HPV genes

Human papillomavirus infection is an infection by human papillomavirus (HPV).[1] Most HPV infections cause no symptoms and resolve spontaneously.[2] In some, they persist and result in warts or precancerous lesions.[3] The precancerous lesions increase the risk of cancer of the cervix, vulva, vagina, penis, anus, mouth, or throat.[2][3] Nearly all cervical cancer is due to HPV with two types, HPV16 and HPV18, accounting for 70% of cases.[2][4] Between 60 and 90% of the other cancers are also linked to HPV.[4] HPV6 and HPV11 are common causes of genital warts and respiratory papillomatosis.[2]

HPV infection is caused by a human papillomavirus, a DNA virus from the papillomavirus family, of which over 150 types are known.[1][5] More than 40 types are transmitted through sexual contact and infect the anus and genitals.[5] Risk factors for persistent HPV infections include early age of first sexual intercourse, multiple partners, smoking, and poor immune function.[2] HPV is typically spread by sustained direct skin-to-skin contact with vaginal and anal sex being the most common methods.[5] Occasionally, it can spread from a mother to her baby during pregnancy. It does not spread via common items like toilet seats. People can become infected with more than one type of HPV.[6] HPV only affects humans.[1]

HPV vaccines can prevent the most common types of infection.[5] To be effective, they must be used before an infection occurs and are therefore recommended between the ages of nine and 13. 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.[2] Screening has reduced both the number and deaths from cervical cancer in the developed world.[7] Warts can be removed by freezing.[1]

HPV is the most common sexually transmitted infection globally.[1] Most people are infected at some point in their lives.[5] In 2012, about 528,000 new cases and 266,000 deaths occurred from cervical cancer worldwide.[8] Around 85% of these occurred in the developing world.[2] In the United States, about 27,000 cases of cancer due to HPV occur each year. About 1% of sexually active adults have genital warts.[6] While cases of warts have been described since the time of ancient Greece, their viral nature was discovered in 1907.[9]

Signs and symptoms

Notable HPV[10] types and associated diseases

Over 170 types of HPV have been identified, and they are designated by numbers.[11][12][13]

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.[citation needed] HPV types 6 and 11 can cause genital warts and respiratory papillomatosis.[2] HPV types 16, 18, 31, 33, 35, 39, 45, 51, 52, 56, 58, 59, 68, 73, and 82 are considered carcinogenic.[14]

This table lists common symptoms of HPV infection and associated strains of HPV:

Disease HPV type
Common warts 2, 7, 22
Plantar warts 1, 2, 4, 63
Flat warts 3, 10, 8
Anogenital warts 6, 11, 42, 44 and others[15]
Anal dysplasia (lesions) 6, 16, 18, 31, 53, 58[16]
Genital cancers
  • Highest risk:[15] 16, 18, 31, 45
  • Other high-risk:[15][17] 33, 35, 39, 51, 52, 56, 58, 59
  • Probably high-risk:[17] 26, 53, 66, 68, 73, 82
Epidermodysplasia verruciformis more than 15 types
Focal epithelial hyperplasia (mouth) 13, 32
Mouth papillomas 6, 7, 11, 16, 32
Oropharyngeal cancer 16
Verrucous cyst 60
Laryngeal papillomatosis 6, 11

Warts

Papilloma

Skin infection (“cutaneous” infection) with HPV is very widespread.[18] 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.[19] While cases of warts have been described since the time of ancient Greece, their viral cause was not known until 1907.[9]

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 an individual may become resistant to one HPV type while remaining susceptible to other types. In one study, infection by HPV types 2, 27, and 57 was found in people with warts, while infection by HPV types 1, 2, 63, and 27 was found in people with clinically normal skin.[20]

Types of warts include:

  • Common warts are usually found on the hands and feet, but can also occur in other areas, such as the elbows or knees. Common warts have a characteristic cauliflower-like surface and are typically slightly raised above the surrounding skin. Cutaneous HPV types can cause genital warts but are not associated with the development of cancer.
  • Plantar warts are found on the soles of the feet; they grow inward, generally causing pain when walking.
  • Subungual or periungual warts form under the fingernail (subungual), around the fingernail, or on the cuticle (periungual). They are more difficult to treat than warts in other locations.[21]
  • 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.[22]

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

Genital warts

HPV infection of the skin in the genital area is the most common sexually transmitted infection worldwide.[8] 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.

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.[23][24] However, in total more than 40 types of HPV are transmitted through sexual contact and can infect the skin of the anus and genitals.[5] Such infections may cause genital warts, although they may also remain asymptomatic.

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.[8] 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.

Respiratory papillomatosis

In addition to genital warts, infection by HPV types 6 and 11 can cause a rare condition known as recurrent respiratory papillomatosis, in which warts form on the larynx[25] or other areas of the respiratory tract.[26][27] 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.[26][28]

Cancer

HPV-induced cancers[29]

About a dozen HPV types (including types 16, 18, 31, and 45) are called “high-risk” types because persistent infection has been linked to cancers such as cancer of the vulva, vagina, cervix, penis, and anus. These cancers in common involve sexually transmitted infection of HPV to the stratified epithelial tissue.[29] [2][3]

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.[29] 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.[29]

In the United States, about 27,000 cases of cancer due to HPV occur each year.[6]

The number of HPV-associated cancers in the period of 2004-2008 in the US.[30]
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 (women) 3,089 2,900 2,700
Anus (men) 1,678 1,600 1,500
Oropharynx (women) 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

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

In some infected individuals, their immune systems may fail to control HPV. Lingering infection with high-risk HPV types, such as types 16, 18, 31, and 45, can favor the development of cancer.[31]Co-factors such as cigarette smoke can also enhance the risk of such HPV-related cancers.[32][33]

HPV-induced cancers arise when viral sequences are accidentally integrated into the DNA of host cells. Some of the “early genes” carried by the HPV virus, such as genes E6 and E7, act as oncogenes that promote tumor growth and malignant transformation. Furthermore, HPV can induce a tumorigenic process through integration into a host genome which is associated with alterations in DNA copy number.[34]

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.

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.

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.[35]

Cervical cancer

Nearly all cases of cervical cancer are associated with HPV infection, with two types, HPV16 and HPV18, present in 70% of cases.[2][4][36][37][38][39]

HPV type 16 is the most malignant strain, present in 41 to 54% of all cervical cancers,[36][40] and in many cases of vaginal/vulvar cancer,[41] penile cancers, anal cancers, and cancers of the head and neck.[42]

In 2012, about 528,000 new cases and 266,000 deaths from cervical cancer occurred worldwide.[8] Around 85% of these occurred in the developing world.[2]

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).[26][43]

Genital cancers[edit]

Studies show a link between HPV infection and penile and anal cancers. Sexually transmitted HPVs are found in a large percentage of anal cancers.[29] Moreover, the risk for anal cancer is 17 to 31 times higher among gay and bisexual men than among heterosexual men[44][45] – though one survey did not find a difference between the HPV infection rate of men who had sex with men versus those who had sex only with women.[46]

Anal Pap smear screening for anal cancer might benefit some subpopulations of men or women engaging in anal sex.[47] No consensus exists, though, that such screening is beneficial, or who should get an anal Pap smear.[48][49]

Cancers of the head and neck

High-risk carcinogenic HPV types (including HPV 16 and HPV 18) are associated with an increasing number of head and neck cancers.[38]

Sexually transmitted forms of HPV account for about 25% of cancers of the mouth and upper throat (the oropharynx).[29] The latter commonly present in the tonsil area, and HPV is linked to the increase in oral cancers in nonsmokers.[50][51] Engaging in anal or oral sex with an HPV-infected partner may increase the risk of developing these types of cancers.[52] Oral infection with several types of HPV, in particular type 16, have been found to be associated with HPV-positive oropharyngeal cancer, a form of head and neck cancer.[52][53] This association is independent of tobacco and alcohol use.[53] In the United States, HPV is expected to replace tobacco as the main causal agent for oral cancer, and the number of newly diagnosed, HPV-associated head and neck cancers is expected to surpass that of cervical cancer cases by 2020.[54][55]

In recent years, the United States has experienced an increase in the number of cases of throat cancer caused by 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.[56] Researchers explain these 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.[57] 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.[58]

The mutational profile of HPV-positive and HPV-negative head and neck cancer has been reported, further demonstrating that they are fundamentally distinct diseases.[59]

Lung cancer

Some evidence links HPV to benign and malignant tumors of the upper respiratory tract. The International Agency for Research on Cancer has found that people with lung cancer were significantly more likely to have several high-risk forms of HPV antibodies compared to those who did not have lung cancer.[60] 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.[61] In addition, expression of HPV structural proteins by immunohistochemistry and in vitro studies suggest HPV presence in bronchial cancer and its precursor lesions.[62] 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.[63] 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.[64]

Immunocompromised individuals

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

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