Article: Human papillomavirus

? Papillomavirus
Virus classification
Group: Group I (dsDNA) Family: Papillomaviridae
The naked protein coat (capsid) of a papillomavirus

"HPV" redirects here. For human-powered vehicles, see human-powered transport. For other uses, see HPV (disambiguation).

Papillomaviruses are a diverse group of DNA-based viruses that infect the skin and mucous membranes of humans and a variety of animals (replicating exclusively in keratinocytes). More than 100 different human papillomavirus (HPV) types have been characterized. The main article papillomavirus covers the general biological features of human and animal papillomaviruses.

Introduction

Some HPV types cause benign skin warts, or papillomas, for which the virus family is named. HPVs associated with the development of common warts are transmitted environmentally or by casual skin-to-skin contact.

A separate group of about 30 HPVs are typically transmitted through sexual contact. Some sexually-transmitted HPVs, such as types 6 and 11, can cause genital warts. However, most HPV types that infect the genitals tend not to cause noticeable symptoms. Persistent infection with a subset of about a dozen sexually-transmitted HPVs, including types 16 and 18, can lead to the development of cancer of the cervix. HPV infection is a necessary factor in the development of nearly all cases of cervical cancer (Walboomers 1999). Some cancer-causing HPV types (particularly HPV-16) are also believed to cause a substantial fraction of other genital cancers, as well as some cancers of the mouth, throat and anus (Parkin 2006).

Papillomaviruses replicate exclusively in body surface tissues such as the skin, or the mucosal surfaces of the genitals, anus, mouth, or airways (Doorbar 2005). Most papillomavirus types are adapted to infection of particular body surfaces. For example, HPV types 1 and 2 tend to infect the soles of the feet or the palms of the hands, respectively, where they may cause warts (De Villiers 2004). HPV types 6 and 11 are adapted to infection of the genitals, where they can cause irregular warts known medically as condyloma accuminata. In general, these wart-causing HPV types are not associated with an increased risk of cancer.

Although papillomaviruses were initially discovered because of their ability to cause warts, sampling of apparently normal skin and mucosal surfaces has revealed that many papillomavirus types tend not to cause overt symptoms. For example, HPV-5 can often be found in the plucked eyebrow hairs or normal skin of healthy individuals, but is associated with wart-like skin lesions only in a handful of immunocompromised patients (Ramoz 2002).

Some HPV types have evolved to be transmitted through sexual contact. Many sexually-transmitted HPV types do not cause easily-discernable symptoms in most infected individuals. However, a minority of individuals who are persistently-infected with a subset sexually-transmitted HPVs, such as types 16 and 18, can go on to develop cervical cancer, anal/genital cancer or head/neck cancer. Cancers caused by a dozen or so “high-risk” HPV types kill several hundred thousand people per year worldwide and are a major focus of public health research (Schiffman 2003).

Notable HPV types and associated diseases

Genital HPV infection is very common, with estimates suggesting that up to 75% of women will become infected with one or more of the sexually-transmitted HPV types at some point during adulthood (Baseman 2005). Although condoms are highly effective for preventing the transmission of other sexually-transmitted diseases (STDs), recent studies have concluded that condoms only offer limited protection against the transmission of genital HPVs (Holmes 2004), though a more recent, limited study suggested that they are effective 70% of the time. This may be due to the fact that HPVs can infect genital skin areas that are not covered by condoms.

Cervical Pap smear testing is used to detect HPV-induced cellular abnormalities. This allows targeted surgical removal of pre-cancerous lesions prior the development of invasive cervical cancer. In the absence of Pap testing or treatment, about 1% of women with genital HPV infections will eventually go on to develop cervical cancer. Although the widespread use of Pap testing has reduced the incidence and lethality of cervical cancer in developed countries, the disease still kills several hundred thousand women per year worldwide. It is hoped that a recently-approved HPV vaccine that blocks initial infection with several of the most common sexually-transmitted HPV types will lead to further decreases in the incidence of HPV-induced cancer (Lowy and Schiller 2006).

HPV-induced diseases

Skin warts

• Common warts: Some "cutaneous" HPV types, such as HPV-1 and HPV-2, 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 do not usually cause genital warts and are not associated with the development of cancer.
• Plantar warts are found on the soles of the feet. Plantar warts closely resemble common warts.
• 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 recognised 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 (Greer 1995)(Gearheart et al, 2004). 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 don't display overt symptoms of infection.

It is important to note that HPV types that tend to cause genital warts are NOT the same ones that cause cervical cancer.

Cancer

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)

About a dozen HPV types (including types 16, 18, 31 and 45) are called "high-risk" types because they can cause cervical cancer, anal cancer, vulvar cancer, head and neck cancers, and penile cancer. High-risk HPV types can cause intraepithelial neoplasias, or abnormal and precancerous cell growth, which can progress to 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.

A history of infection with one or more high-risk HPV types is believed to be a prerequisite for the development of cervical cancer; according to the American Cancer Society, women with no history of the virus do not develop this type of cancer. However, 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 who have been infected with HPV for a long time, usually over a decade or more (Greenblatt, 2005; Sinal and Woods, 2005).

Sexually-transmitted HPVs also cause a major fraction of anal cancers and a small fraction of cancers of the mouth and upper throat (known as the oropharynx) (see figure). Engaging in anal sex or oral sex may increase the risk of developing these types of cancers.

HPV-induced cancers

Although it has been proposed that HPV may induce other forms of cancer, including breast cancer, colorectal cancer and non-melanoma skin cancer, a causal relationship between HPV infection and these cancer types has not yet been firmly established.

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 (Wu et al., 2003; Sinal and Woods, 2005). These warts can recur frequently, may require repetitive surgery, may interfere with breathing, and in extremely rare cases can progress to cancer (Moore et al., 1999; Sinal and Woods, 2005).

Epidemiology

Cutaneous HPVs

Infection with cutaneous HPVs is ubiquitous (Antonsson 2000). 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 likely HPV type-specific, meaning that an individual may become immunologically resistant to one HPV type while remaining susceptible to other types.

Genital HPVs

A large increase in the incidence of genital HPV infection occurs when individuals begin to engage in sexual activity (see figure). The great majority of genital HPV infections never cause any overt symptoms and are spontaneously cleared by the immune system in a matter of months. As with cutaneous HPVs, immunity is believed to be HPV type-specific. A subset of 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 (Schiffman and Castle 2005). High-risk HPV types 16 and 18 are together responsible for over 70% of cervical cancer cases (Baseman and Koutsky, 2005; Cohen, 2005). Type 16 causes 41 to 54% of cervical cancers (Noel et al., 2001; Baseman and Koutsky, 2005) and accounts for an even greater majority of HPV-induced vaginal/vulvar cancers (Edwards et al., 2005), penile cancers, anal cancers and head and neck cancers (Bolt et al., 2005).

Perinatal transmission

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 (Sinal and Woods 2005). 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%.

Prevention

Most people become infected with various cutaneous HPV types during childhood. Papillomaviruses have a sturdy outer protein shell or "capsid" that renders them capable of lingering in the environment for long periods of time. Avoiding contact with contaminated surfaces, such as the floors of communal showers or airport security lines, might reduce the risk of cutaneous HPV infection. Treating common warts soon after they first appear may also reduce the spread of the infection to additional sites.

Genital HPV infections may be distributed widely over genital skin and mucosal surfaces, and transmission can occur even when there are no overt symptoms. Several strategies should be employed to minimize the risk of developing diseases caused by genital HPVs:

Pap smear

Main article: Pap smear

ThinPrep Pap smear with group of normal cervical cells on left and HPV-infected cells on right

Papanicolaou screening, colloquially known as "Pap" smear testing, is an effective strategy for reducing the risk of invasive cervical cancer. In March 2003, the US FDA approved HPV DNA testing as a primary screening tool for detecting high-risk HPV infections that may lead to cervical cancer. The HPV DNA test, which is marketed by Digene, can also serve as an adjunct to Pap smear testing, and may be ordered in response to abnormal Pap smear results. Detailed inspection of the cervix by colposcopy may be indicated if abnormal cells are detected by routine Pap smear.

It has been suggested that Pap smear screening for anal cancer might be of benefit for relatively promiscuous individuals, for example some sub-populations of gay men (Chin-Hong 2005).

Vaccine

Main article: HPV vaccine

On June 8th, 2006, the FDA approved Gardasil, a prophylactic HPV vaccine developed by Merck. The vaccine protects women against initial infection with HPV types 16 and 18, which together cause 70 percent of cervical cancers. The vaccine also protects against HPV types 6 and 11, which cause 90 percent of genital warts. Women aged nine through twenty-six can be vaccinated. GlaxoSmithKline is expected to seek approval for a prophylactic vaccine targeting HPV types 16 and 18 early in 2007. Since the vaccine will not protect women against all the HPV types that cause cervical cancer, it will be important for women to continue to seek Pap smear testing, even after receiving the vaccine.

Avoiding risky sexual behavior

The fact that prostitutes have much higher rates of cervical cancer than nuns was a key early observation leading researchers to speculate about a causal link between sexually-transmitted HPVs and cervical cancer.^{[citation needed]} It remains clear that people with greater numbers of sexual partners are at increased risk of developing genital HPV-related diseases. Co-infection with other sexually-transmitted pathogens, such as HIV, may also increase the risk of developing HPV-related diseases.

Condoms offer at most a limited degree of protection against the initial transmission of HPV infections (Holmes 2004). On the other hand, some studies have suggested that regular condom use can effectively limit the ongoing persistence and spread of HPV to additional genital sites in individuals who are already infected (Moscicki 2005)(Bleecker 2005) [1]. Thus, condom use may reduce the risk that infected individuals will progress to cervical cancer or develop additional genital warts. A 2006 study of 82 college students suggests that condoms prevent HPV infection in 70% of cases.[2][3] Both Planned Parenthood and the Centers for Disease Control recommend condom use to reduce the risk of HPV-related diseases.

Ongoing research has suggested that several inexpensive chemicals might serve to block HPV transmission if applied to the genitals prior to sexual contact (Howett 2005). These candidate agents, which are known as topical microbicides, are currently undergoing clinical efficacy testing.

Avoiding smoking

Tobacco smoking increases the risk of developing of invasive cervical cancer, as well as other HPV-induced cancers. Smoking decreases the ablility to absorb folic acid, and taking folic acid is a respected way of treating cervical dysplasia, an extremely common symptom of HPV.

Research

In vitro studies indicate that carrageenan is a potent inhibitor of papillomavirus infection [4].

Treatment

Therapies are addressed in main articles covering the various HPV-related diseases.