Human papillomavirus

Human papillomavirus (HPV) is a member of the papillomavirus family of viruses 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 nearly 200 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, and anus in women or cancers of the anus and penis in men. It can also cause cancers of the head and neck (tongue, tonsils and throat).

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 15–20 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.

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
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, and 59 are "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).

Cancer


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 cause 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.



Most HPV infections are cleared rapidly by the immune system and do not progress to cervical cancer. 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
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: Genital warts are quite contagious, while common, flat, and plantar warts are much less likely to spread from person to person.
 * 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
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.

Prenatal
Although genital HPV types are sometimes 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.

At least 40 identified HPV types infect the genital tract. 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.

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
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.

E6/E7 proteins
E6 and E7 are the HPV proteins associated with cancer. The HPV genome is composed of six early (E1, E2, E3, E4, E6, and E7) and two late (L1 and L2) proteins. 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.

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.
 * Role in cancer

Latency period
Once an HPV viron 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.

Prevention
Condoms offer some protection against genital infection, but any exposed skin can transmit the virus. In short, condoms are not 100% effective in preventing HPV. Genital HPV infection is the most frequent sexually transmitted disease in the world.

Vaccines
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. 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 have gotten 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. Possible benefits and efficacy of vaccinating men are being studied.

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. Thus, condom use reduces the risk that already infected individuals will progress to cervical cancer or develop genital warts.

Microbicides
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 studies 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. lh

Cervical testing
In March 2003, the U.S. Food and Drug Administration (FDA) approved a test manufactured by Qiagen, which is a "hybrid-capture" test, as the primary screening tool for detecting HPV cervical infection as an adjunct to Pap testing. The test may be performed during a routine Pap smear. It can detect the DNA of the 18 HPV types that most commonly affect the cervix and distinguish between "low-risk" and "high-risk" HPV types, but it cannot determine the specific HPV types.

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.

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 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. At this time, HPV test for males are used only in research.

Treatment
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. 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.

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. Like remora suckerfish that hitchhike harmlessly on sharks, these HPV types can be thought of as human commensals. Other cutaneous HPVs, such as HPV types 1 or 2, may cause common warts in some infected individuals. 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. 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.

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 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. However, only 3.4% were infected with one or more of the four types prevented by the Gardasil vaccine, which was lower than previous estimates.

The prevalence for high-risk and low-risk types is roughly similar over time. The overall prevalence of high- and low-risk HPV types was 15.2% and 17.8%, respectively.

Note that prevalence decreases with age. This may be due to the HPV infection's being cleared by the immune system, or sinking to undetectable levels while still present in the body. Recent studies from the Albert Einstein College of Medicine and from the University of Washington suggest that HPV may eventually be cleared in most people with well-functioning immune systems.

History
In 1972, the association of the human papilloma viruses with skin cancer in epidermodysplasia verruciformis was proposed by Stefania Jablonska in Poland. In 1978, Jablonska 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.