Human papillomavirus infection
Other names	Human papillomavirus
The major capsid protein L1 of HPV 11
Specialty	Infectious disease, gynecology, oncology
Symptoms	None, warts[1][2]
Complications	Cancer of the cervix, vulva, vagina, penis, anus, mouth, tonsils, or throat[1][2][3]
Causes	Human papillomavirus spread by direct contact[4][5]
Risk factors	Sexual contact
Prevention	HPV vaccines, condoms[4][6]
Frequency	Most people are infected at some point in time[4]

Human papillomavirus infection (HPV infection) is caused by a DNA virus from the Papillomaviridae family.^[5] Many HPV infections cause no symptoms and 90% resolve spontaneously within two years.^[1] In some cases, an HPV infection persists and results in either warts or precancerous lesions.^[2] These lesions, depending on the site affected, increase the risk of cancer of the cervix, vulva, vagina, penis, anus, mouth, tonsils, or throat.^[1][2][3] Nearly all cervical cancer is due to HPV and two strains – HPV16 and HPV18 – account for 70% of cases.^[1][7] HPV16 is responsible for almost 90% of HPV-positive oropharyngeal cancers.^[3] Between 60% and 90% of the other cancers listed above are also linked to HPV.^[7] HPV6 and HPV11 are common causes of genital warts and laryngeal papillomatosis.^[1]

An HPV infection is caused by human papillomavirus, a DNA virus from the papillomavirus family.^[8] Over 170 types have been described.^[8] An individual can become infected with more than one type of HPV,^[9] and the disease is only known to affect humans.^[5][10] More than 40 types may be spread through sexual contact and infect the anus and genitals.^[4] Risk factors for persistent infection by sexually transmitted types include early age of first sexual intercourse, multiple sexual partners, smoking, and poor immune function.^[1] These types are typically spread by sustained direct skin-to-skin contact, with vaginal and anal sex being the most common methods.^[4] HPV infection can also spread from a mother to baby during pregnancy.^[9] There is no evidence that HPV can spread via common items like toilet seats,^[11] but the types that cause warts may spread via surfaces such as floors.^[12] HPV is not killed by common hand sanitizers and disinfectants, increasing the possibility of the virus being transferred via non-living infectious agents called fomites.^[13]

HPV vaccines can prevent the most common types of infection.^[4] To be most effective, inoculation should occur before the onset of sexual activity, and are therefore recommended between the ages of 9–13 years.^[1] Cervical cancer screening, such as the Papanicolaou test ("pap smear"), or examination of the cervix after applying acetic acid, can detect both early cancer and abnormal cells that may develop into cancer.^[1] Screening allows for early treatment which results in better outcomes.^[1] Screening has reduced both the number of cases and the number of deaths from cervical cancer.^[14] Genital warts can be removed by freezing.^[5]

Nearly every sexually active individual is infected by HPV at some point in their lives.^[4] HPV is the most common sexually transmitted infection (STI), globally.^[5] Worldwide in 2018, an estimated 569,000 new cases of cervical cancer occurred, with 311,000 deaths.^[15] Around 85% of these cervical cancers occurred in low- and middle-income countries.^[1] In the United States, about 30,700 cases of cancer due to HPV occur each year.^[16] Roughly 1% of sexually active adults have genital warts.^[9] Cases of skin warts have been described since the time of ancient Greece, but that they were caused by a virus was not determined until 1907.^[17]

Signs and symptoms

Some HPV types, such as HPV-5, may establish infections that persist for the lifetime of the individual without ever manifesting any clinical symptoms. HPV types 1 and 2 can cause common warts in some infected individuals.^[18] HPV types 6 and 11 can cause genital warts and laryngeal papillomatosis.^[1]

Many HPV types are carcinogenic.^[19] The table below lists common symptoms of HPV infection and the associated strains of HPV.

Warts

Papilloma

A sample DNA test report for HPV genotype from a laboratory

Skin infection ("cutaneous" infection) with HPV is very widespread.^[23] Skin infections with HPV can cause noncancerous skin growths called warts (verrucae). Warts are caused by a rapid growth of cells on the outer layer of the skin.^[24] While cases of warts have been described since the time of ancient Greece, their viral cause was not known until 1907.^[17]

Skin warts are most common in childhood and typically appear and regress spontaneously over the course of weeks to months. Recurring skin warts are common.^[25] All HPVs are believed to be capable of establishing long-term "latent" infections in small numbers of stem cells present in the skin. Although these latent infections may never be fully eradicated, immunological control is thought to block the appearance of symptoms such as warts. Immunological control is HPV type-specific, meaning an individual may become resistant to one HPV type while remaining susceptible to other types.^{[citation needed]}

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. Common warts have a characteristic cauliflower-like surface and are typically slightly raised above the surrounding skin. Cutaneous HPV types can cause genital warts but are not associated with the development of cancer.^{[citation needed]}
• 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.^[26]
• 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.^[27]

Common, flat, and plantar warts are much less likely to spread from person to person.

Genital warts

HPV infection of the skin in the genital area is the most common sexually transmitted infection worldwide.^[28] Such infections are associated with genital or anal warts (medically known as condylomata acuminata or venereal warts), and these warts are the most easily recognized sign of genital HPV infection.^{[citation needed]}

The strains of HPV that can cause genital warts are usually different from those that cause warts on other parts of the body, such as the hands or feet, or even the inner thighs. A wide variety of HPV types can cause genital warts, but types 6 and 11 together account for about 90% of all cases.^[29][30] However, in total more than 40 types of HPV are transmitted through sexual contact and can infect the skin of the anus and genitals.^[4] Such infections may cause genital warts, although they may also remain asymptomatic.^{[citation needed]}

The great majority of genital HPV infections never cause any overt symptoms and are cleared by the immune system in a matter of months. Moreover, 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.^[28] A large increase in the incidence of genital HPV infection occurs at the age when individuals begin to engage in sexual activity. As with cutaneous HPVs, immunity to genital HPV is believed to be specific to a specific strain of HPV.^{[citation needed]}

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^[31] or other areas of the respiratory tract.^[32][33] 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.^[32][34]

Cancer

HPV-induced cancers^[35]

Virus types

About a dozen HPV types (including types 16, 18, 31, and 45) are called "high-risk" types because persistent infection has been linked to cancer of the oropharynx,^[3] larynx,^[3] vulva, vagina, cervix, penis, and anus.^[36][37] These cancers all involve sexually transmitted infection of HPV to the stratified epithelial tissue.^[1][2][35] Individuals infected with both HPV and HIV have an increased risk of developing cervical or anal cancer.^[36] HPV type 16 is the strain most likely to cause cancer and is present in about 47% of all cervical cancers,^[38][39] and in many vaginal and vulvar cancers,^[40] penile cancers, anal cancers, and cancers of the head and neck.^[41]

Case statistics

An estimated 561,200 new cancer cases worldwide (5.2% of all new cancers) were attributable to HPV in 2002, making HPV one of the most important infectious causes of cancer.^[35] HPV-associated cancers make up over 5% of total diagnosed cancer cases worldwide, and this incidence is higher in developing countries where it is estimated to cause almost half a million cases each year.^[35]

In the United States, about 30,700 cases of cancer due to HPV occur each year.^[16]

Cancer development

Genome organization of human papillomavirus type 16, one of the subtypes known to cause cervical cancer (E1-E7 early genes, L1-L2 late genes: capsid)

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.^[42] Co-factors such as cigarette smoke can also enhance the risk of such HPV-related cancers.^[43][44]

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.^[17] HPV genome integration can also cause carcinogenesis by promoting genomic instability associated with alterations in DNA copy number.^[45]

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.^[46][47] 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.^[48] Thus, the degradation of p53, induced by E6, promotes unregulated cell division, cell growth and cell survival, all characteristics of cancer.^[49]

It is important to note, that while the interaction between E6, E6AP and p53 was the first to be characterized, there are multiple other proteins in the host cell which interact with E6 and assist the induction of cancer.^[50]

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.^[51]

Cervical cancer

Artist's impression of cervical cancer caused by HPV.

Nearly all cases of cervical cancer are associated with HPV infection, with two types, HPV16 and HPV18, present in 70% of cases.^{[1][7][38][52][53][54]} 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.^[55] HPV is necessary for cervical cancer to occur.^[56] 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.^[57][58]

The carcinogenic HPV types in cervical cancer belong to the alphapapillomavirus genus and can be grouped further into HPV clades.^[59] The two major carcinogenic HPV clades, alphapapillomavirus-9 (A9) and alphapapillomavirus-7 (A7), contain HPV16 and HPV18, respectively.^[60] 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.^[61]

In 2012, about 528,000 new cases and 266,000 deaths from cervical cancer occurred worldwide.^[28] Around 85% of these occurred in the developing world.^[1]

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 having been infected with HPV for a long time, usually over a decade or more (persistent infection).^[32][62] 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.^[63]

Non-European (NE) HPV16 variants are significantly more carcinogenic than European (E) HPV16 variants.^[64]

Anal cancer

Studies show a link between HPV infection and anal cancers. Sexually transmitted HPVs are found in a large percentage of anal cancers.^[35] Moreover, the risk for anal cancer is 17 to 31 times higher among HIV-positive individuals who were coinfected with high-risk HPV, and 80 times higher for particularly HIV-positive men who have sex with men.^[65]

Anal Pap smear screening for anal cancer might benefit some subpopulations of men or women engaging in anal sex.^[66] No consensus exists, though, that such screening is beneficial, or who should get an anal Pap smear.^[67][68]

Penile cancer

HPV is associated with approximately 50% of penile cancers. In the United States, penile cancer accounts for about 0.5% of all cancer cases in men. HPV16 is the most commonly associated type detected. The risk of penile cancer increases 2- to 3-fold for individuals who are infected with HIV as well as HPV.^[65]

Head and neck cancers

Oral infection with high-risk carcinogenic HPV types (most commonly HPV 16)^[16] is associated with an increasing number of head and neck cancers.^{[69][53][70][71]} This association is independent of tobacco and alcohol use.^[71][72][73]

Sexually transmitted forms of HPV account for about 25% of cancers of the mouth and upper throat (the oropharynx) worldwide,^[35] but the local percentage varies widely, from 70% in the United States^[74] to 4% in Brazil.^[75] Engaging in anal or oral sex with an HPV-infected partner may increase the risk of developing these types of cancers.^[70]

In the United States, the number of newly diagnosed, HPV-associated head and neck cancers has surpassed that of cervical cancer cases.^[69] The rate of such cancers has increased from an estimated 0.8 cases per 100,000 people in 1988^[76] to 4.5 per 100,000 in 2012,^[16] and, as of 2015, the rate has continued to increase.^[69] Researchers explain these recent data by an increase in oral sex. This type of cancer is more common in men than in women.^[77]

The mutational profile of HPV-positive and HPV-negative head and neck cancer has been reported, further demonstrating that they are fundamentally distinct diseases.^[78]

Lung cancer

Some evidence links HPV to benign and malignant tumors of the upper respiratory tract. The International Agency for Research on Cancer has found that people with lung cancer were significantly more likely to have several high-risk forms of HPV antibodies compared to those who did not have lung cancer.^[79] Researchers looking for HPV among 1,633 lung cancer patients and 2,729 people without the lung disease found that people with lung cancer had more types of HPV than noncancer patients did, and among lung cancer patients, the chances of having eight types of serious HPV were significantly increased.^[80] In addition, expression of HPV structural proteins by immunohistochemistry and in vitro studies suggest HPV presence in bronchial cancer and its precursor lesions.^[81] Another study detected HPV in the exhaled breath condensate (EBC), bronchial brushing and neoplastic lung tissue of cases, and found a presence of an HPV infection in 16.4% of the subjects affected by nonsmall cell lung cancer, but in none of the controls.^[82] The reported average frequencies of HPV in lung cancers were 17% and 15% in Europe and the Americas, respectively, and the mean number of HPV in Asian lung cancer samples was 35.7%, with a considerable heterogeneity between certain countries and regions.^[83]

Skin cancer

In very rare cases, HPV may cause epidermodysplasia verruciformis (EV) in individuals with a weakened immune system. The virus, unchecked by the immune system, causes the overproduction of keratin by skin cells, resulting in lesions resembling warts or cutaneous horns which can ultimately transform into skin cancer, but the development is not well understood.^[84][85] The specific types of HPV that are associated with EV are HPV5, HPV8, and HPV14.^[85]

Cause

Transmission

Sexually transmitted HPV is divided into two categories: low-risk and high-risk. Low-risk HPVs cause warts on or around the genitals. Type 6 and 11 cause 90% of all genital warts and recurrent respiratory papillomatosis that causes benign tumors in the air passages. High-risk HPVs cause cancer and consist of about a dozen identified types. Types 16 and 18 are responsible for causing most of HPV-caused cancers. These high-risk HPVs cause 5% of the cancers in the world. In the United States, high-risk HPVs cause 3% of all cancer cases in women and 2% in men.^[86]

Risk factors for persistent genital HPV infections, which increases the risk for developing cancer, include early age of first sexual intercourse, multiple partners, smoking, and immunosuppression.^[1] Genital HPV is spread by sustained direct skin-to-skin contact, with vaginal, anal, and oral sex being the most common methods.^[4][36] Occasionally it can spread from a mother to her baby during pregnancy. HPV is difficult to remove via standard hospital disinfection techniques, and may be transmitted in a healthcare setting on re-usable gynecological equipment, such as vaginal ultrasound transducers.^[87] The period of communicability is still unknown, but probably at least as long as visible HPV lesions persist. HPV may still be transmitted even after lesions are treated and no longer visible or present.^[88]

Perinatal

Although genital HPV types can be transmitted from mother to child during birth, the appearance of genital HPV-related diseases in newborns is rare. However, the lack of appearance does not rule out asymptomatic latent infection, as the virus has proven to be capable of hiding for decades. Perinatal transmission of HPV types 6 and 11 can result in the development of juvenile-onset recurrent respiratory papillomatosis (JORRP). JORRP is very rare, with rates of about 2 cases per 100,000 children in the United States.^[32] Although JORRP rates are substantially higher if a woman presents with genital warts at the time of giving birth, the risk of JORRP in such cases is still less than 1%.^{[citation needed]}

Genital infections

Genital HPV infections are transmitted primarily by contact with the genitals, anus, or mouth of an infected sexual partner.^[89]

Of the 120 known human papilloma viruses, 51 species and three subtypes infect the genital mucosa.^[90] Fifteen are classified as high-risk types (16, 18, 31, 33, 35, 39, 45, 51, 52, 56, 58, 59, 68, 73, and 82), three as probable high-risk (26, 53, and 66), and twelve as low-risk (6, 11, 40, 42, 43, 44, 54, 61, 70, 72, 81, and 89).^[19]

Condoms do not completely protect from the virus because the areas around the genitals including the inner thigh area are not covered, thus exposing these areas to the infected person's skin.^[91]

Hands

Studies have shown HPV transmission between hands and genitals of the same person and sexual partners. Hernandez tested the genitals and dominant hand of each person in 25 heterosexual couples every other month for an average of seven months. She found two couples where the man's genitals infected the woman's hand with high-risk HPV, two where her hand infected his genitals, one where her genitals infected his hand, two each where he infected his own hand, and she infected her own hand.^[92][93] Hands were not the main source of transmission in these 25 couples, but they were significant.^{[citation needed]}

Partridge reports men's fingertips became positive for high risk HPV at more than half the rate (26% per two years) as their genitals (48%).^[94] Winer reports 14% of fingertip samples from sexually active women were positive.^[95]

Non-sexual hand contact seems to have little or no role in HPV transmission. Winer found all fourteen fingertip samples from virgin women negative at the start of her fingertip study.^[95] In a separate report on genital HPV infection, 1% of virgin women (1 of 76) with no sexual contact tested positive for HPV, while 10% of virgin women reporting non-penetrative sexual contact were positive (7 of 72).^[96]

Shared objects

Sharing of possibly contaminated objects, for example, razors,^[88] may transmit HPV.^[97][98][99] Although possible, transmission by routes other than sexual intercourse is less common for female genital HPV infection.^[89] Fingers-genital contact is a possible way of transmission but unlikely to be a significant source.^[95][100]

Blood

Though it has traditionally been assumed that HPV is not transmissible via blood – as it is thought to only infect cutaneous and mucosal tissues – recent studies have called this notion into question. Historically, HPV DNA has been detected in the blood of cervical cancer patients.^[101] In 2005, a group reported that, in frozen blood samples of 57 sexually naive pediatric patients who had vertical or transfusion-acquired HIV infection, 8 (14.0%) of these samples also tested positive for HPV-16.^[102] This seems to indicate that it may be possible for HPV to be transmitted via blood transfusion. However, as non-sexual transmission of HPV by other means is not uncommon, this could not be definitively proven. In 2009, a group tested Australian Red Cross blood samples from 180 healthy male donors for HPV, and subsequently found DNA of one or more strains of the virus in 15 (8.3%) of the samples.^[103] However, it is important to note that detecting the presence of HPV DNA in blood is not the same as detecting the virus itself in blood, and whether or not the virus itself can or does reside in blood in infected individuals is still unknown. As such, it remains to be determined whether HPV can or cannot be transmitted via blood.^[101] This is of concern, as blood donations are not currently screened for HPV, and at least some organizations such as the American Red Cross and other Red Cross societies do not presently appear to disallow HPV-positive individuals from donating blood.^[104]

Surgery

Hospital transmission of HPV, especially to surgical staff, has been documented. Surgeons, including urologists and/or anyone in the room, is subject to HPV infection by inhalation of noxious viral particles during electrocautery or laser ablation of a condyloma (wart).^[105] There has been a case report of a laser surgeon who developed extensive laryngeal papillomatosis after providing laser ablation to patients with anogenital condylomata.^[105]

Virology

Cryo-electron microscopy structure of the HPV type 16 viral capsid protein. Rendered from PDB: 5KEQ​^[106]

HPV infection is limited to the basal cells of stratified epithelium, the only tissue in which they replicate.^[107] The virus cannot bind to live tissue; instead, it infects epithelial tissues through micro-abrasions or other epithelial trauma that exposes segments of the basement membrane.^[107] The infectious process is slow, taking 12–24 hours for initiation of transcription. It is believed that involved antibodies play a major neutralizing role while the virions still reside on the basement membrane and cell surfaces.^[107]

HPV lesions are thought to arise from the proliferation of infected basal keratinocytes. Infection typically occurs when basal cells in the host are exposed to the infectious virus through a disturbed epithelial barrier as would occur during sexual intercourse or after minor skin abrasions. HPV infections have not been shown to be cytolytic; rather, viral particles are released as a result of degeneration of desquamating cells. HPV can survive for many months and at low temperatures without a host; therefore, an individual with plantar warts can spread the virus by walking barefoot.^[30]

HPV is a small double-stranded circular DNA virus with a genome of approximately 8000 base pairs.^[36][108] The HPV life cycle strictly follows the differentiation program of the host keratinocyte. It is thought that the HPV virion infects epithelial tissues through micro-abrasions, whereby the virion associates with putative receptors such as alpha integrins, laminins, and annexin A2^[109] leading to entry of the virions into basal epithelial cells through clathrin-mediated endocytosis and/or caveolin-mediated endocytosis depending on the type of HPV.^[110] At this point, the viral genome is transported to the nucleus by unknown mechanisms and establishes itself at a copy number of 10-200 viral genomes per cell. A sophisticated transcriptional cascade then occurs as the host keratinocyte begins to divide and become increasingly differentiated in the upper layers of the epithelium.^{[citation needed]}

Evolutionedit

The phylogeny of the various strains of HPV generally reflects the migration patterns of Homo sapiens and suggests that HPV may have diversified along with the human population. Studies suggest that HPV evolved along five major branches that reflect the ethnicity of human hosts, and diversified along with the human population.^[111]

Researchers initially identified two major variants of HPV16, European (HPV16-E), and Non-European (HPV16-NE).^[112] More recent analyses based on thousands of HPV16 genomes show that indeed two major clades exist, that are further subdivided into four lineages (designated A-D) and even further subdivided into 16 sublineages (A1–4, B1–4, C1–4 and D1–4).^[113][114] The A1-A3 sublineages constitute the European variant, A4 the Asian variant, B1-B4 the African type I variant, C1–C4 the African type II variant, D1 the North American variant, D2 the Asian American type I variant, D3 the Asian American type II variant.^[113] The various lineages and sublineages have different oncogenic capacity, where overall, the non-European lineages are considered to increase the risk for cancer.^[115] Although HPV16 is a DNA virus, there are signs of recombination among the different lineages.^[114][116] Based on an analysis of more than 3600 genomes, between 0.3 and 1.2% of them could be recombinant.^[114] Thus, ideally, genotyping (for cancer-risk assessment) of HPV16 should not be based only on certain genes, but on all genes from the entire genome.^[114]

A bioinformatics tool named HPV16-Genotyper performs i) HPV16 lineage genotyping, ii) it detects potential recombination events, iii) it identifies, within the submitted sequences, mutations/SNPs that have been reported (in literature) to increase the risk for cancer.^[114]

E6/E7 proteinsedit

Structure of the HPV type 16 oncoprotein E6 (purple), as obtained by X-ray crystallography, shown bound to the LxxLL peptide motif of the human protein UBE3A (cyan). Rendered from PDB: 4GIZ​.^[117]

The two primary oncoproteins of high risk HPV types are E6 and E7. The "E" designation indicates that these two proteins are early proteins (expressed early in the HPV life cycle), while the "L" designation indicates that they are late proteins (late expression).^[53] The HPV genome is composed of six early (E1, E2, E4, E5, E6, and E7) open reading frames (ORF), two late (L1 and L2) ORFs, and a non-coding long control region (LCR).^[118] After the host cell is infected viral early promoter is activated and a polycistronic primary RNA containing all six early ORFs is transcribed. This polycistronic RNA then undergoes active RNA splicing to generate multiple isoforms of mRNAs.^[119] One of the spliced isoform RNAs, E6*I, serves as an E7 mRNA to translate E7 protein.^[120] However, viral early transcription subjects to viral E2 regulation and high E2 levels repress the transcription. HPV genomes integrate into host genome by disruption of E2 ORF, preventing E2 repression on E6 and E7. Thus, viral genome integration into host DNA genome increases E6 and E7 expression to promote cellular proliferation and the chance of malignancy. The degree to which E6 and E7 are expressed is correlated with the type of cervical lesion that can ultimately develop.^[108]

Role in cancer

The E6/E7 proteins inactivate two tumor suppressor proteins, p53 (inactivated by E6) and pRb (inactivated by E7).^[121] The viral oncogenes E6 and E7^[122] are thought to modify the cell cycle so as to retain the differentiating host keratinocyte in a state that is favourable to the amplification of viral genome replication and consequent late gene expression. E6 in association with host E6-associated protein, which has ubiquitin ligase activity, acts to ubiquitinate p53, leading to its proteosomal degradation. E7 (in oncogenic HPVs) acts as the primary transforming protein. E7 competes for retinoblastoma protein (pRb) binding, freeing the transcription factor E2F to transactivate its targets, thus pushing the cell cycle forward. All HPV can induce transient proliferation, but only strains 16 and 18 can immortalize cell lines in vitro. It has also been shown that HPV 16 and 18 cannot immortalize primary rat cells alone; there needs to be activation of the ras oncogene. In the upper layers of the host epithelium, the late genes L1 and L2 are transcribed/translated and serve as structural proteins that encapsidate the amplified viral genomes. Once the genome is encapsidated, the capsid appears to undergo a redox-dependent assembly/maturation event, which is tied to a natural redox gradient that spans both suprabasal and cornified epithelial tissue layers. This assembly/maturation event stabilizes virions, and increases their specific infectivity.^[123] Virions can then be sloughed off in the dead squames of the host epithelium and the viral lifecycle continues.^[124] A 2010 study has found that E6 and E7 are involved in beta-catenin nuclear accumulation and activation of Wnt signaling in HPV-induced cancers.^[125]

Latency periodedit

Once an HPV virion invades a cell, an active infection occurs, and the virus can be transmitted. Several months to years may elapse before squamous intraepithelial lesions (SIL) develop and can be clinically detected. The time from active infection to clinically detectable disease may make it difficult for epidemiologists to establish which partner was the source of infection.^[105]

Clearanceedit

Most HPV infections are cleared up by most people without medical action or consequences. The table provides data for high-risk types (i.e. the types found in cancers).^{[citation needed]}

Clearing an infection does not always create immunity if there is a new or continuing source of infection. Hernandez' 2005-6 study of 25 couples reports "A number of instances indicated apparent reinfection from partner after viral clearance."^[92]

Diagnosisedit

Notable HPV^[127] types and associated diseases

Over 170 types of HPV have been identified, and they are designated by numbers.^[8][121] They may be divided into "low-risk" and "high-risk" types. Low-risk types cause warts and high-risk types can cause lesions or cancer.^[128][129]

Cervical testingedit