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What types of cells HPV can infect?

What types of cells HPV can infect?


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I am wondering if there is any new information on which cells HPV is able to infect. Is it still limited to squamous cells or are there other cells such as columnar cells it is able to infect?


Basic Information about HPV and Cancer

Cancer is a disease in which cells in the body grow out of control. Cancer is always named for the part of the body where it starts, even if it spreads to other body parts later.

Genital human papillomavirus (HPV) is the most common sexually transmitted infection in the United States. More than 40 HPV types can infect the genital areas of men and women, including the skin of the penis, vulva (area outside the vagina), and anus, and the linings of the vagina, cervix, and rectum. These types can also infect the lining of the mouth and throat.


Contents

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. [19] HPV types 6 and 11 can cause genital warts and laryngeal papillomatosis. [1]

Many HPV types are carcinogenic. [20] The table below lists common symptoms of HPV infection and the associated strains of HPV.

  • Highest risk: [21] 16, 18, 31, 45
  • Other high-risk: [21][23] 33, 35, 39, 51, 52, 56, 58, 59
  • Probably high-risk: [23] 26, 53, 66, 68, 73, 82

Warts Edit

Skin infection ("cutaneous" infection) with HPV is very widespread. [24] 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. [25] While cases of warts have been described since the time of ancient Greece, their viral cause was not known until 1907. [18]

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. [26] 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 ]

    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. 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. [27] 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. [28]

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

Genital warts Edit

HPV infection of the skin in the genital area is the most common sexually transmitted infection worldwide. [29] 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. [30] [31] 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. [29] 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 Edit

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 [32] or other areas of the respiratory tract. [33] [34] 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. [33] [35]

Cancer Edit

Virus types Edit

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. [37] [38] These cancers all involve sexually transmitted infection of HPV to the stratified epithelial tissue. [1] [2] [36] Individuals infected with both HPV and HIV have an increased risk of developing cervical or anal cancer. [37] HPV type 16 is the strain most likely to cause cancer and is present in about 47% of all cervical cancers, [39] [40] and in many vaginal and vulvar cancers, [41] penile cancers, anal cancers, and cancers of the head and neck. [42]

Case statistics Edit

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. [36] 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. [36]

In the United States, about 30,700 cases of cancer due to HPV occur each year. [17]

The number of HPV-associated cancers in the period of 2008–2012 in the US. [17]
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 Edit

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. [43] Co-factors such as cigarette smoke can also enhance the risk of such HPV-related cancers. [44] [45]

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. [18] HPV genome integration can also cause carcinogenesis by promoting genomic instability associated with alterations in DNA copy number. [46]

E6 produces a protein (also called E6) that binds to and inactivates a protein in the host cell called p53. 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 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, inactivation of p53 by E6 can promote unregulated cell division, cell growth, and cell survival, characteristics of cancer. [ citation needed ]

E6 also has a close relationship with the cellular protein E6-associated protein (E6-AP), which is involved in the ubiquitin ligase pathway, a system that acts to degrade proteins. E6-AP binds ubiquitin to the p53 protein, thereby flagging it for proteosomal degradation. [ citation needed ]

Squamous cell carcinoma of the skin Edit

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. [47]

Cervical cancer Edit

Nearly all cases of cervical cancer are associated with HPV infection, with two types, HPV16 and HPV18, present in 70% of cases. [1] [7] [39] [48] [49] [50] 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. [51] HPV is necessary for cervical cancer to occur. [52] 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. [53] [54]

The carcinogenic HPV types in cervical cancer belong to the alphapapillomavirus genus and can be grouped further into HPV clades. [55] The two major carcinogenic HPV clades, alphapapillomavirus-9 (A9) and alphapapillomavirus-7 (A7), contain HPV16 and HPV18, respectively. [56] 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. [57]

In 2012, about 528,000 new cases and 266,000 deaths from cervical cancer occurred worldwide. [29] 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). [33] [58]

Non-European (NE) HPV16 variants are significantly more carcinogenic than European (E) HPV16 variants. [59]

Anal cancer Edit

Studies show a link between HPV infection and anal cancers. Sexually transmitted HPVs are found in a large percentage of anal cancers. [36] 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. [60]

Anal Pap smear screening for anal cancer might benefit some subpopulations of men or women engaging in anal sex. [61] No consensus exists, though, that such screening is beneficial, or who should get an anal Pap smear. [62] [63]

Penile cancer Edit

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. [60]

Head and neck cancers Edit

Oral infection with high-risk carcinogenic HPV types (most commonly HPV 16) [17] is associated with an increasing number of head and neck cancers. [64] [49] [65] [66] This association is independent of tobacco and alcohol use. [66] [67] [68]

Sexually transmitted forms of HPV account for about 25% of cancers of the mouth and upper throat (the oropharynx) worldwide, [36] but the local percentage varies widely, from 70% in the United States [69] to 4% in Brazil. [70] Engaging in anal or oral sex with an HPV-infected partner may increase the risk of developing these types of cancers. [65]

In the United States, the number of newly diagnosed, HPV-associated head and neck cancers has surpassed that of cervical cancer cases. [64] The rate of such cancers has increased from an estimated 0.8 cases per 100,000 people in 1988 [71] to 4.5 per 100,000 in 2012, [17] and, as of 2015, the rate has continued to increase. [64] Researchers explain these recent data by an increase in oral sex. This type of cancer is more common in men than in women. [72]

The mutational profile of HPV-positive and HPV-negative head and neck cancer has been reported, further demonstrating that they are fundamentally distinct diseases. [73]

Lung cancer Edit

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. [74] 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. [75] In addition, expression of HPV structural proteins by immunohistochemistry and in vitro studies suggest HPV presence in bronchial cancer and its precursor lesions. [76] Another study detected HPV in the 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. [77] 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. [78]

Skin cancer Edit

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. [79] [80] The specific types of HPV that are associated with EV are HPV5, HPV8, and HPV14. [80]

Transmission Edit

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. Type 16 and 18 are two that 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. [81]

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] [37] 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. [82] 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. [83]

Perinatal Edit

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. [33] 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 Edit

Genital HPV infections are transmitted primarily by contact with the genitals, anus, or mouth of an infected sexual partner. [84]

Of the 120 known human papilloma viruses, 51 species and three subtypes infect the genital mucosa. [85] 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). [20]

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. [86]

Hands Edit

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 twenty-five 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. [87] [88] Hands were not the main source of transmission in these twenty-five 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%). [89] Winer reports 14% of fingertip samples from sexually active women were positive. [90]

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. [90] 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). [91]

Shared objects Edit

Sharing of possibly contaminated objects, for example, razors, [83] may transmit HPV. [92] [93] [94] Although possible, transmission by routes other than sexual intercourse is less common for female genital HPV infection. [84] Fingers-genital contact is a possible way of transmission but unlikely to be a significant source. [90] [95]

Blood Edit

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. [96] 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. [97] 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. [98] 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. [96] 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. [99]

Surgery Edit

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). [100] There has been a case report of a laser surgeon who developed extensive laryngeal papillomatosis after providing laser ablation to patients with anogenital condylomata. [100]

Virology Edit

HPV infection is limited to the basal cells of stratified epithelium, the only tissue in which they replicate. [102] 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. [102] 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. [102]

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. [31]

HPV is a small double-stranded circular DNA virus with a genome of approximately 8000 base pairs. [37] [103] 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 [104] 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. [105] 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 ]

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. [106] Researchers have identified two major variants of HPV16, European (HPV16-E), and Non-European (HPV16-NE). [107]

E6/E7 proteins Edit

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). [49] 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). [109] 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. [110] One of the spliced isoform RNAs, E6*I, serves as an E7 mRNA to translate E7 protein. [111] 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. [103]

The E6/E7 proteins inactivate two tumor suppressor proteins, p53 (inactivated by E6) and pRb (inactivated by E7). [112] The viral oncogenes E6 and E7 [113] 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. [114] Virions can then be sloughed off in the dead squames of the host epithelium and the viral lifecycle continues. [115] 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. [116]

Latency period Edit

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. [100]

Clearance Edit

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 ]

Clearance rates of high risk types of HPV [117]
Months after initial positive test 8 months 12 months 18 months
% of men tested negative 70% 80% 100%

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." [87]

Over 170 types of HPV have been identified, and they are designated by numbers. [8] [112] 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. [119] [120]

Cervical testing Edit

Guidelines from the American Cancer Society recommend different screening strategies for cervical cancer based on a woman's age, screening history, risk factors and choice of tests. [121] Because of the link between HPV and cervical cancer, the ACS currently recommends early detection of cervical cancer in average-risk asymptomatic adults primarily with cervical cytology by Pap smear, regardless of HPV vaccination status. Women aged 30–65 should preferably be tested every 5 years with both the HPV test and the Pap test. In other age groups, a Pap test alone can suffice unless they have been diagnosed with atypical squamous cells of undetermined significance (ASC-US). [122] Co-testing with a Pap test and HPV test is recommended because it decreases the rate of false-negatives. According to the National Cancer Institute, "The most common test detects DNA from several high-risk HPV types, but it cannot identify the types that are present. Another test is specific for DNA from HPV types 16 and 18, the two types that cause most HPV-associated cancers. A third test can detect DNA from several high-risk HPV types and can indicate whether HPV-16 or HPV-18 is present. A fourth test detects RNA from the most common high-risk HPV types. These tests can detect HPV infections before cell abnormalities are evident. [ citation needed ]

"Theoretically, the HPV DNA and RNA tests could be used to identify HPV infections in cells taken from any part of the body. However, the tests are approved by the FDA for only two indications: for follow-up testing of women who seem to have abnormal Pap test results and for cervical cancer screening in combination with a Pap test among women over age 30." [123]

Mouth testing Edit

Guidelines for oropharyngeal cancer screening by the Preventive Services Task Force and American Dental Association in the U.S. suggest conventional visual examination, but because some parts of the oropharynx are hard to see, this cancer is often only detected in later stages. [60]

The diagnosis of oropharyngeal cancer occurs by biopsy of exfoliated cells or tissues. The National Comprehensive Cancer Network and College of American Pathologists recommend testing for HPV in oropharyngeal cancer. [60] However, while testing is recommended, there is no specific type of test used to detect HPV from oral tumors that is currently recommended by the FDA in the United States. Because HPV type 16 is the most common type found in oropharyngeal cancer, p16 immunohistochemistry is one test option used to determine if HPV is present, [124] which can help determine course of treatment since tumors that are negative for p16 have better outcomes. Another option that has emerged as a reliable option is HPV DNA in situ hybridization (ISH) which allows for visualization of the HPV. [60]

Testing men Edit

There is not a wide range of tests available even though HPV is common most studies of HPV used tools and custom analysis not available to the general public. [125] [ needs update ] Clinicians often depend on the vaccine among young people and high clearance rates (see Clearance subsection in Virology) to create a low risk of disease and mortality, and treat the cancers when they appear. Others believe that reducing HPV infection in more men and women, even when it has no symptoms, is important (herd immunity) to prevent more cancers rather than just treating them. [126] [127] [ needs update ] Where tests are used, negative test results show safety from transmission, and positive test results show where shielding (condoms, gloves) is needed to prevent transmission until the infection clears. [128]

Studies have tested for and found HPV in men, including high-risk types (i.e. the types found in cancers), on fingers, mouth, saliva, anus, urethra, urine, semen, blood, scrotum and penis. [125]

The Qiagen/Digene kit mentioned in the previous section was used successfully off label to test the penis, scrotum and anus [129] of men in long-term relationships with women who were positive for high-risk HPV. 60% of them were found to carry the virus, primarily on the penis. [129] [ needs update ] Other studies used cytobrushes and custom analysis. [130] [131] [ needs update ]

In one study researchers sampled subjects' urethra, scrotum and penis. [130] [131] [ needs update ] Samples taken from the urethra added less than 1% to the HPV rate. Studies like this led Giuliano to recommend sampling the glans, shaft and crease between them, along with the scrotum, since sampling the urethra or anus added very little to the diagnosis. [89] Dunne recommends the glans, shaft, their crease, and the foreskin. [125]

In one study the subjects were asked not to wash their genitals for 12 hours before sampling, including the urethra as well as the scrotum and the penis. [130] Other studies are silent on washing - a particular gap in studies of the hands. [ citation needed ]

One small study used wet cytobrushes, rather than wet the skin. [131] It found a higher proportion of men to be HPV-positive when the skin was rubbed with a 600 grit emery paper before being swabbed with the brush, rather than swabbed with no preparation. It's unclear whether the emery paper collected the virions or simply loosened them for the swab to collect.

Studies have found self-collection (with emery paper and Dacron swabs) as effective as collection done by a clinician, and sometimes more so, since patients were more willing than a clinician to scrape vigorously. [132] [ needs update ] [133] Women had similar success in self-sampling using tampons, swabs, cytobrushes and lavage. [134] [ needs update ]

Several studies used cytobrushes to sample fingertips and under fingernails, without wetting the area or the brush. [90] [95] [135] [ needs update ]

Other studies analyzed urine, semen, and blood and found varying amounts of HPV, [125] but there is not a publicly available test for those yet.

Other testing Edit

Although it is possible to test for HPV DNA in other kinds of infections, [125] there are no FDA-approved tests for general screening in the United States [136] or tests approved by the Canadian government, [137] since the testing is inconclusive and considered medically unnecessary. [138]

Genital warts are the only visible sign of low-risk genital HPV and can be identified with a visual check. These visible growths, however, are the result of non-carcinogenic HPV types. Five percent acetic acid (vinegar) is used to identify both warts and squamous intraepithelial neoplasia (SIL) lesions with limited success [ citation needed ] by causing abnormal tissue to appear white, but most doctors have found this technique helpful only in moist areas, such as the female genital tract. [ citation needed ] At this time, HPV tests for males are used only in research. [ citation needed ]

Research into testing for HPV by antibody presence has been done. The approach is looking for an immune response in blood, which would contain antibodies for HPV if the patient is HPV positive. [139] [140] [141] [142] The reliability of such tests has not been proven, as there has not been a FDA approved product as of August 2018 [143] testing by blood would be a less invasive test for screening purposes.

The HPV vaccines can prevent the most common types of infection. [4] To be effective they must be used before an infection occurs and are therefore recommended between the ages of nine and thirteen. Cervical cancer screening, such as with the Papanicolaou test (pap) or looking at the cervix after using acetic acid, can detect early cancer or abnormal cells that may develop into cancer. This allows for early treatment which results in better outcomes. [1] Screening has reduced both the number and deaths from cervical cancer in the developed world. [15] Warts can be removed by freezing. [5]

Vaccines Edit

Three vaccines are available to prevent infection by some HPV types: Gardasil, Gardasil 9 and Cervarix all three protect against initial infection with HPV types 16 and 18, which cause most of the HPV-associated cancer cases. Gardasil also protects against HPV types 6 and 11, which cause 90% of genital warts. Gardasil is a recombinant quadrivalent vaccine, whereas Cervarix is bivalent, and is prepared from virus-like particles (VLP) of the L1 capsid protein. Gardasil 9 is nonavalent, it has the potential to prevent about 90% of cervical, vulvar, vaginal, and anal cancers. It can protect for HPV types 6, 11, 16, 18, 31, 33, 45, 52, and 58 the latter five cause up to 20% of cervical cancers which were not previously covered. [144]

The vaccines provide little benefit to women already infected with HPV types 16 and 18. [145] For this reason, the vaccine is recommended primarily for those women not yet having been exposed to HPV during sex. The World Health Organization position paper on HPV vaccination clearly outlines appropriate, cost-effective strategies for using HPV vaccine in public sector programs. [146]

There is high-certainty evidence that HPV vaccines protect against precancerous cervical lesions in young women, particularly those vaccinated aged 15 to 26. [147] HPV vaccines do not increase the risk of serious adverse events. [147] Longer follow-up is needed to monitor the impact of HPV vaccines on cervical cancer. [147]

The CDC recommends the vaccines be delivered in two shots at an interval of least 6 months for those aged 11–12, and three doses for those 13 and older. [148] In most countries, they are funded only for female use, but are approved for male use in many countries, and funded for teenage boys in Australia. The vaccine does not have any therapeutic effect on existing HPV infections or cervical lesions. [149] In 2010, 49% of teenage girls in the US got the HPV vaccine. [ citation needed ]

Following studies suggesting that the vaccine is more effective in younger girls [150] than in older teenagers, the United Kingdom, Switzerland, Mexico, the Netherlands and Quebec began offering the vaccine in a two-dose schedule for girls aged under 15 in 2014. [ citation needed ]

Cervical cancer screening recommendations have not changed for females who receive HPV vaccine. It remains a recommendation that women continue cervical screening, such as Pap smear testing, even after receiving the vaccine, since it does not prevent all types of cervical cancer. [149] [151]

Both men and women are carriers of HPV. [152] The Gardasil vaccine also protects men against anal cancers and warts and genital warts. [153]

Duration of both vaccines' efficacy has been observed since they were first developed, and is expected to be longlasting. [154]

In December 2014, the FDA approved a nine-valent Gardasil-based vaccine, Gardasil 9, to protect against infection with the four strains of HPV covered by the first generation of Gardasil as well as five other strains responsible for 20% of cervical cancers (HPV-31, HPV-33, HPV-45, HPV-52, and HPV-58). [155]

Condoms Edit

The Centers for Disease Control and Prevention says that male "condom use may reduce the risk for genital human papillomavirus (HPV) infection" but provides a lesser degree of protection compared with other sexual transmitted diseases "because HPV also may be transmitted by exposure to areas (e.g., infected skin or mucosal surfaces) that are not covered or protected by the condom." [156]

Disinfection Edit

The virus is unusually hardy, and is immune to most common disinfectants. It is the first virus ever shown to be resistant to inactivation by glutaraldehyde, which is among the most common strong disinfectants used in hospitals. [157] Diluted sodium hypochlorite bleach is effective, [157] but cannot be used on some types of re-usable equipment, such as ultrasound transducers. [82] As a result of these difficulties, there is developing concern about the possibility of transmitting the virus on healthcare equipment, particularly reusable gynecological equipment that cannot be autoclaved. [158] [159] For such equipment, some health authorities encourage use of UV disinfection [160] or a non-hypochlorite "oxidizing‐based high‐level disinfectant [bleach] with label claims for non‐enveloped viruses", [161] such as a strong hydrogen peroxide solution [162] [160] or chlorine dioxide wipes. [160] Such disinfection methods are expected to be relatively effective against HPV. [ citation needed ]

There is currently no specific treatment for HPV infection. [163] [164] [165] However, the viral infection is usually cleared to undetectable levels by the immune system. [166] According to the Centers for Disease Control and Prevention, the body's immune system clears HPV naturally within two years for 90% of cases (see Clearance subsection in Virology for more detail). [163] However, experts do not agree on whether the virus is completely eliminated or reduced to undetectable levels, and it is difficult to know when it is contagious. [167] [ needs update ]

Follow up care is usually recommended and practiced by many health clinics. [168] Follow-up is sometimes not successful because a portion of those treated do not return to be evaluated. In addition to the normal methods of phone calls and mail, text messaging and email can improve the number of people who return for care. [169] As of 2015 it is unclear the best method of follow up following treatment of cervical intraepithelial neoplasia. [170]

Globally, 12% of women are positive for HPV DNA, with rates varying by age and country. [171] The highest rates of HPV are in younger women, with a rate of 24% in women under 25 years. [172] Rates decline in older age groups in Europe and the Americas, but less so in Africa and Asia. The rates are highest in Sub-Saharan Africa (24%) and Eastern Europe (21%) and lowest in North America (5%) and Western Asia (2%). [171]

The most common types of HPV worldwide are HPV16 (3.2%), HPV18 (1.4%), HPV52 (0.9%), HPV31 (0.8%), and HPV58 (0.7%). High-risk types of HPV are also distributed unevenly, with HPV16 having a rate around 13% in Africa and 30% in West and Central Asia. [172]

Like many diseases, HPV disproportionately affects low-income and resource-poor countries. The higher rates of HPV in Sub-Saharan Africa, for example, may be related to high exposure to human immunodeficiency virus (HIV) in the region. Other factors that impact the global spread of disease are sexual behaviors including age of sexual debut, number of sexual partners, and ease of access to barrier contraception, all of which vary globally. [171] [173]

United States Edit

HPV prevalence among women by age, including 20 low-risk types and 23 high-risk types [174]
Age (years) Prevalence (%)
14 to 19 24.5%
20 to 24 44.8%
25 to 29 27.4%
30 to 39 27.5%
40 to 49 25.2%
50 to 59 19.6%
14 to 59 26.8%

HPV is estimated to be the most common sexually transmitted infection in the United States. [174] Most sexually active men and women will probably acquire genital HPV infection at some point in their lives. [39] The American Social Health Association estimates that about 75–80% of sexually active Americans will be infected with HPV at some point in their lifetime. [175] [176] By the age of 50 more than 80% of American women will have contracted at least one strain of genital HPV. [174] [177] It was estimated that, in the year 2000, there were approximately 6.2 million new HPV infections among Americans aged 15–44 of these, an estimated 74% occurred to people between ages of 15 and 24. [178] Of the STDs studied, genital HPV was the most commonly acquired. [178] In the United States, it is estimated that 10% of the population has an active HPV infection, 4% has an infection that has caused cytological abnormalities, and an additional 1% has an infection causing genital warts. [179]

Estimates of HPV prevalence vary from 14% to more than 90%. [180] One reason for the difference is that some studies report women who currently have a detectable infection, while other studies report women who have ever had a detectable infection. [181] [182] Another cause of discrepancy is the difference in strains that were tested for. [ citation needed ]

One study found that, during 2003–2004, at any given time, 26.8% of women aged 14 to 59 were infected with at least one type of HPV. This was higher than previous estimates 15.2% were infected with one or more of the high-risk types that can cause cancer. [174] [183]

The prevalence for high-risk and low-risk types is roughly similar over time. [174]

Human papillomavirus is not included among the diseases that are typically reportable to the CDC as of 2011. [184] [185]

Ireland Edit

On average 538 cases of HPV-associated cancers were diagnosed per year in Ireland during the period 2010 to 2014. [186] Cervical cancer was the most frequent HPV-associated cancer with on average 292 cases per year (74% of the female total, and 54% of the overall total of HPV-associated cancers). [186] A study of 996 cervical cytology samples in an Irish urban female, opportunistically screened population, found an overall HPV prevalence of 19.8%, HPV 16 at 20% and HPV 18 at 12% were the commonest high-risk types detected. In Europe, types 16 and 18 are responsible for over 70% of cervical cancers. [187] Overall rates of HPV-associated invasive cancers may be increasing. Between 1994 and 2014, there was a 2% increase in the rate of HPV-associated invasive cancers per year for both sexes in Ireland. [186]

As HPV is known to be associated with ano-genital warts, these are notifiable to the Health Protection Surveillance Centre (HPSC). Genital warts are the second most common STI in Ireland. [188] There were 1,281 cases of ano-genital warts notified in 2017, which was a decrease on the 2016 figure of 1,593. [189] The highest age-specific rate for both male and female was in the 25-29 year old age range, 53% of cases were among males. [189]

Sri Lanka Edit

In Sri Lanka, the prevalence of HPV is 15.5% regardless of their cytological abnormalities. [190]

In 1972, the association of the human papillomaviruses with skin cancer in epidermodysplasia verruciformis was proposed by Stefania Jabłońska in Poland. In 1978, Jabłońska and Gerard Orth at the Pasteur Institute discovered HPV-5 in skin cancer. [191] In 1976 Harald zur Hausen published the hypothesis that human papilloma virus plays an important role in the cause of cervical cancer. In 1983 and 1984 zur Hausen and his collaborators identified HPV16 and HPV18 in cervical cancer. [192]

The HeLa cell line contains extra DNA in its genome that originated from HPV type 18. [193]

The Ludwig-McGill HPV Cohort is one of the world's largest longitudinal studies of the natural history of human papillomavirus (HPV) infection and cervical cancer risk. It was established in 1993 by Ludwig Cancer Research and McGill University in Montreal, Canada. [ citation needed ]


EPIDEMIOLOGY OF HUMAN PAPILLOMAVIRUS INFECTIONS

Approximately 6.2 million new HPV infections occur every year in the United States, and approximately 20 million individuals are currently infected [1]. HPV is spread by skin-to-skin sexual contact and is prevalent in all sexually active populations. The Centers for Disease Control estimates that at least half of all sexually active individuals will acquire HPV at some point in their lives, whereas at least 80% of women will acquire an HPV infection by age 50 [1]. In the United States, it is estimated that 10% of the population has an active HPV infection, 4% has an infection that has caused cytological abnormalities, and an additional 1% have infection causing genital warts [2]. Although 1% of Americans have clinically visible genital warts, as many as 13% of those attending STD clinics have genital warts [2]. The greatest risk factors for infection are gender, youth, and sexual activity, with the highest rates being consistently found in sexually active women less than 25 years of age. Winer et al followed 148 female university students as they initiated sexual activity ( Figure 1 ) [3]. They found a cumulative incidence of HPV of 38.9% at 24 months. HPV 16 was the most common type, with a cumulative infection rate of 10.4% at 24 months the cumulative incidence of HPV 18 infection was 4.1% for the same time period. Brown et al studied a smaller cohort of mid-adolescent women for two years. Of the women studied, 82% were infected with HPV during the 2-year study period [4]. DNA from both low-risk and high-risk HPV types has even been found in women who have sex with women, a population that would be expected to have a low incidence of HPV infection [5]. It should be noted that prevalence estimates vary depending on the technique used to assess viral load polymerase chain reaction analysis is a more sensitive detection method and yields higher rates of prevalence.

Cumulative rate of HPV infection among college-aged women who were virgins at baseline. Adapted from Winer et al [3].

HPV 16 alone is linked to more than 50% of all cervical cancers [6] thus, the prevalence of HPV 16 is of special interest. One study utilized an experimental serological test to determine the presence of antibodies to HPV 16, which signify prior exposure to HPV, instead of the more commonly assessed viral DNA which is indicative of active infection. More than 7000 sera were tested from a national sample from the United States. Gender and age specific findings are shown in Figure 2 . Women were more likely to be seropositive for HPV 16 (17.9%) than were men (7.9%). However, this methodology may in fact underestimate the true prior exposure to HPV 16, because 㱠% of women infected with HPV 16 develop type-specific antibodies [6].

Seroprevalence of HPV 16 by age and gender. Modified from Stone et al [6].

Sexual activity is the primary risk factor for HPV infection, but condoms, although effective at preventing the spread of many other sexually transmitted infections, may not prevent all HPV infections. A meta-analysis of more than 20 trials investigating the role of condoms in HPV transmission and the development of clinical complications concluded that, although condoms do not protect against cervical infection, they may offer some protection against HPV-associated disease. Specifically, although there is conflicting evidence as to whether condom use protects against CIN 2/3, condoms may protect against cervical cancer [7]. A recent prospective study by Hogewoning et al studied the effect of condom use on the regression of CIN lesions. Women with abnormal cervical smears or CIN were randomized to use condoms after the initial diagnosis. The 2-year cumulative regression rate was 53% in the 𠇌ondom” group and 35% in the “noncondom” group. The 2-year cumulative rate of HPV clearance was 23% in the condom group and 4% in the noncondom group [8]. It is difficult to accurately assess the role of condoms in preventing HPV infection and the development of clinical complications of infections, not least because investigators rely on patient self-report to assess condom use. The available evidence does, however, suggest that condom use protects against some clinical sequelae of HPV infection and aids clearance of infection and clinical symptoms, even if it does not prevent primary infection.


Management and Treatment

How is human papilloma virus (HPV) treated?

There is no cure for the virus itself, but many HPV infections go away on their own. In fact, about 70 to 90 percent of cases of HPV infection are cleared from the body by the immune system.

When treatment is needed, the goal is to relieve symptoms by removing any visible warts and abnormal cells in the cervix. Treatments might include:

    : Freezing the warts off with liquid nitrogen. : Using a special wire loop to remove the abnormal cells.
  • Electrocautery: Burning the warts off with an electrical current.
  • Laser therapy: Using an intense light to destroy the warts and any abnormal cells.
  • Prescription cream: Applying medicated cream directly to the warts. (Do not use over-the-counter wart treatments on the genital area.)

In some cases, no treatment is needed. However, your doctor will closely watch any cell changes during your regular screening appointments.

Only a small number of women infected with HPV will develop cellular changes that need to be treated.


Access and Law

Private insurance carriers tend to follow ACIP guidelines, and this has proven to be the case with the HPV quadrivalent vaccine as well. As of September 29, 2007, health plans covering about 98% of privately insured individuals in the United States had decided at the national level to reimburse for the quadrivalent vaccine. Nevertheless, these decisions at the national level can still be affected by state and regional decisions and coverage may vary. Although most girls and women in the target age for HPV vaccination have private insurance, 1 in 10 (12%) girls aged 9 to 18 and 3 in 10 (29%) women aged 19 to 26 are uninsured. 30

The Vaccines for Children (VCF) Program is a federally funded program that vaccinates children who are covered by Medicaid, or who are Medicaid-eligible, uninsured, American Indian or Alaskan Native. VCF has added the Gardasil vaccine to its coverage list. States that have a State Children’s Health Insurance Program separate from their Medicaid program are also required to cover ACIP-recommended vaccines, though the funding for this must come at the state level. 30

For adults with Medicaid, vaccination coverage is optional and is decided on a state-by-state basis. There is currently no public funding available for uninsured adults for the HPV vaccine however, Merck has established a vaccination assistance program for uninsured women whose income is below 200% of the poverty level, and on an individual basis additional exceptions can be made for patients with higher incomes. 31

Since the ACIP recommendations to vaccinate all girls aged 11 to 12 were issued, there has been a tremendous amount of debate regarding whether to mandate the HPV vaccine as part of school vaccination programs. The debate includes considerations about the vaccine’s safety, cost, and moral objections to vaccinating girls against a sexually transmitted infection. School vaccination programs are regulated by the state and, in 2007, at least 24 states and the District of Columbia introduced legislation that would mandate HPV vaccine coverage, the majority of which are still under consideration. In February 2007, Texas was the first state to enact a mandate for vaccination by executive order of the governor however, this mandate was later overturned by the state legislature. Virginia is the only other state that so far has also passed a bill mandating vaccination, which would go into effect October 2008, and a bill that would delay the requirement is currently under consideration.


Natural History of Cutaneous HPV Infections and Clinical Implications

Cutaneous HPV types are ubiquitous and are widespread in the general population. Up to 90% of healthy individuals tested positive for beta HPV types (72�). The infection occurs in young children through skin-to-skin contact (75, 76). The cutaneous HPVs have been proposed to infect hair follicle stem cells of healthy individuals, where they constitute a reservoir of persistent infection (77, 78). DNA from cutaneous HPVs is frequently detected in hair bulbs, independently of the anatomical region where the hairs were plucked (79). Schmitt et al. (80) showed that keratinocyte stem cells (KSCs) in rabbit hair follicles co-localize with the primary target cells of cottontail rabbit papillomavirus (CRPV). They showed presence of CRPV early transcripts in clonogenic cells of the hair follicles soon after infection, suggesting that hair follicle stem cells are the initial target cells for CRPV (80), which was shown to induce cutaneous warts and carcinomas (81).

Epidemiological studies in humans showed that the cutaneous HPV population present in hair follicles mirrors the HPV prevalence in the skin of the same individual, which makes eyebrow hair an excellent sampling method to characterize the individual cutaneous HPV population (79, 82). Studies on intra-familial transmission showed that similar spectra of beta HPV types are present within members of the same family. Babies and their parents share some of the beta HPV types (83), which can persist for many years on healthy skin (84, 85). Transmission of beta and gamma HPVs has been demonstrated in couples (86).

Exposure to cutaneous HPV is common. Serological studies measuring antibodies against the type-specific L1 major capsid protein of HPV showed that 52% of the Dutch population and 67% of the Italian population were exposed to beta HPV infections (74). A recent seroprevalence study, based on ten beta HPV types, showed that 39% of healthy men were seropositive for at least one beta HPV type (87). Seroconversion for beta and gamma HPV types appears to be slow and to increase with age (88). Low viral loads in immunocompetent individuals (89) and continuous renewal of the infected keratinocytes may explain why only half of the infected individuals develop antibodies against cutaneous HPV types (90, 91).

Cutaneous HPVs are highly prevalent in the rare hereditary disease epidermodysplasia verruciformis (EV), which tends to progress to cutaneous SCC (cSCC), frequently located at sun-exposed anatomical sites (92). HPV5 and 8, two members of species 㬡, were isolated from cSCC in patients with EV (93). These two types were classified as possibly carcinogenic to humans (IARC Group 2B) (10).

In organ transplant recipients, a 65�-fold increased risk of developing SCC compared with the general population was reported (94, 95). In addition, in HIV-positive individuals, several studies reported at least a 2-fold increased risk of cSCC compared with HIV-uninfected people (96, 97). The correlation between the immunodeficiency state and an increased risk of developing NMSC suggested a possible role of infectious agents (98), such as cutaneous HPV.

This observation is corroborated by growing evidence showing an association between cutaneous infection and the risk of developing NMSC in immunocompetent individuals under certain conditions (e.g., UV radiation exposure) [reviewed in (21, 99)], in particular in cSCC (100�).

Epidemiological and biological data suggested that beta HPV types, and species 㬡 and 㬢 in particular, may be linked to cSCC development in immunocompetent individuals (99, 100) [reviewed in (21)].

Interestingly, the cutaneous HPV viral load was higher in actinic keratosis, which is considered to be the precursor lesion of cSCC, compared with cSCC (< 1 copy per cell), suggesting a possible role of cutaneous HPV types in the initiation of skin carcinogenesis but not in the maintenance of the cancer phenotype, by exacerbating the accumulation of UV radiation-induced DNA breaks and somatic mutations (the hit-and-run mechanism) (103, 104). The absence of HPV mRNA (105) and the lack of evidence for the integration event in skin tumors support this scenario.

The Mastomys natalensis papillomavirus (MnPV)-infected rodent model Mastomys coucha was previously described and used to evaluate the role of PVs in NMSC. In these mice, which can be naturally infected by MnPV, skin lesions such as papillomas or keratoacanthomas can be induced (106). Using this model, Hasche et al. (107) clearly demonstrated cooperation between UVB radiation exposure and MnPV infection in the first step of NMSC initiation. MnPV-positive animals chronically exposed to UVB radiation developed lesions significantly more frequently than MnPV-negative animals (107). Moreover, the authors showed higher MnPV viral loads in well-differentiated and keratinizing SCCs (KSCCs) compared with normal skin. Of note, these KSCC lesions share histological similarities to human SCC pre-malignant lesions, such as actinic keratosis, that normally show higher cutaneous HPV DNA loads than SCC, as discussed above. In addition, non-keratinizing SCCs (nKSCCs) occurring in mice UV-irradiated at higher doses showed low levels of (or no) viral DNA and often harbored p53 mutations, again mirroring the evolution of SCC in humans. The loss of viral DNA and viral gene expression in nKSCC lesions is most likely due to their undifferentiated state, which no longer sustains the infection. However, despite the lack of viral DNA, animals with nKSCCs developed antibody response to MnPV capsids, which clearly highlights past exposure to the virus, similar to the situation observed in SCC cases (108). Therefore, the Mastomys model shows parallels with a natural infection by cutaneous HPV and provides a good model to study the association between cutaneous HPV infection, UV radiation and SCC. Most importantly, this model provides further evidence for a hit-and-run mechanism.

Many independent studies reported the presence of beta HPV types at different anatomical regions other than the skin, such as the oral mucosal epithelium, genital sites, and the anal canal (109�), or investigated the role of cutaneous HPV in various malignancies (e.g., male external lesions, breast cancers, salivary gland tumors, esophageal cancer) other than skin cancer, without showing any association (113�). However, a recent study reported an increased risk of HNC in individuals who tested positive for HPV5 of species 㬡, as well as other HPV types of species 𻌑 and 𻌒 (117). The same trend was reported in another study, in which 㬡 HPV5 and 㬢 HPV122 were significantly associated with HNC (118).

Whereas, beta HPVs are known to infect cutaneous tissues, epidemiological data showed that 㬣 HPV types are also present in the mucosal epithelium, suggesting a dual tropism (111, 119). Moreover, this species shares biological similarities with mucosal HR HPV types such as HPV16 in in vitro and in vivo experimental models (120, 121). A study showed that 㬣 HPV49 transgenic mice, after 4-nitroquinoline 1-oxide treatment, were prone to develop upper digestive tract tumors (121).

Epidemiological and biological data on the role of gamma HPV types are sparse, and do not support an etiological role in NMSC. However, this genus includes an increasing number of members that may deserve more investigation. Using deep sequencing, a member of species 𻌧 (HPV197) has been isolated exclusively from skin cancers. However, additional studies are required to demonstrate an etiological link between this type and skin cancer (122, 123).


What types of cells HPV can infect? - Biology

Papillomaviruses are a diverse group of DNA-based viruses that infect the skin and mucous membranes of humans and a variety of animals (replicating exclusively in keratinocytes).

More than 100 different human papillomavirus (HPV) types have been characterized.

Some HPV types cause benign skin warts, or papillomas, for which the virus family is named.

HPVs associated with the development of such "common warts" are transmitted environmentally or by casual skin-to-skin contact.

A separate group of about 30 HPVs are typically transmitted through sexual contact.

Genital HPV infection is very common, with estimates suggesting that up to 75% of women will become infected with one or more of the sexually transmitted HPV types at some point during adulthood.

HPV infection is a necessary factor in the development of nearly all cases of cervical cancer.

Cervical Pap smear testing is used to detect HPV-induced cellular abnormalities.


Detailed map shows how viruses infect humans

Biologists at Columbia University Vagelos College of Physicians and Surgeons have leveraged a computational method to map protein-protein interactions between all known human-infecting viruses and the cells they infect. The method, along with the data that it generated, has generated a wealth of information about how viruses manipulate the cells that they infect and cause disease. Among the study's findings are the role of estrogen receptors in regulating Zika virus infection and how human papillomavirus (HPV) causes cancer.

The study, led by Sagi Shapira, PhD, assistant professor of systems biology at Columbia University Vagelos College of Physicians and Surgeons, was published today in the journal Cell.

LIMITED UNDERSTANDING OF HOW VIRUSES WORK

At the molecular level, viruses invade cells and manipulate them to replicate, survive, and cause disease. Since they depend on human cells for their life cycle, one way viruses co-opt cellular machinery is through protein-protein interactions within their cell host. Similarly, cells respond to infection by initiating immune responses that control and limit viral replication -- these too, depend on protein-protein interactions.

To date, considerable effort has been invested in identifying these key interactions -- and many of these efforts have resulted in many fundamental discoveries, some with therapeutic implications. However, traditional methods are limited in terms of scalability, efficiency, and even access. To address this challenge, Dr. Shapira and his collaborators developed and implemented a computational framework, P-HIPSTER, that infers interactions between pathogen and human proteins -- the building blocks of viruses and cells.

Until now, our knowledge about many viruses that infect people is limited to their genome sequences. Yet for most viruses, little has been uncovered about the underlying biological interactions that drive these relationships and give rise to disease.

"There are over 1,000 unique viruses that are known to infect people," says Dr. Shapira. "Yet, despite their unquestionable public health importance, we know virtually nothing about the vast majority of them. We just know they infect human cells. The idea behind this effort was to systematically catalogue the interactions that viruses have with the cells they infect. And, by doing so, also reveal some really interesting biology and provide the scientific community with a resource that they can use to make interesting observations of their own."

Using a novel algorithm, P-HIPSTer exploits protein structural information to systematically interrogate virus-human protein-protein interactions with remarkable accuracy. Dr. Shapira and his collaborators applied P-HIPSTer to all 1,001 human-infecting viruses and the approximately 13,000 proteins they encode. The algorithm predicted roughly 280,000 likely pairs of interacting proteins that represent a comprehensive catalogue of human virus protein-protein interactions with an accuracy rate of almost 80 percent.

"This is the first step towards building a comprehensive cartography of physical interactions between different organisms," Dr. Shapira says.

ZIKA, HPV, VIRAL EVOLUTION

In addition to defining pan-viral protein interactions, P-HIPSTer has yielded new biological insights into Zika virus, HPV, and the impact of viruses in shaping human genetics.

Among their discoveries, the researchers found that Zika virus interacts with estrogen receptor, the protein that allows cells to effectively respond to the estrogen hormone. Importantly, they found estrogen receptor has potential to inhibit Zika virus replication. Says Dr. Shapira, "And, in fact, estrogen receptor inhibits viral replication even more than interferon, a protein that is the body's first line of defense to viral infection and our gold standard for anti-viral defense."

The finding is particularly relevant to clinical disease as pregnant women are most susceptible to Zika during their first trimester, which is when estrogen levels are at their lowest. This period also is when the fetus is most susceptible to Zika, a virus for which there is no vaccine or specific treatment and that can cause sever birth defects.

Dr. Shapira and his team also explored interactions between HPV, the leading cause of cervical cancer, and the cells that it infects. HPV is the most common sexually transmitted viral infection with approximately 80 percent of sexually active individuals contracting one of the 200 different types of HPV at some point in their lives. Dr. Shapira and his team used the data generated by P-HIPSTer to identify protein-protein interactions that distinguish HPV infections associated with cancer from those that are not. In addition to providing insights into how HPV may cause disease, the finding could lead to improved diagnostics for those infected with HPV, and P-HIPSTer could potentially be used to help predict whether or not any particular virus is likely to be highly pathogenic.

The researchers also examined whether the interactions mediated by viruses have impacted human genetics. The researchers found evidence of strong selection pressure for several dozen cellular proteins have been shaped by viral infection, unlocking new insights into how our genome has been impacted by viruses.

"One of the things we can do with this data is drill down and ask whether virus infection has changed the history of human genetics," notes Dr. Shapira. "That is certainly not a novel idea but to have a catalogue of what those proteins are is significant. There are a lot of areas that we can explore now that we couldn't before."

FUTURE WORK

Dr. Shapira and his team intend to apply P-HIPSTer on more complex pathogens, such as parasites and bacteria, and use it to better understand how bacteria in the human gut communicate with each other. In the future, the algorithm could also be used to explore viruses or pathogens that effect agricultural plants or livestock.

The Shapira Laboratory at Columbia University is working to decipher the genetic and molecular circuitry at the interface of host-pathogen interactions. A deeper understanding of these relationships provides important insights into cellular machinery that control basic cell biology and has broad implications in human translational immunology and infectious disease research.


Conclusion

In conclusion, the present study found that one-fifth of the patients with ESCC proved to have HPV-positive tumors in Hungary’s Southwestern region. HPV positivity was accompanied by significantly increased expressions of Hsp 90 and 16.2. HPV-positive cases and cases expressing high intensity Hsp 90 and 16.2 levels showed a significantly poorer response to oncological treatment and worse overall survival. We admit the limitations of our study. Given the limited sample size, the results of this report should be interpreted with caution. To confirm the significance of our observation further larger scale studies are needed.



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