Human papillomavirus infection (HPV infection) is an infection caused by a DNA virus from the Papillomaviridae family. Many HPV infections cause no symptoms and 90% resolve spontaneously within two years. Sometimes an HPV infection persists and results in warts or precancerous lesions. These lesions, depending on the site affected, increase the risk of cancer of the cervix, vulva, vagina, penis, anus, mouth, tonsils, or throat. Nearly all cervical cancer is due to HPV and two strains, HPV16 and HPV18, account for 70% of all cases. HPV16 is responsible for almost 90% of HPV-related cancers of the mouth, throat, or tonsils. Between 60% and 90% of the other cancers listed above are also linked to HPV. HPV6 and HPV11 are common causes of genital warts and laryngeal papillomatosis.
Over 200 types of HPV have been described. An individual can become infected with more than one type of HPV and the disease is only known to affect humans. More than 40 types may be spread through sexual contact and infect the anus and genitals. Risk factors for persistent infection by sexually transmitted types include early age of first sexual intercourse, multiple sexual partners, smoking and poor immune function. These types are typically spread by direct skin-to-skin contact, with vaginal and anal sex being the most common methods. HPV infection can spread from a mother to baby during pregnancy. There is limited evidence that HPV can spread indirectly, but some studies suggest it is theoretically possible to spread via contact with contaminated surfaces. HPV is not killed by common hand sanitizers or disinfectants, increasing the possibility of the virus being transferred via non-living infectious agents called fomites.
HPV vaccines can prevent the most common types of infection. Many public health organisations now test directly for HPV. Screening allows for early treatment, which results in better outcomes. Nearly every sexually active individual is infected with HPV at some point in their lives. HPV is the most common sexually transmitted infection (STI), globally.
High-risk HPVs cause about 5% of all cancers worldwide and about 37,300 cases of cancer in the United States each year. Cervical cancer is among the most common cancers worldwide, causing an estimated 604,000 new cases and 342,000 deaths in 2020. About 90% of these new cases and deaths of cervical cancer occurred in low and middle income countries. Roughly 1% of sexually active adults have genital warts.
HPV types HPV is a group of more than 200 viruses, which are designated by a number for each virus type. Some HPV types, such as HPV5, may establish infections that persist for the lifetime of the individual, without manifesting any clinical symptoms. HPV types 1 and 2 can cause warts in some infected individuals. HPV types 6 and 11 can cause genital warts and laryngeal papillomatosis.
Many HPV types are carcinogenic. About twelve HPV types (including types 16, 18, 31, and 45) are called because persistent infection has been linked to cancer of the oropharynx, larynx, vulva, vagina, cervix, penis, and anus. These cancers all involve sexually transmitted infection of HPV to the stratified epithelial tissue. HPV type 16 is the strain most likely to cause cancer and is present in about 47% of all cervical cancers, and in many vaginal and vulvar cancers, penile cancers, anal cancers and cancers of the head and neck.
The table below lists common signs of HPV infection and the associated types of HPV.
Disease HPV type Common warts 2, 7, 22 Plantar warts 1, 2, 4, 63 Flat warts 3, 10, 28 Anogenital warts 6, 11, 42, 44, and others Anal dysplasia (lesions) 16, 18, 31, 53, 58 Genital cancers Highest risk: 16, 18, 31, 45 Other high-risk: 33, 35, 39, 51, 52, 56, 58, 59, 66, 68 Probably high-risk: 26, 53, 73, 82 Epidermodysplasia verruciformis more than 15 types Focal epithelial hyperplasia (mouth) 13, 32 Mouth papillomas 6, 7, 11, 16, 32 Oropharyngeal cancer 16 Verrucous cyst 60 Laryngeal papillomatosis 6, 11
Conditions and diseases
Warts
Skin infection ("cutaneous" infection) with HPV is common and can cause noncancerous skin growths called warts (verrucae). Warts are caused by rapid cell growth on the outer layer of the skin.Mayo Clinic.com, Common warts, http://www.mayoclinic.com/print/common-warts/DS00370/
While cases of warts have been described since ancient Greece, their viral cause was not known until 1907, when Dr. Giuseppe Ciuffo showed their viral nature by inoculating a wart extract into the skin.
Skin warts are most common in childhood and typically appear and regress spontaneously over weeks to months. Recurrence is common.
Types of warts include: Common warts are usually found on the hands and feet, but can also occur in other areas, such as the elbows or knees. Cutaneous HPV types can cause genital warts but are not associated with the development of cancer. Plantar warts are found on the soles of the feet; they grow inward, generally causing pain when walking. Subungual or periungual warts form under the fingernail (subungual), around the fingernail, or on the cuticle (periungual). They are more difficult to treat than warts in other locations. Flat warts are most commonly found on the arms, face, or forehead. Like common warts, flat warts occur most frequently in children and teens. In people with normal immune function, flat warts are not associated with the development of cancer.MedlinePlus, Warts, https://www.medlineplus.gov/warts.html#cat42 (general reference with links). Also, see
Genital warts HPV infection of the skin in the genital area is the most common sexually transmitted infection world wide.Such infections are associated with genital or anal warts (medically known as condylomata acuminata or venereal warts) and these warts can be diagnosed on visual inspection and confirmed by biopsy.
The strains of HPV that can cause genital warts are usually different from those that cause warts on other parts of the body. A wide variety of HPV types can cause genital warts, but types 6 and 11 together account for about 90% of all cases.
The great majority of genital HPV infections never cause any overt symptoms and are cleared by the immune system in a matter of months. People may transmit the virus to others even if they do not display overt symptoms of infection.
Most people acquire genital HPV infections at some point in their lives, and about 10% of women are currently infected.
Laryngeal papillomatosis In addition to genital warts, infection by HPV types 6 and 11 can cause a rare condition known as recurrent laryngeal papillomatosis, in which warts form on the larynx or other areas of the respiratory tract. These warts can recur frequently, may interfere with breathing, and in extremely rare cases can progress to cancer. For these reasons, repeated surgery to remove the warts may be advisable.
Cancer Case statistics Cervical cancer is among the most common cancers worldwide, causing an estimated 604,000 new cases and 342,000 deaths in 2020. About 90% of these new cases and deaths occurred in low and middle income countries, where screening tests and treatment of early cervical cell changes are not readily available.
In the USA, cervical cancer accounts for 0.7% of new cancer cases. Oral cavity and pharynx cancer accounts for 2.9% of new cancer cases and predominantly affects men. HPV is thought to cause 60% to 70% of oropharyngeal cancers. 37,300 cases of cancer, caused by HPV, occur each year.
+The number of HPV-associated cancers in the period of 2008–2012 in the U.S. Cancer area Average annual number of cases HPV attributable (estimated) HPV 16/18 attributable (estimated) Cervix 11,771 10,700 7,800 Oropharynx (men) 12,638 9,100 8,000 Oropharynx (women) 3,100 2,000 1,600 Vulva 3,554 2,400 1,700 Anus (women) 3,260 3,000 2,600 Anus (men) 1,750 1,600 1,400 Penis 1,168 700 600 Vagina 802 600 400 Rectum (women) 513 500 400 Rectum (men) 237 200 200 Total 38,793 30,700 24,600
Cancer development
In some infected individuals, their immune systems may fail to control HPV. Lingering infection with high-risk HPV types, such as types 16, 18, 31, and 45, can favor the development of cancer. Co-factors such as cigarette smoke can also enhance the risk of HPV-related cancers.
HPV is believed to cause cancer by integrating its genome into nuclear DNA. Some of the early genes expressed by HPV, such as E6 and E7, act as oncogenes that promote tumor growth and malignant transformation. HPV genome integration can also cause carcinogenesis by promoting genomic instability associated with alterations in DNA copy number.
E6 produces a protein (also called E6) that simultaneously binds to two host cell proteins called p53 and E6-Associated Protein (E6-AP). E6AP is an E3 ubiquitin ligase, an enzyme whose purpose is to tag proteins with a post-translational modification called Ubiquitin. By binding both proteins, E6 induces E6AP to attach a chain of ubiquitin molecules to p53, thereby flagging p53 for proteosomal degradation. Normally, p53 acts to prevent cell growth and promotes cell death in the presence of DNA damage. p53 also upregulates the p21 protein, which blocks the formation of the cyclin D/Cdk4 complex, thereby preventing the phosphorylation of retinoblastoma protein (RB), and in turn, halting cell cycle progression by preventing the activation of E2F. In short, p53 is a tumor-suppressor protein that arrests the cell cycle and prevents cell growth and survival when DNA damage occurs. Thus, the degradation of p53, induced by E6, promotes unregulated cell division, cell growth, and cell survival, all characteristics of cancer.
Although the interaction between E6, E6AP, and p53 was the first to be characterized, several other host cell proteins interact with E6, supporting the induction of cancer.
Squamous cell carcinoma of the skin Studies have also shown a link between a wide range of HPV types and squamous cell carcinoma of the skin. In such cases, in vitro studies suggest that the E6 protein of the HPV virus may inhibit apoptosis induced by ultraviolet light.
Cervical cancer Nearly all cases of cervical cancer are associated with HPV infection, with two types, HPV16 and HPV18, present in 70% of cases. In 2012, twelve HPV types were considered carcinogenic for cervical cancer by the International Agency for Research on Cancer: 16, 18, 31, 33, 35, 39, 45, 51, 52, 56, 58, and 59. One study found that 74% of squamous cell carcinomas and 78% of adenocarcinomas tested positive for HPV types 16 or 18. Persistent HPV infection increases the risk for developing cervical carcinoma. Individuals who have an increased incidence of these types of infection are women with HIV/AIDS, who are at a 22-fold increased risk of cervical cancer.
The carcinogenic HPV types in cervical cancer belong to the alphapapillomavirus genus. They can be grouped further into HPV clades. The two major carcinogenic HPV clades, alphapapillomavirus-9 (A9) and alphapapillomavirus-7 (A7), contain HPV16 and HPV18, respectively. These two HPV clades were shown to have different effects on tumour molecular characteristics and patient prognosis, with clade A7 being associated with more aggressive pathways and an inferior prognosis.
In 2020, about 604,000 new cases and 342,000 deaths from cervical cancer occurred worldwide. Around 90% of these occurred in the developing world.
Most HPV infections of the cervix are cleared rapidly by the immune system and do not progress to cervical cancer (see below the Clearance subsection in Virology). Because the process of transforming normal cervical cells into cancerous ones is slow, cancer occurs in people who have been infected with HPV for a long time, usually over a decade or more (persistent infection). Furthermore, both the HPV infection and cervical cancer drive metabolic modifications that may be correlated with the aberrant regulation of enzymes related to metabolic pathways.