Human papillomavirus

ヒトパピローマウイルス

WordNet

1. relating to a person; "the experiment was conducted on 6 monkeys and 2 human subjects"
2. characteristic of humanity; "human nature"
3. having human form or attributes as opposed to those of animals or divine beings; "human beings"; "the human body"; "human kindness"; "human frailty"

PrepTutorEJDIC

1. (動物・神に対して)『人間の』,人の / 『人間らいし』,人間的な,人情味のある / 〈C〉《複数形》(動物に怠して)人間(human being) / 〈U〉《the human》人類

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出典(authority):フリー百科事典『ウィキペディア（Wikipedia）』「2012/11/30 21:18:22」(JST)

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"HPV" redirects here. For other uses, see HPV (disambiguation).

The Papillomavirus article covers the general biological features of human and animal papillomaviruses.

Human papillomavirus
Classification and external resources
ICD-10	B97.7
ICD-9	078.1 079.4
DiseasesDB	6032
eMedicine	med/1037
MeSH	D030361

Human papillomavirus (HPV) is a virus from the papillomavirus family that is capable of infecting humans. Like all papillomaviruses, HPVs establish productive infections only in keratinocytes of the skin or mucous membranes. While the majority of the known types of HPV cause no symptoms in most people, some types can cause warts (verrucae), while others can – in a minority of cases – lead to cancers of the cervix, vulva, vagina, penis, oropharynx and anus. Recently, HPV has been linked with an increased risk of cardiovascular disease. In addition, HPV 16 and 18 infections are strongly associated with an increased odds ratio of developing oropharyngeal (throat) cancer.

More than 30 to 40 types of HPV are typically transmitted through sexual contact and infect the anogenital region. Some sexually transmitted HPV types may cause genital warts. Persistent infection with "high-risk" HPV types — different from the ones that cause skin warts — may progress to precancerous lesions and invasive cancer. HPV infection is a cause of nearly all cases of cervical cancer. However, most infections with these types do not cause disease.

Most HPV infections in young females are temporary and have little long-term significance. Seventy percent of infections are gone in 1 year and ninety percent in 2 years. However, when the infection persists — in 5% to 10% of infected women — there is high risk of developing precancerous lesions of the cervix, which can progress to invasive cervical cancer. This process usually takes 10–15 years, providing many opportunities for detection and treatment of the pre-cancerous lesion. Progression to invasive cancer can be almost always prevented when standard prevention strategies are applied, but the lesions still cause considerable burden necessitating preventive surgeries, which do in many cases involve loss of fertility.

In more developed countries, cervical screening using a Papanicolaou (Pap) test or liquid-based cytology is used to detect abnormal cells that may develop into cancer. If abnormal cells are found, women are invited to have a colposcopy. During a colposcopic inspection, biopsies can be taken and abnormal areas can be removed with a simple procedure, typically with a cauterizing loop or, more commonly in the developing world — by freezing (cryotherapy). Treating abnormal cells in this way can prevent them from developing into cervical cancer.

Pap smears have reduced the incidence and fatalities of cervical cancer in the developed world, but even so there were 11,000 cases and 3,900 deaths in the U.S. in 2008. Cervical cancer has substantial mortality in resource-poor areas; worldwide, there are an estimated 490,000 cases and 270,000 deaths each year.

HPV vaccines (Cervarix and Gardasil), which prevent infection with the HPV types (16 and 18) that cause 70% of cervical cancer, may lead to further decreases.

Signs and symptoms

Notable HPV types and associated diseases

Over 120 HPV types have been identified and are referred to by number. Types 16, 18, 31, 33, 35, 39, 45, 51, 52, 56, 58, 59, 68, 73, and 82 are carcinogenic "high-risk" sexually transmitted HPVs and may lead to the development of cervical intraepithelial neoplasia (CIN), vulvar intraepithelial neoplasia (VIN), penile intraepithelial neoplasia (PIN), and/or anal intraepithelial neoplasia (AIN).

Disease	HPV type
Common warts	2, 7
Plantar warts	1, 2, 4, 63
Flat warts	3, 10, 8
Anogenital warts	6, 11, 42, 44 and others
Anal lesions	6, 16, 18, 31, 53, 58 reference
Genital cancers	Highest risk: 16, 18, 31, 45 Other high-risk: 33, 35, 39, 51, 52, 56, 58, 59 Probably high-risk: 26, 53, 66, 68, 73, 82
Epidermodysplasia verruciformis	more than 15 types
Focal epithelial hyperplasia (oral)	13, 32
Oral papillomas	6, 7, 11, 16, 32
Oropharyngeal cancer	16
Verucous cyst	60
Laryngeal papillomatosis	6,11

Cancer

HPV-induced cancers

In August 2012, the Medscape website released a slides presentation about HPV and cancer risk. The following table shows the incidence of HPV associated cancers in the period of 2004-2008 at US.

Cancer area	Average Annual Number of cases	HPV Attributable (Estimated)	HPV 16/18 Attributable (Estimated)
Cervix	11,967	11,500	9,100
Vulva	3,136	1,600	1,400
Vagina	729	500	400
Penis	1,046	400	300
Anus (woman)	3,089	2,900	2,700
Anus (men)	1,678	1,600	1,500
Oropharynx (woman)	2,370	1,500	1,400
Oropharynx (men)	9,356	5,900	5,600
Total (women)	21,291	18,000	15,000
Total (men)	12,080	7,900	7,600

Worldwide in 2002, an estimated 561,200 new cancer cases (5.2% of all new cancers) were attributable to HPV, making HPV one of the most important infectious causes of cancer. 84% of new cervical cancers were in the developing world, compared with about 50% of all new cancers.

About a dozen HPV types (including types 16, 18, 31, and 45) are called "high-risk" types because they can lead to cervical cancer, as well as anal cancer, vulvar cancer, vaginal cancer, and penile cancer . Several types of HPV, in particular type 16, have been found to be associated with HPV-positive oropharyngeal cancer (OSCC), a form of head and neck cancer. HPV-induced cancers often have viral sequences integrated into the cellular DNA. Some of the HPV "early" genes, such as E6 and E7, are known to act as oncogenes that promote tumor growth and malignant transformation. Oral infection with HPV increased the risk of HPV-positive oropharyngeal cancer independent of tobacco and alcohol use. In the United States, HPV is expected to replace tobacco as the main causative agent for oral cancer.

The p53 protein prevents cell growth and stimulates apoptosis in the presence of DNA damage. The 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 gene that arrests the cell cycle when there is DNA damage.

E6 has a close relationship with the cellular protein E6-AP (E6-associated protein). E6-AP 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.

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)

Most HPV infections are cleared rapidly by the immune system and do not progress to cervical cancer (see 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).

Sexually transmitted HPVs also cause a major fraction of anal cancers and approximately 25% of cancers of the mouth and upper throat (the oropharynx) (see figure). The latter commonly present in the tonsil area, and HPV is linked to the increase in oral cancers in non-smokers. Engaging in anal sex or oral sex with an HPV-infected partner may increase the risk of developing these types of cancers.

Studies show a link between HPV infection and penile and anal cancer, and the risk for anal cancer is 17 to 31 times higher among gay and bisexual men than among heterosexual men. It has been suggested that anal Pap smear screening for anal cancer might benefit some sub-populations of men or women engaging in anal sex. There is no consensus that such screening is beneficial, or who should get an anal Pap smear.

Further studies have also shown a link between a wide range of HPV types and squamous cell carcinoma of the skin. In vitro studies suggest that the E6 protein of the HPV types implicated may inhibit apoptosis induced by ultraviolet light.

Skin warts

Papilloma

Some HPV infections can cause warts (verrucae), which are noncancerous skin growths. Infection with these types of HPV causes a rapid growth of cells on the outer layer of the skin. Types of warts include:

• Common warts: Some "cutaneous" HPV types cause common skin warts. Common warts are often 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.
• Plantar warts are found on the soles of the feet. Plantar warts 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 may be more difficult to treat than warts in other locations.
• Flat warts: 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.

Genital warts are quite contagious, while common, flat, and plantar warts are much less likely to spread from person to person.

Genital warts

Genital or anal warts (condylomata acuminata or venereal warts) are the most easily recognized sign of genital HPV infection. Although a wide variety of HPV types can cause genital warts, types 6 and 11 account for about 90% of all cases.

Most people who acquire genital wart-associated HPV types clear the infection rapidly without ever developing warts or any other symptoms. People may transmit the virus to others even if they do not display overt symptoms of infection.

HPV types that tend to cause genital warts are not those that cause cervical cancer. Since an individual can be infected with multiple types of HPV, the presence of warts does not rule out the possibility of high-risk types of the virus also being present.

The types of HPV that cause genital warts are usually different from the types that cause warts on other parts of the body, such as the hands or inner thighs.

Respiratory papillomatosis

HPV types 6 and 11 can cause a rare condition known as recurrent respiratory papillomatosis, in which warts form on the larynx or other areas of the respiratory tract.

These warts can recur frequently, may require repetitive surgery, may interfere with breathing, and in extremely rare cases can progress to cancer.

In the immunocompromised

In very rare cases, HPV may cause epidermodysplasia verruciformis in immunocompromised individuals. The virus, unchecked by the immune system, causes the overproduction of keratin by skin cells, resulting in lesions resembling warts or cutaneous horns.

For instance, Dede Koswara, an Indonesian man developed warts that spread across his body and became root-like growths. Attempted treatment by both Indonesian and American doctors included surgical removal of the warts.

Transmission

Prenatal

Although genital HPV types can be transmitted from mother to child during birth, the appearance of genital HPV-related diseases in newborns is rare. 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. 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%.

Genital infections

Since cervical and female genital infection by specific HPV types is highly associated with cervical cancer, those types of HPV infection have received most of the attention from scientific studies.

HPV infections in that area are transmitted primarily via sexual activity.

Of the 120 known human papillomaviruses, 51 species and three subtypes infect the genital mucosa. Of these 31 are considered to present a low risk of carcinogensis; 17 are considered to be high risk and 6 are of intermediate risk.

If a college woman has at least one different partner per year for four years, the probability that she will leave college with an HPV infection is greater than 85%. 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.

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 couples every other month for an average of 7 months. She found 2 couples where the man's genitals infected the woman's hand with high risk HPV, 2 where her hand infected his genitals, 1 where her genitals infected his hand, 2 each where he infected his own hand, and she infected her own hand. Hands were not the main source of transmission in these 25 couples, but they were significant.

Partridge reports men's fingertips became positive for high risk HPV at more than half the rate (26% per 2 years) as their genitals (48%). Winer reports 14% of fingertip samples from sexually active women were positive. None of these studies reports whether participants were asked to wash or not wash their hands before testing.

Non-sexual hand contact seems to have little or no role in HPV transmission. Winer found all 14 fingertip samples from virgin women negative at the start of her fingertip study. 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).

Shared objects

Sharing of possibly contaminated objects may transmit HPV. Although possible, transmission by routes other than sexual intercourse is less common for female genital HPV infection. Fingers-genital contact is a possible way of transmission but unlikely to be a significant source.

Virology

Human papillomavirus
TEM of papillomavirus
Virus classification
Group:	Group I (dsDNA)
Order:	Unranked
Family:	Papillomaviridae
Genera
Alphapapillomavirus Betapapillomavirus Gammapapillomavirus Mupapillomavirus Nupapillomavirus

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

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 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. The HPV virus 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.

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 and laminins, 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. At this point, the viral genome is transported to the nucleus by unknown mechanisms and establishes itself at a copy number between 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.

E6/E7 proteins

E6 and E7 are the HPV proteins associated with cancer. The HPV genome is composed of six early (E1, E2, E4, E5, E6, and E7) genes, two late (L1 and L2) genes, and a non-coding long control region (LCR). After the host cell is infected E1 and E2 are expressed first. High E2 levels repress expression of the E6 and E7 proteins. When the host and HPV genomes integrate, E2 function is disrupted, preventing repression of E6/E7.

Role in cancer

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

E2 Research

Human Papillomaviruses are DNA viruses that cause skin lesions keratinocytes. There are two categories of HPVs, high and low risk. High-risk papillomaviruses are HPVs-16, 18, 31, 33, 35, 39, 45, 51, 55, 58, and 59, which are often found on cancer cells. HPVs that produce skin lesions are low risk HPVs, but HPV-6 and HPV-11 are associated with genital warts. The mechanism of infection of these viruses has been widely researched, particularly the oncogene protein Papillomaviridae E2/E1 and E6/E7, since they are considered the essential part for the development of cancer cells.

In a recent study, 99.7% of one thousand cases of invasive cervical cancer were HPV positive to HPV16, being the most common followed by HPV-18 DNA. High Risk HPV E6 and E7 are more active than E2 in cellular transformation than low risk HPVs. The oncogenes E7 and E6 have been found to change Keratinocytes by altering their cell cycle. E6 binds to P53 and degrades it preventing cell death apoptosis and promoting the replication of viral DNA. P53 is a repair mechanism that destroys any abnormal cells or arrests the cell cycle. Genetic changes in the DNA, such as, the introduction of viral DNA, which transforms and destabilizes the cell. Additional research has been performed in the apoptotic effects of papillomavirus E2. The research findings that the E2 protein in HeLa cells induce p53, causing arrest of the cell cycle and apoptosis. But, the induce p53 accumulation was not correlated to the cell growth arrest at G1 phase. This suggests that apoptosis and cell cycle arrest are independent of each other. Researchers used biochemical and genetic approaches to test the hypothesis that apoptosis by BPVI and HPV18 E2 proteins in HeLa cells is independent of p53. One experiment demonstrated that E2 induced apoptosis was set off by Bax, one of the best-known p53 promoting genes. Corroborating the independent pathway for cellular apoptosis and cell cycle arrest.

A comparative research study was conducted to study the transcription activity of high and low risk papillomaviruse E2 protein and affinity of the E2 binding regions of high and low risk HPVs. The study used protein encoded in HPV 16, HPV18, and HPV11 and Bovine -1, along with comparative DNA binding shift assays, cell free transcription systems, cofactors, to determine the affinity the oncoprotein E2 of both types of HPVs. The BPV1 has been used to model the replication of papillomaviruse. The viral gene of BPV1 gene contains several promoters that are activated by E2 protein.In vivo studies of DNA using HeLa cells revealed that different types of E2 proteins showed different transcription and repression activities based on the binding sites of E2. In vivo studies also revealed the high transcriptional activity of high risk HPV-16 E2, which suggests that HPV-16 has a very efficient E2 that regulates the E6/E7 oncoproteins that results in the control of the viral life cycle. The less efficient E6/E7 oncoproteins are expressed all lower levels in low risks HPVs. The regulation of the E6 promoter of the high risk E2 protein of the HPVs can lead to the development of cancer due to the viral integration.

Latency period

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.

Clearance

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).

Clearance Rates of High Risk Types of HPV

Months after Initial Positive Test	8 Months	12 Months	18 Months
% of Men Tested Negative	70%	80%	100%
% of Women Tested Negative	50%	75%	97%

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."

Prevention

HPV infection is the most frequent sexually transmitted disease in the world. Methods of prevention include abstinence, condoms, vaccination and microbicides.

Vaccines

Main article: HPV vaccine

Two vaccines are available to prevent infection by some HPV types: Gardasil, marketed by Merck, and Cervarix, marketed by GlaxoSmithKline. Both 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.

The vaccines provide little benefit to women having already been infected with HPV types 16 and 18, which includes most sexually active females^{[citation needed]}. 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.

Both vaccines are delivered in three shots over six months. In most countries, they are approved only for female use, but are approved for male use in countries like USA and UK. The vaccine does not have any therapeutic effect on existing HPV infections or cervical lesions. In 2010, 49% of teenage girls in the US got the HPV vaccine, while in comparison around two-thirds of teens received shots for meningitis and DPT vaccine.

Women should continue to seek cervical screening, such as Pap smear testing, even after receiving the vaccine. Cervical cancer screening recommendations have not changed for females who receive HPV vaccine. Without continued screening, the number of cervical cancers preventable by vaccination alone is less than the number of cervical cancers prevented by regular screening alone.

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

No efficacy trials for children under 15 have been performed. Duration of vaccine efficacy is not yet answered by rigorous methodologic trials. Cervarix efficacy is proven for 7.4 years with published data through 6.4 years while Gardasil efficacy is proven for 5 years. Age of vaccination is less important than the duration of efficacy.

Condoms

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."

Female condoms provide somewhat greater protection than male condoms, as the female condom allows for less skin contact.

Studies have suggested that regular condom use can effectively limit the ongoing persistence and spread of HPV to additional genital sites in individuals already infected.

Microbicides

See also main articles: Microbicides, Microbicides for sexually transmitted diseases

Ongoing research has suggested that several inexpensive chemicals might serve to block HPV transmission if applied to the genitals prior to sexual contact. These candidate agents, known as topical microbicides, are currently undergoing clinical efficacy testing. A recent study indicates that some sexual lubricant brands that use a gelling agent called carrageenan prevent papillomavirus infection in animal model systems. Clinical trial results announced at the 2010 International Papillomavirus Conference indicate that a carrageenan-based personal lubricant called Carraguard is effective for preventing HPV infection in women. The results suggest that use of carrageenan-based personal lubricant products, such as Divine No 9, Bioglide and Oceanus Carrageenan, may likewise be effective for preventing HPV infection.

Oral infection

A review of scientific studies in healthy subjects has found carcinogenic HPV in 3.5% of the study's subjects and HPV16 in 1.3%. Men have higher prevalence of oral HPV than women.

Oral HPV infection is associated with HPV-positive oropharyngeal cancer. Odds of oral HPV infection increases with the number of recent oral sex partners or open-mouthed kissing partners. Nonsexual oral infection through salivary or cross transmission is also plausible.

Diagnosis

Cervical testing

In March 2003, the U.S. Food and Drug Administration (FDA) approved a test manufactured by Qiagen/Digene, which is a "hybrid-capture" test as an adjunct to Pap testing. The test may be performed during a routine Pap smear. It can detect the DNA of 18 "high-risk" HPV types that most commonly affect the cervix, but it cannot determine the specific HPV types. Unfortunately, this test produces too many false positives and caution should be exercised when taking this test.

According to the National Cancer Institute, "testing samples of cervical cells is an effective way to identify high-risk types of HPV that may be present. The FDA has approved an HPV test as a follow-up for women who have an ambiguous Pap test and, for women over the age of 30, for general cervical cancer screening. This HPV test can identify at least 13 of the high-risk types of HPV associated with the development of cervical cancer. The test can detect high-risk types of HPV even before there are any conclusive visible changes to the cervical cells."

The recent outcomes in the identification of molecular pathways involved in cervical cancer provide helpful information about novel bio- or oncogenic markers that allow monitoring of these essential molecular events in cytological smears, histological, or cytological specimens. These bio- or onco- markers are likely to improve the detection of lesions that have a high risk of progression in both primary screening and triage settings. E6 and E7 mRNA detection PreTect HPV-Proofer, (HPV OncoTect) or p16 cell-cycle protein levels are examples of these new molecular markers. According to published results, these markers, which are highly sensitive and specific, allow to identify cells going through malignant transformation.

In October 2011 the US Food and Drug Administration approved the Aptima HPV Assay test for RNA created when and if any HPV strains start creating cancers (see virology).

The vulva/vagina has been sampled with Dacron swabs and shows more HPV than the cervix. Among women who were HPV positive in either place, 90% were positive in the vulvovaginal region, 46% in the cervix.

Oral testing

In February 2010 Quest Diagnostics released OraRisk, a test to identify which HPV types are present in saliva.

Saliva was positive for HPV in Iran in 41% of 22 patients with oral squamous cell carcinoma, and in 25% of 20 people without cancer. Studies have found heightened HPV in mouth cell samples from people with oral squamous cell carcinoma. Studies have not found significant HPV in mouth cells after sampling with toothbrushes (5 of 2,619 samples) and cytobrushes (no oral transmission found).

Testing men

Research studies have tested for and found HPV, including high-risk types (i.e. the types found in cancers), on fingers, mouth, saliva, anus, urethra, urine, semen, blood, scrotum and penis. However most research tests have used Dacron swabs and custom analysis not available to the general public.

A Brazilian study used the readily available Qiagen/Digene test mentioned above (off label) to test men's penis, scrotum and anus. Each of the 50 men had been a partner for at least 6 months of a woman who was positive for high risk HPV. They found high risk HPV on 60% of these men, primarily the penis. "The specimens were obtained using a vigorous motion of the conical brush included in the Digene kit" "after spraying the anogenital region with saline solution."

A slightly different method also used cytobrushes (but custom lab analysis) and found 37% of 582 Mexican army recruits positive for high risk HPV. They were told not to wash genitals for 12 hours before sampling. (Other studies are silent on washing, a particular gap in studies of hands). They included the urethra as well as scrotum and penis, but 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 and scrotum, since sampling the urethra or anus added very little to diagnosis. Dunne recommends glans, shaft, their crease, and foreskin.

A small study of cytobrushes on 10 US men where the brush was wet, rather than the skin, found 2 of 10 men were positive for HPV (type not reported). Their lab analysis was not the same as either study above. This small study found 4 of 10 men positive for HPV when skin was rubbed with 600 grit emery paper, then swabbed with a wet Dacron swab. Since emery paper and brush were analyzed together at the lab, it is not known if the emery paper collected viruses or loosened them for the swab to collect.

Studies have found collection by men from their own skin (with emery paper and Dacron swabs) as effective as by a clinician, sometimes more so, since patients were more willing to scrape vigorously.

Other studies have used similar cytobrushes to sample fingertips and under the fingernails, though without wetting the area or brush.

Other studies analyzed urine, semen and blood and found varying amounts of HPV, but there is no publicly available test for them.

There is not a wide range of tests even though HPV is common. Clinicians 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. 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.

Other testing

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

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 test for males are used only in research.^{[citation needed]}

Treatment

See also: Genital_warts

There is currently no specific treatment for HPV infection. However, the viral infection, more often than not, clears by itself. 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). 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.

Epidemiology

Cutaneous HPVs

Infection with cutaneous HPVs is ubiquitous. Some HPV types, such as HPV-5, may establish infections that persist for the lifetime of the individual without ever manifesting any clinical symptoms. Other cutaneous HPVs, such as HPV types 1 or 2, may cause common warts in some infected individuals.^{[citation needed]} Skin warts are most common in childhood and typically appear and regress spontaneously over the course of weeks to months. About 10% of adults also suffer from recurring skin warts.^{[citation needed]} 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 that an individual may become resistant to one HPV type while remaining susceptible to other types.

Lung cancer

There has been evidence linking HPV to benign and malignant tumors of the upper respiratory tract. The International Agency for Research on Cancer (IARC) have 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. 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 non-cancer patients did, and among lung cancer patients, the chances of having eight types of serious HPV were significantly increased. In addition, there has been expression of HPV structural proteins by immunohistochemistry and in vitro studies that suggests HPV presence in bronchial cancer and its precursor lesions. 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 non-small cell lung cancer, but in none of the controls. The reported average frequencies of HPV in lung cancers were 17% and 15% in Europe and the America, respectively, and the mean number of HPV in Asian lung cancer samples was 35.7%, with a considerable heterogeneity between certain countries and regions.

Throat cancer

In recent years, the United States has experienced an increase in the number of cases of throat cancer caused by the human papillomavirus (HPV) Type 16. Throat cancers associated with HPV have been estimated to have increased from 0.8 cases per 100,000 people in 1988 to 2.6 per 100,000 in 2004. Researchers explain this recent data by an increase in oral sex. Moreover, findings indicate this type of cancer is much more prevalent in men than in women, something that needs to be further explored. Currently, two immunizations, Gardasil and Cervarix, are recommended to girls to prevent HPV related cervical cancer but not as a precaution against HPV related throat cancer.

Genital HPVs

A large increase in the incidence of genital HPV infection occurs at the age when individuals begin to engage in sexual activity. The great majority of genital HPV infections never cause any overt symptoms and are cleared by the immune system in a matter of months. As with cutaneous HPVs, immunity is believed to be HPV type-specific. Some infected individuals may fail to bring genital HPV infection under immunological control. Lingering infection with high-risk HPV types, such as HPVs 16, 18, 31, and 45, can lead to the development of cervical cancer or other types of cancer. In addition to persistent infection with high-risk HPV types, epidemiological and molecular data suggest that co-factors such as the cigarette smoke carcinogen benzo[a]pyrene (BaP) enhance development of certain HPV-induced cancers.

High-risk HPV types 16 and 18 are together responsible for over 65% of cervical cancer cases. Type 16 causes 41 to 54% of cervical cancers, and accounts for an even greater majority of HPV-induced vaginal/vulvar cancers, penile cancers, anal cancers and head and neck cancers.

United States of America

HPV prevalence by age, including 20 low-risk types and 23 high-risk types

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. Most sexually active men and women will probably acquire genital HPV infection at some point in their lives. The American Social Health Association reported estimates that about 75-80% of sexually active Americans will be infected with HPV at some point in their lifetime. By the age of 50 more than 80% of American women will have contracted at least one strain of genital HPV.

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. Of the STDs studied, genital HPV was the most commonly acquired.

Estimates of HPV prevalence vary from 14% to more than 90%. 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. Another cause of discrepancy is the difference in strains that were tested for.

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.

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

History

In 1972, the association of the human papilloma viruses 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. 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.

The mutant HeLa cell line contains extra DNA in its genome that originated from HPV.

References

External links

• HPV Fact sheets from the Centers for Disease Control and Prevention
• Myths and misconceptions about HPV – American Social Health Association
• HPV's links to oral cancers peer reviewed information from The Oral Cancer Foundation
• STI: HPV a website information for adolescents
• HPV found under the fingernails of young men The Daily, University of Washington
• "Human Papillomavirus (HPV) Vaccines", National Cancer Institute Fact Sheet, US National Institutes of Health, October 22, 2009.

UpToDate Contents

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• 1. ヒトパピローマウイルス感染症：疫学および疾患関連性human papillomavirus infections epidemiology and disease associations [show details]
  … protect against oropharyngeal HPV infection . There is a bidirectional epidemiologic interaction between HIV and HPV infections. Several studies have shown that HPV infection is more common among HIV-infected …
• 2. ヒトパピローマウイルスワクチンhuman papillomavirus vaccination [show details]
  … Human papillomavirus (HPV) is a sexually transmitted pathogen that causes anogenital and oropharyngeal disease in males and females. Persistent viral infection with high-risk HPV genotypes causes virtually …
• 3. ヒトパピローマウイルス（HPV）感染のウイルス学および癌との関連virology of human papillomavirus infections and the link to cancer [show details]
  …manifestations, diagnosis, epidemiology, prevention, and treatment of HPV infection are discussed separately. Human papillomavirus (HPV) is a small deoxyribonucleic acid (DNA) virus of approximately …
• 4. 子宮頸部のHPV核酸検出検査：HPV陽性の場合のマネージメントhuman papillomavirus testing of the cervix management of abnormal results [show details]
  … Cervical cancer screening utilizes combinations of cervical cytology (Pap test) and testing for human papillomavirus (HPV) strains that are high risk for causing cervical cancer ; testing protocols vary by age …
• 5. 頭頚部癌に関連するヒトパピローマウイルスhuman papillomavirus associated head and neck cancer [show details]
  … Human papillomavirus (HPV) infection is the most commonly diagnosed sexually transmitted disease in the United States. HPV infection has been etiologically linked with condyloma acuminatum, squamous intraepithelial …

English Journal

• [The testing strategy for detection of biologically relevant infection of human papillomavirus in head and neck tumors for routine pathological analysis].

• Kašpírková J, Ondič O, Cerná K, Skálová A.AbstractThere is a subgroup among head and neck squamous cell carcinomas, which is etiologically linked to the infection of high-risk human papillomavirus (HPV). In recent studies, HPV related squamous cell carcinomas have been placed in a separate group because of their different epidemiology, distinctive histopathological characteristics, therapeutic response and clinical outcome. The reported prevalence of high-risk HPV in head and neck tumors varies in different studies. This fact occurs mainly due to the absence of a widely accepted consensus for HPV detection in head and neck malignancies. We present a methodological algorithm for detection of biologically relevant HPV infection: a combination of an immunohistochemical staining of the p16 protein - a surrogate marker for a transforming HPV infection, and a molecular genetic identification of HPV DNA by three different polymerase chain reactions (PCR). The study group consisted of 41 patients with a tumor in head and neck region. A verification of detection of biologically relevant HPV infection has been performed in 10 available samples using an alternative approach, which comprised the detection of RNA transcript of HPV by reverse transcription followed by PCR (RT-PCR), and further in situ hybridization (ISH) with a commercial high-risk HPV probe. We have found a high correlation between HPV DNA detection using triple-PCR approach and strong diffuse positivity of the p16 protein (correlation coefficient 0.94) and have confirmed the validity of this algorithm. In 94 % of HPV related squamous cell carcinomas HPV type 16 was detected. In one case HPV type 33 was identified. That is in agreement with earlier published data. A more appropriate alternative method for the detection of biologically relevant- transforming HPV infection seems to be RT-PCR, which proved 100 % agreement with the original methodological approach of p16 determination and PCR status. Interpretation of the ISH has been complicated by frequent nonspecific staining of the sample and its routine usage in the diagnostic algorithm of our laboratory is currently not feasible.Keywords: HPV - squamous cell carcinoma - head and neck tumors - p16.
• Ceskoslovenská patologie.Cesk Patol.2013 Dec;49(1):29-34.
• There is a subgroup among head and neck squamous cell carcinomas, which is etiologically linked to the infection of high-risk human papillomavirus (HPV). In recent studies, HPV related squamous cell carcinomas have been placed in a separate group because of their different epidemiology, distinctive
• PMID 23432073

• Expression, purification and characterization of a recombinant fusion protein based on the human papillomavirus-16 E7 antigen.

• Granadillo M, Batte A, Lugo VM, Musacchio A, Bequet-Romero M, Betancourt L, Besada V, Javier L, Molina R, Falcón V, Torrens I.SourceCenter for Genetic Engineering and Biotechnology, P.O. Box 6162, Cubanacan, Playa, Havana, 10600 Cuba.
• SpringerPlus.Springerplus.2013 Dec;2(1):12. Epub 2013 Jan 12.
• A fusion protein comprising a cell penetrating and immunostimulatory peptide corresponding to residues 32 to 51 of the Limulus polyphemus protein linked to human papillomavirus (HPV)-16 E7 antigen (LALF32-51-E7) was expressed in E. coli BL21 (DE3) cells. The recombinant protein in E. coli accounted
• PMID 23483788

• Naked-eye detection of nucleic acids through rolling circle amplification and magnetic particle mediated aggregation.

• Lin C, Zhang Y, Zhou X, Yao B, Fang Q.SourceInstitute of Microanalytical Systems, Department of Chemistry, Zhejiang University, Hangzhou 310058, China.
• Biosensors & bioelectronics.Biosens Bioelectron.2013 Sep 15;47:515-9. doi: 10.1016/j.bios.2013.03.056. Epub 2013 Apr 6.
• We are presenting a new method for sequence-specific and naked-eye detection of nucleic acids (NAs) through isothermal amplification and magnetic particle mediated aggregation. A padlock probe was designed to hybridize to specific sequence on target genes followed by ligation and rolling circle ampl
• PMID 23643944

Japanese Journal

• 子宮頸部上皮内腫瘍合併妊婦の対応と予後

• 笹 秀典,古谷 健一,高橋 明美,菊地 まゆみ
• 母性衛生 54(2), 366-369, 2013-07-00
• 【目的】子宮頸部細胞診異常の妊婦の精検の意義は,浸潤がんを否定することにあるが,妊娠中の細胞診やコルポスコピーは,粘液増加,易出血性,膣壁の膨隆などで,判定が困難になりがちである。当施設の子宮頸部上皮内腫瘍(CIN)合併妊婦の対応と予後について報告する。【方法】対象は,過去6年間の妊婦のCIN 75例で,原則として妊娠初期に,コルポスコピーを行い異常所見部位から組織診を行った。妊娠後期にも細胞診を …
• NAID 110009624960

• Human papillomavirus 16-positive uterine cervical squamous cell carcinoma with coinfection with human papillomavirus 34 has a lower incidence in lymph node metastasis than that without coinfection with human papillomavirus 34

• Michimata Rie,Watari Hidemichi,Tomaru Utano,Sakuragi Noriaki,Ishizu Akihiro
• Pathobiology 80(5), 259-264, 2013-06-00
• … Our earlier study demonstrated high prevalence of multiple human papillomavirus (HPV) infection in patients with invasive uterine cervical cancer, including squamous cell carcinoma (SCC). …
• NAID 120005311820

• E6 and E7 variants of human papillomavirus-16 and -52 in Japan, the Philippines, and Vietnam

• Ishizaki Azumi,Matsushita Kaori,Hoang Huyen Thi Thanh,Agdamag Dorothy M.,Nguyen Cuong Hung,Tran Vuong Thi,Sasagawa Toshiyuki,Saikawa Kunikazu,Lihana Raphael,Pham Hung Viet,Bi Xiuqiong,Ta Van Thanh,Pham Thuc Van,Ichimura Hiroshi
• Journal of Medical Virology 85(6), 1069-1076, 2013-06-00
• … Human papillomavirus (HPV) has several intragenotypic variants with different geographical and ethnic distributions. …
• NAID 120005254073

Related Links

• STD Facts - Human papillomavirus (HPV)

Centers for Disease Control and Prevention. CDC twenty four seven. Saving Lives, Protecting People Centers for Disease Control and Prevention. CDC twenty four ... Human papillomavirus (HPV) is the most common sexually ...

• Human Papillomavirus Infection: Symptoms and Prevention

Genital human papillomavirus (HPV) infection is a common sexually transmitted infection (STI) caused by human papillomavirus. There are several different strains, some of which can cause cancer. Learn more about ...

• Information About Human Papillomavirus (HPV)

Infection by HPV (the human papillomavirus) is common. WebMD explains the risks of infection and the strains of HPV that can lead to cancer. ... HPV isn’t just one virus. There are more than 100 kinds, and some are ...

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国試過去問	「106D030」
関連記事	「human」「papillomavirus」「human papillomavirus」

「106D030」

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• 29歳の男性。排尿時痛を主訴に来院した。 14日前に性行為感染の機会があった。2日前から排尿時痛と漿液性の尿道分泌物とを自覚するようになったため受診した。外尿道口周囲に発赤を認めない。触診で陰嚢部に異常を認めない。直腸指診で前立腺に異常を認めない。尿所見:蛋白1+、糖(-)、潜血(-)、沈渣に赤血球1-5/1視野、白血球10-20/1視野。尿道分泌物のGram染色で細菌を認めない。
• この疾患の原因として考えられるのはどれか。

• a　Chlamydia trachomatis
• b　Herpes simplex virus
• c　Human papillomavirus
• d　Neissena gonorrhoeae
• e　Treponema pallidum

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