Human papillomavirus infection

• 1. Introduction

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  Human papillomavirus infection, usually shortened to HPV infection, is caused by a DNA virus from the Papillomaviridae family. Nearly every sexually active person is infected at some point in life. That makes it the most common sexually transmitted infection in the world.

  For most people, the infection passes without a single symptom. About 90 percent of infections resolve on their own within two years. Yet the same family of viruses is linked to roughly 5 percent of all cancers worldwide.

  More than 200 types have been described, and the disease is only known to affect humans. How can a virus that so often vanishes without a trace sometimes lead to cancer? What does it actually do inside a cell? Who first spotted the connection, and what can be done to stop it?

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• 2. Hundreds of Types

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  Each HPV type is known only by a number, and that number tells doctors a great deal. Types 1 and 2 can cause warts in some people. HPV5, by contrast, can settle in for the lifetime of a person without ever causing a visible sign.

  Warts have been described since ancient Greece, but their viral cause stayed hidden until 1907. That year Dr. Giuseppe Ciuffo inoculated an extract from a wart into skin and showed the growths were infectious. Warts form when cells on the outer layer of the skin multiply rapidly.

  Childhood is the most common time for skin warts. They typically appear and fade on their own over weeks to months, though they often come back. Common warts, linked to types such as 2, 7 and 22, usually show up on the hands and feet, and sometimes on elbows or knees.

  Plantar warts, tied to types including 1, 2, 4 and 63, grow inward on the soles of the feet. They tend to hurt when a person walks. Warts that form under or around a fingernail are harder to treat than warts elsewhere. Flat warts, linked to types 3, 10 and 28, favor the arms, face and forehead of children and teenagers.

  Genital warts are medically called condylomata acuminata. Doctors can diagnose them by looking and confirm them with a biopsy. Types 6 and 11 together account for about 90 percent of cases, and roughly 1 percent of sexually active adults have them.

  Types 6 and 11 can also cause a rare condition called recurrent laryngeal papillomatosis. Warts grow on the larynx or elsewhere in the airway and may interfere with breathing. Because they return so often, repeated surgery to remove them may be advisable.

  A separate group of about twelve types, including 16, 18, 31 and 45, has a far graver reputation.

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• 3. Ways It Travels

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  More than 40 HPV types can spread through sexual contact and infect the anus and genitals. These types travel by sustained skin-to-skin contact. Vaginal, anal and oral sex are the most common routes, and manual sex occasionally passes the virus along.

  Risk factors for a persistent infection include an early age at first intercourse, multiple partners, smoking and a weakened immune system. Condoms help but do not offer complete protection. The skin around the genitals, including the inner thigh, stays uncovered.

  A mother can pass genital HPV to her baby during birth, but disease in newborns is rare. The virus has proven capable of hiding for decades, so a lack of symptoms does not rule out a silent infection. Types 6 and 11 can cause juvenile-onset recurrent respiratory papillomatosis, at about 2 cases per 100,000 children in the United States. Even when a mother has genital warts at delivery, the risk stays below 1 percent.

  A researcher named Hernandez followed 25 heterosexual couples, testing the genitals and dominant hand of each person every other month for an average of seven months. Hands were not the main route of spread, but they mattered. In some couples a man's genitals infected a woman's hand, and in others her hand infected his genitals.

  Another researcher, Partridge, reported that men's fingertips turned positive for high-risk HPV at 26 percent per two years, against 48 percent for their genitals. Winer found that 14 percent of fingertip samples from sexually active women were positive. All fourteen fingertip samples from virgin women were negative at the start of that study. In a separate report, 1 of 76 virgin women with no sexual contact tested positive, against 7 of 72 who reported non-penetrative contact.

  Razors and other shared objects may carry the virus. The virus can survive for many months and at low temperatures without a host. A person with plantar warts can therefore spread it by walking barefoot.

  Blood is a puzzle. In 2005 a group tested frozen blood from 57 sexually naive pediatric patients with HIV and found 8 of them, or 14.0 percent, positive for HPV-16. In 2009 Australian Red Cross samples from 180 healthy male donors were tested, and 15 of them, or 8.3 percent, carried HPV DNA. DNA in blood is not the same as virus in blood, so transmission by transfusion remains unproven. Blood donations are not currently screened for HPV.

  One case report describes a laser surgeon who developed extensive laryngeal papillomatosis after removing anogenital warts from patients. Surgical staff can breathe in viral particles released during electrocautery or laser ablation of a wart.

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• 4. Inside the Cell

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  The HPV genome is a small circular loop of double-stranded DNA, roughly 8000 base pairs long. It can only replicate in the basal cells of stratified epithelium, the deep layer of the skin and mucous membranes. Intact tissue is closed to it. The virus gets in through micro-abrasions or other injuries that expose the basement membrane.

  Once there, virions attach to putative receptors such as alpha integrins, laminins and annexin A2. They enter basal cells by endocytosis, and the genome travels to the nucleus by mechanisms that remain unknown. It settles in at 10-200 copies per cell. The process is slow, taking 12-24 hours before transcription begins.

  The virus follows the host cell's own program of maturation. As a keratinocyte divides and differentiates in the upper layers, a cascade of viral gene activity unfolds. Infection does not burst the cells. Viral particles are shed as dying cells flake off at the surface.

  The genome holds six early genes, E1, E2, E4, E5, E6 and E7, and two late genes, L1 and L2. It also carries a non-coding long control region. The late genes build the protein shell that packages new genomes. The early proteins E6 and E7 are the troublemakers in high-risk types.

  Protein E2 normally holds E6 and E7 in check. When the viral genome integrates into the host's DNA, it tends to break the E2 gene. Without that brake, E6 and E7 production climbs, and cells proliferate. The level of E6 and E7 expression is correlated with the type of cervical lesion that develops.

  E6 grabs two host proteins at once, p53 and a ligase called E6-AP. The ligase tags p53 with ubiquitin, marking it for destruction. Normally p53 halts cell growth and promotes cell death when DNA is damaged. Remove it, and damaged cells keep dividing.

  E7 goes after a second guardian, the retinoblastoma protein pRb. By competing for pRb, E7 frees the transcription factor E2F to drive the cell cycle forward. Of all the types, only 16 and 18 can immortalize cell lines in vitro. Even they cannot immortalize primary rat cells without activation of the ras oncogene.

  The family tree of HPV seems to follow human history. The phylogeny reflects the migration of Homo sapiens, which suggests the virus diversified along with its hosts. Studies point to five major branches that mirror the ethnicity of human hosts.

  For HPV16, analyses of thousands of genomes show two major clades, four lineages labeled A to D, and 16 sublineages. The A1-A3 sublineages make up the European variant. Others are Asian, African and North American variants. Non-European lineages are considered to raise cancer risk.

  Even a DNA virus can recombine. Among more than 3600 HPV16 genomes, between 0.3 and 1.2 percent could be recombinant. For that reason, risk testing of HPV16 should ideally look at the entire genome, not just a few genes. A bioinformatics tool called HPV16-Genotyper handles lineage calls and flags possible recombination.

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• 5. The Road to Cancer

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  In 2020, cervical cancer caused an estimated 604,000 new cases and 342,000 deaths worldwide. About 90 percent of them occurred in low and middle income countries. There, screening tests and treatment of early cervical cell changes are not readily available.

  Nearly all cervical cancer is associated with HPV. Types 16 and 18 are present in 70 percent of cases, and HPV16 alone is present in about 47 percent. In 2012 the International Agency for Research on Cancer considered twelve types carcinogenic for the cervix. One study found 74 percent of squamous cell carcinomas and 78 percent of adenocarcinomas positive for type 16 or 18.

  The transformation is slow. Cancer usually appears in people who have carried the infection for a decade or more. Women with HIV/AIDS face a 22-fold increased risk of cervical cancer. Smoking is another co-factor.

  The two leading clades differ in their effects. Clade A9 contains HPV16, and clade A7 contains HPV18. Clade A7 is associated with more aggressive pathways and a poorer prognosis. Non-European HPV16 variants are significantly more carcinogenic than European ones.

  Cervical cancer is often silent at first. Advanced disease can bring pain during sex, unusual vaginal bleeding, changes to discharge, lower back pain and pelvic pain.

  About 90 percent of anal cancers are linked to HPV. The risk of anal cancer is 17 to 31 times higher in HIV-positive people co-infected with a high-risk type. It is 80 times higher for HIV-positive men who have sex with men. About half of penile cancers are associated with HPV, and HIV raises that risk 2- to 3-fold.

  The sharpest shift has been in the throat. HPV16 is responsible for almost 90 percent of HPV-related cancers of the mouth, throat or tonsils. The share of head and neck cancers tied to HPV varies from 70 percent in the United States to 4 percent in Brazil. The association holds regardless of tobacco and alcohol use.

  In the United States, newly diagnosed HPV-associated head and neck cancers now outnumber cervical cancer cases. The rate rose from an estimated 0.8 per 100,000 people in 1988 to 4.5 per 100,000 in 2012. Researchers explain the trend by an increase in oral sex. These cancers are more common in men. HPV-positive and HPV-negative head and neck cancers are fundamentally distinct diseases.

  In the United States, HPV-caused cancers total about 37,300 cases each year. Across 2008-2012, an estimated 9,100 of the 12,638 average yearly oropharynx cancers in men were attributable to HPV.

  The evidence for lung cancer is less settled. Researchers compared 1,633 lung cancer patients with 2,729 people without the disease. Patients carried more types of HPV. Another study found HPV in 16.4 percent of people with non-small cell lung cancer and in none of the controls.

  A rarer path runs through the skin. In people with weakened immune systems, HPV5, HPV8 and HPV14 can cause epidermodysplasia verruciformis. Wart-like lesions or cutaneous horns appear, and they can transform into skin cancer.

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• 6. Counting the Infected

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  Globally, 12 percent of women test positive for HPV DNA. Rates run highest in young women, at 24 percent for those under 25. By region they range from 24 percent in Sub-Saharan Africa and 21 percent in Eastern Europe down to 5 percent in North America and 2 percent in Western Asia.

  The most common types worldwide are HPV16 at 3.2 percent, HPV18 at 1.4 percent, HPV52 at 0.9 percent, HPV31 at 0.8 percent and HPV58 at 0.7 percent. HPV16 itself ranges from around 13 percent in Africa to 30 percent in West and Central Asia. The higher rates in Sub-Saharan Africa may relate to high exposure to HIV. Age at first sex, number of partners and access to barrier contraception also shape the global picture.

  In the United States, the American Social Health Association estimates that 75-80 percent of sexually active Americans will be infected at some point. By age 50, more than 80 percent of American women will have contracted at least one genital strain. In the year 2000 there were approximately 6.2 million new infections among Americans aged 15-44. About 74 percent of those occurred between ages 15 and 24.

  One study covering 2003-2004 found that 26.8 percent of women aged 14 to 59 carried at least one HPV type at a given time. For women aged 20 to 24, the figure reached 44.8 percent. Estimates elsewhere range from 14 percent to more than 90 percent. Some studies count current infections and others count anyone who ever had one. As of 2011, HPV was not among the diseases typically reportable to the CDC.

  Ireland recorded an average of 538 HPV-associated cancers per year from 2010 to 2014. Cervical cancer led, with an average of 292 cases per year. Anogenital warts notified in Ireland fell from 1,593 in 2016 to 1,281 in 2017, and 53 percent of 2017 cases were among males.

  In Sri Lanka, the prevalence of HPV is 15.5 percent. In Inner Mongolia, overall prevalence is 14.5 percent, but the split is stark. Mongolian women show 14.9 percent while Han women show 4.3 percent. Researchers see this region as an example of how HPV epidemiology follows cultural and ethnic factors more than geography.

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• 7. Testing and Defense

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  The American Cancer Society recommends that women aged 30-65 preferably be tested every 5 years with both an HPV test and a Pap test. Pairing the two reduces false negatives. The National Cancer Institute describes four test styles. Some detect DNA from several high-risk types, some detect only types 16 and 18, and one detects RNA. The FDA has approved these tests for only two uses, follow-up of abnormal Pap results and screening alongside a Pap test in women over 30.

  Mouth cancer has no routine HPV screen. Guidelines suggest a visual exam, but some parts of the oropharynx are hard to see, so this cancer is often found late. Doctors may use p16 immunohistochemistry on a biopsy, since tumors negative for p16 have worse outcomes.

  Testing men is far less settled. In one study, a kit from Qiagen and Digene was used off-label on men in long-term relationships with women who carried high-risk HPV. Sixty percent of the men carried the virus, mostly on the penis. Sampling the urethra added less than 1 percent to the detection rate.

  One small study rubbed skin with 600-grit emery paper before swabbing and found more men positive. Self-collection with emery paper and Dacron swabs worked as well as a clinician and sometimes better. Patients were more willing than clinicians to scrape vigorously. A blood test for antibodies was still unproven, with no FDA-approved product as of August 2018.

  There is currently no specific treatment for the infection itself. The immune system clears it to undetectable levels in 90 percent of cases within two years, according to the CDC. In one table for high-risk types, 70 percent of men tested negative at 8 months, 80 percent at 12 months and 100 percent at 18 months. Clearing does not guarantee immunity, though. Hernandez's couples showed apparent reinfection from a partner after clearance. Warts can be removed by freezing, and text messages and email can improve the number of patients who return for follow-up.

  The virus is unusually hardy. It was the first virus ever shown to resist inactivation by glutaraldehyde, a strong hospital disinfectant. Diluted bleach works but damages some reusable equipment, such as ultrasound transducers. Some health authorities encourage UV disinfection or a strong hydrogen peroxide solution.

  Six prophylactic vaccines are licensed, including Cervarix, Cecolin, Walrinvax, Cervavax, Gardasil and Gardasil 9. All protect against types 16 and 18. In December 2014 the FDA approved Gardasil 9, which adds five more types responsible for 20 percent of cervical cancers.

  Timing matters. Vaccination is recommended between ages 9-13. Effectiveness is reported at 74-93 percent for children aged 9-14, falling to 12-90 percent for adolescents aged 15-18. The CDC recommends two shots at least 6 months apart for ages 11-12, and three doses for those 13 and older. The vaccine has no therapeutic effect on existing infections.

  In 2014 the United Kingdom, Switzerland, Mexico, the Netherlands and Quebec began a two-dose schedule for girls under 15. Women still need cervical screening after vaccination, since the vaccine does not prevent every type of cervical cancer. Its protection is expected to last a long time.

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• 8. Tracing the Virus

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  In 1842, in Verona, Dr. Domenico Rigoni-Stern noticed something odd about uterine cancer. Catholic nuns in countrysid convents had a lower incidence than women in the city. The highest incidence appeared among prostitutes. He linked the disease to the number of sexual partners and suggested a sexually transmissible component.

  The next big step came in Poland. In 1972, Stefania Jabłońska proposed an association between human papillomaviruses and skin cancer in epidermodysplasia verruciformis. Four years later, in 1976, Harald zur Hausen published a hypothesis that HPV plays an important role in the cause of cervical cancer.

  In 1978, Jabłońska and Gérard Orth at the Pasteur Institute discovered HPV-5 in skin cancer. Then in 1983 and 1984, zur Hausen and his collaborators identified HPV16 and HPV18 in cervical cancer. Those two types remain the main culprits today.

  A famous laboratory tool carries the virus too. The HeLa cell line contains extra DNA in its genome that originated from HPV type 18.

  In 1993, Ludwig Cancer Research and McGill University in Montreal established the Ludwig-McGill HPV Cohort. It has become one of the world's largest longitudinal studies of HPV infection and cervical cancer risk.

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