic material of all cells. Eukaryotic and prokaryotic organisms normally contain DNA in a double-stranded state, yet several important biological processes transiently involve single-stranded regions. DNA, which consists of a polysugar-phosphate backbone possessing projections of purines (adenine and guanine) and pyrimidines (thymine and cytosine), forms a double helix that is held together by hydrogen bonds between these purines and pyrimidines (adenine to thymine and guanine to cytosine). DNA Types and Structure may: 
    • Integrate into host DNA DNA A deoxyribonucleotide polymer that is the primary genetic material of all cells. Eukaryotic and prokaryotic organisms normally contain DNA in a double-stranded state, yet several important biological processes transiently involve single-stranded regions. DNA, which consists of a polysugar-phosphate backbone possessing projections of purines (adenine and guanine) and pyrimidines (thymine and cytosine), forms a double helix that is held together by hydrogen bonds between these purines and pyrimidines (adenine to thymine and guanine to cytosine). DNA Types and Structure
    • Remain as an independent episome 
  • Viral oncogenic proteins Proteins Linear polypeptides that are synthesized on ribosomes and may be further modified, crosslinked, cleaved, or assembled into complex proteins with several subunits. The specific sequence of amino acids determines the shape the polypeptide will take, during protein folding, and the function of the protein. Energy Homeostasis (e.g., E6 and E7) degrade p53 and RB RB Chlamydia protein → leads to:
    • Basal epithelial cell proliferation → warts Warts Benign epidermal proliferations or tumors; some are viral in origin. Female Genitourinary Examination
    • ↓ Ability to keep cells with damaged DNA DNA A deoxyribonucleotide polymer that is the primary genetic material of all cells. Eukaryotic and prokaryotic organisms normally contain DNA in a double-stranded state, yet several important biological processes transiently involve single-stranded regions. DNA, which consists of a polysugar-phosphate backbone possessing projections of purines (adenine and guanine) and pyrimidines (thymine and cytosine), forms a double helix that is held together by hydrogen bonds between these purines and pyrimidines (adenine to thymine and guanine to cytosine). DNA Types and Structure in G1 phase G1 Phase The period of the cell cycle preceding DNA replication in s phase. Subphases of g1 include ‘competence’ (to respond to growth factors), g1a (entry into g1), g1b (progression), and g1c (assembly). Progression through the g1 subphases is effected by limiting growth factors, nutrients, or inhibitors. Cell Cycle and ↓ ability to initiate apoptosis Apoptosis A regulated cell death mechanism characterized by distinctive morphologic changes in the nucleus and cytoplasm, including the endonucleolytic cleavage of genomic DNA, at regularly spaced, internucleosomal sites, I.e., DNA fragmentation. It is genetically-programmed and serves as a balance to mitosis in regulating the size of animal tissues and in mediating pathologic processes associated with tumor growth. Ischemic Cell Damage → 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 serotypes Disease Clinical features
1, 2, 3, 4, 10, 27, 57 Cutaneous warts Warts Benign epidermal proliferations or tumors; some are viral in origin. Female Genitourinary Examination:
  • Common
  • Plantar
  • Flat
  • Benign Benign Fibroadenoma
  • Soft, tan-colored, cauliflower-like papules
  • Usually on hands and feet
  • Can be single or grouped
6 and 11 Anogenital warts Warts Benign epidermal proliferations or tumors; some are viral in origin. Female Genitourinary Examination ( condylomata acuminata Condylomata Acuminata Condylomata acuminata are a clinical manifestation of genital HPV infection. Condylomata acuminata are described as raised, pearly, flesh-colored, papular, cauliflower-like lesions seen in the anogenital region that may cause itching, pain, or bleeding. Condylomata Acuminata (Genital Warts))
Laryngeal papillomatosis
16 and 18 Neoplasia:
  • Cervical cancer Cervical cancer Cervical cancer, or invasive cervical carcinoma (ICC), is the 3rd most common cancer in women in the world, with > 50% of the cases being fatal. In the United States, ICC is the 13th most common cancer and the cause of < 3% of all cancer deaths due to the slow progression of precursor lesions and, more importantly, effective cancer screening. Cervical Cancer
  • Vulvar and vaginal cancer Vaginal cancer Primary vaginal cancers are malignant tumors that originate from cells in the vagina. Squamous cell carcinoma (SCC) is by far the most common (80%-85%); other histologic types include adenocarcinomas, sarcomas (including sarcoma botryoides, typically seen in children), and melanomas. Vaginal Cancer
  • Penile cancer Penile cancer Malignant lesions of the penis arise from the squamous epithelium of the glans, prepuce, or penile shaft. Penile cancer is rare in the United States, but there is a higher prevalence in lower socioeconomic regions. The most common histologic subtype is squamous cell carcinoma. Penile Cancer
  • Anal cancer Anal cancer Anal cancer accounts for 2.7% of all gastrointestinal tract cancers. Squamous cell carcinoma is the most common type of anal cancer. The patient can present with rectal bleeding (most common), change in bowel habits, perianal pruritic mass, or perianal painful ulceration. 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 DNA Viruses Viruses whose nucleic acid is DNA. Virology:

Organism Human papillomavirus Herpes simplex Herpes Simplex A group of acute infections caused by herpes simplex virus type 1 or type 2 that is characterized by the development of one or more small fluid-filled vesicles with a raised erythematous base on the skin or mucous membrane. It occurs as a primary infection or recurs due to a reactivation of a latent infection. Congenital TORCH Infections virus Virus Viruses are infectious, obligate intracellular parasites composed of a nucleic acid core surrounded by a protein capsid. Viruses can be either naked (non-enveloped) or enveloped. The classification of viruses is complex and based on many factors, including type and structure of the nucleoid and capsid, the presence of an envelope, the replication cycle, and the host range. Virology
Characteristics
  • Nonenveloped
  • Circular
  • Double-stranded DNA DNA A deoxyribonucleotide polymer that is the primary genetic material of all cells. Eukaryotic and prokaryotic organisms normally contain DNA in a double-stranded state, yet several important biological processes transiently involve single-stranded regions. DNA, which consists of a polysugar-phosphate backbone possessing projections of purines (adenine and guanine) and pyrimidines (thymine and cytosine), forms a double helix that is held together by hydrogen bonds between these purines and pyrimidines (adenine to thymine and guanine to cytosine). DNA Types and Structure
  • > 200 serotypes
  • Enveloped
  • Linear
  • Double-stranded DNA DNA A deoxyribonucleotide polymer that is the primary genetic material of all cells. Eukaryotic and prokaryotic organisms normally contain DNA in a double-stranded state, yet several important biological processes transiently involve single-stranded regions. DNA, which consists of a polysugar-phosphate backbone possessing projections of purines (adenine and guanine) and pyrimidines (thymine and cytosine), forms a double helix that is held together by hydrogen bonds between these purines and pyrimidines (adenine to thymine and guanine to cytosine). DNA Types and Structure
  • 2 serotypes
Transmission
  • Direct skin Skin The skin, also referred to as the integumentary system, is the largest organ of the body. The skin is primarily composed of the epidermis (outer layer) and dermis (deep layer). The epidermis is primarily composed of keratinocytes that undergo rapid turnover, while the dermis contains dense layers of connective tissue. Skin: Structure and Functions contact
  • Sexual activity
  • Contact with saliva Saliva The clear, viscous fluid secreted by the salivary glands and mucous glands of the mouth. It contains mucins, water, organic salts, and ptyalin. Salivary Glands: Anatomy
  • Contact with lesions
Clinical
  • Gingivostomatitis Gingivostomatitis Herpes Simplex Virus 1 and 2
  • Genital herpes Genital Herpes Genital herpes infections are common sexually transmitted infections caused by herpes simplex virus (HSV) type 1 or 2. Primary infection often presents with systemic, prodromal symptoms followed by clusters of painful, fluid-filled vesicles on an erythematous base, dysuria, and painful lymphadenopathy. Labial and Genital Herpes
  • Herpetic whitlow Herpetic whitlow Infection of the finger from inoculation of the virus through a break in the skin Herpes Simplex Virus 1 and 2
  • Proctitis Proctitis Inflammation of the mucous membrane of the rectum, the distal end of the large intestine. Chronic Granulomatous Disease
  • Hepatitis
  • Esophagitis Esophagitis Esophagitis is the inflammation or irritation of the esophagus. The major types of esophagitis are medication-induced, infectious, eosinophilic, corrosive, and acid reflux. Patients typically present with odynophagia, dysphagia, and retrosternal chest pain. Esophagitis
  • Encephalitis Encephalitis Encephalitis is inflammation of the brain parenchyma caused by an infection, usually viral. Encephalitis may present with mild symptoms such as headache, fever, fatigue, and muscle and joint pain or with severe symptoms such as seizures, altered consciousness, and paralysis. Encephalitis and aseptic meningitis Meningitis Meningitis is inflammation of the meninges, the protective membranes of the brain, and spinal cord. The causes of meningitis are varied, with the most common being bacterial or viral infection. The classic presentation of meningitis is a triad of fever, altered mental status, and nuchal rigidity. Meningitis
  • Pneumonitis Pneumonitis Human Herpesvirus 6 and 7
Diagnosis
  • Clinical
  • Biopsy Biopsy Removal and pathologic examination of specimens from the living body. Ewing Sarcoma
  • HPV DNA DNA A deoxyribonucleotide polymer that is the primary genetic material of all cells. Eukaryotic and prokaryotic organisms normally contain DNA in a double-stranded state, yet several important biological processes transiently involve single-stranded regions. DNA, which consists of a polysugar-phosphate backbone possessing projections of purines (adenine and guanine) and pyrimidines (thymine and cytosine), forms a double helix that is held together by hydrogen bonds between these purines and pyrimidines (adenine to thymine and guanine to cytosine). DNA Types and Structure testing
  • Clinical
  • PCR PCR Polymerase chain reaction (PCR) is a technique that amplifies DNA fragments exponentially for analysis. The process is highly specific, allowing for the targeting of specific genomic sequences, even with minuscule sample amounts. The PCR cycles multiple times through 3 phases: denaturation of the template DNA, annealing of a specific primer to the individual DNA strands, and synthesis/elongation of new DNA molecules. Polymerase Chain Reaction (PCR)
  • Viral culture Viral culture West Nile Virus
  • Biopsy Biopsy Removal and pathologic examination of specimens from the living body. Ewing Sarcoma
  • 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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