Human papillomavirus

Human papillomaviruses (HPV) are a large family of small, non-enveloped, double-stranded DNA viruses that infect only the stratified squamous epithelium of skin and mucosa. More than 200 recognised human types fall into five genera, and between them they cause disease ranging from the trivial to the lethal. Most infection is subclinical and cleared within a couple of years; some types cause benign warts of the skin and genitals; and a dozen high-risk mucosal types cause virtually all cervical cancer along with substantial fractions of anal, vulvar, vaginal, penile and oropharyngeal cancer. HPV is the most common sexually transmitted infection, with a lifetime risk above 80 per cent in sexually active people, and it accounts for about 5 per cent of all human cancers. Cervical cancer alone caused around 660,000 new cases and 350,000 deaths in 2022, the fourth commonest cancer in women, with the burden falling overwhelmingly on lower-income countries and on southern and eastern Africa in particular. Against this sits one of the signal achievements of modern virology: highly effective prophylactic vaccines built from the viral capsid protein, which, with cervical screening, have made cervical cancer the first cancer that the World Health Organization (WHO) has committed to eliminating.

Discovery and historical significance

Warts have been recognised since antiquity, but their viral nature was shown only in 1907, when Giuseppe Ciuffo transmitted them with a cell-free filtrate of wart extract. The first oncogenic papillomavirus was found in animals: Richard Shope showed in 1932 that a virus caused the cottontail rabbit papilloma, which could progress to carcinoma, establishing the precedent that a papillomavirus could cause cancer. The decisive insight for human disease came from Harald zur Hausen, who proposed in 1976 that cervical cancer was caused by HPV and, with Gérard Orth, recognised that the papillomaviruses are not one agent but many distinct genotypes. Through the late 1970s and 1980s the high-risk types were isolated from cervical cancers, the low-risk wart types were distinguished from them, and polymerase chain reaction studies later established that high-risk HPV is present in nearly every cervical cancer. zur Hausen was awarded the Nobel Prize in Physiology or Medicine in 2008. The discovery that the major capsid protein self-assembles into immunogenic virus-like particles led directly to the prophylactic vaccines, first licensed in 2006.

Classification, structure, and genome

Classification

The family Papillomaviridae is ancient and host-specific, having co-evolved with vertebrates over tens of millions of years. The human viruses fall into five genera named with Greek letters, which differ in the epithelium they prefer and in their oncogenic potential.

Genus	Main tropism	Notable disease
Alphapapillomavirus	Mucosal and some cutaneous	High-risk cancers and anogenital warts; the oncogenic types live here
Betapapillomavirus	Cutaneous	Epidermodysplasia verruciformis and ultraviolet-associated skin cancer
Gammapapillomavirus	Cutaneous, also mucosal	Common warts; implicated in some head and neck cancer
Mupapillomavirus	Cutaneous	Plantar and common warts (HPV1)
Nupapillomavirus	Cutaneous	Cutaneous lesions; no oncogenic types

Types are defined genetically rather than serologically, because the virus could not historically be cultured and natural infection raises little cross-reacting antibody. These groupings are defined by genetic distance across the L1 gene: members of a genus share more than 60 per cent of their L1 sequence, a species groups types that share about 71 to 89 per cent, and a new type differs by more than 10 per cent from the nearest known type, with smaller differences defining subtypes and variants. New genomes are cloned, submitted to an international reference centre and curated in the Papillomavirus Episteme database. The clinically important distinction is between the high-risk mucosal types (16, 18, 31, 33, 35, 39, 45, 51, 52, 56, 58 and 59, the agents classed as carcinogenic), which the oncogenic alpha species contain, and the low-risk types (chiefly 6 and 11), which cause anogenital warts but not cancer. HPV16 (in species Alphapapillomavirus 9) and HPV18 (Alphapapillomavirus 7) cause most cervical cancer between them. The two numbering schemes do not align: a type number simply records the order of discovery (HPV16 was the sixteenth found), whereas a species number labels a branch of the genus’s evolutionary tree, so one species groups several related types, Alphapapillomavirus 9 holding HPV16 together with 31, 33, 35, 52 and 58. A modern qualification is that the beta and gamma types, once thought purely cutaneous, are now detected at mucosal sites and implicated in some head and neck cancers.

Virion structure

The virion is a non-enveloped icosahedral particle about 55 nm across, with T=7 symmetry. Its shell is 72 pentamers (capsomers) of the major capsid protein L1, which makes up most of the coat, with the minor protein L2 at the centre of the pentamers; the genome inside is packaged on cellular histones as chromatin. The single most consequential property of the virion is that L1, when expressed alone, self-assembles into a virus-like particle that looks like the natural capsid but contains no DNA and cannot infect, which is the molecular basis of the vaccines.

Genome organisation

The genome is a circular double-stranded DNA molecule of about 8 kilobases, with all of its genes carried on one strand. The early genes (E1, E2, E4, E5, E6 and E7) encode regulatory and non-structural proteins, the late genes (L1 and L2) the capsid, and a non-coding upstream regulatory region between them holds the origin of replication and the promoter that drives E6 and E7.

Gene	Function
E1	Origin-binding helicase that initiates viral DNA replication
E2	Loads E1, tethers the genome to host chromatin for partitioning, and represses the E6/E7 promoter
E4	Disrupts the keratin cytoskeleton to aid virion release
E5	Sustains epidermal growth factor receptor (EGFR) signalling and lowers surface MHC class I
E6	High-risk types: directs p53 for degradation and switches on telomerase
E7	High-risk types: inactivates the retinoblastoma protein, forcing cell-cycle entry
L1, L2	Major and minor capsid proteins; L2 chaperones the genome into the nucleus

Replication cycle

The defining feature of papillomavirus biology is that the replication cycle is inseparable from the differentiation of the epithelium it infects: the virus produces progeny only as the cell it occupies matures and dies in the normal way, and there is no lytic burst and no viraemia.

The virus reaches its target, the dividing basal keratinocyte, only where a microabrasion exposes the basement membrane, to which the capsid binds through heparan sulphate proteoglycans before a conformational change engages a secondary receptor. In the cervix the vulnerable cells lie at the transformation zone, the squamocolumnar junction, which is why that site is where oncogenic infection concentrates. After endocytosis the L2 protein ferries the genome out of the endosome and, riding the cell’s own mitotic chromosomes, into the nucleus, so that nuclear entry depends on the cell dividing. In the basal layer the genome is established as a low-copy episome maintained by E1 and E2 and partitioned to daughter cells, held quiet by a repressor so that little viral protein is made: this is a persistent, almost silent reservoir.

Productive replication begins only as infected cells leave the basal layer and differentiate upward. Differentiated keratinocytes have normally exited the cell cycle, so the virus reactivates it: E6 and E7 push the cell back into S phase and recruit the host DNA-replication machinery, and the viral genome amplifies to high copy number. The late promoter switches on, L1 and L2 are made only in the most superficial cells, capsids assemble there, and the E4 protein weakens the cornified envelope so that mature virions are shed passively in desquamating squames. Two departures from this arc matter. The beta cutaneous types often persist latently in hair-follicle stem cells with only occasional production. And malignant transformation is a dead end for the virus: the transformed cell fails to differentiate and makes no virus at all, so cancer is a by-product of infection, never part of its life cycle.

Pathogenesis

Two outcomes of infection must be held apart. A productive infection runs the full differentiation-coupled cycle and is benign, causing at most a wart. A transforming infection arises when a high-risk type deregulates its oncoproteins in cells that are no longer making virus, and it is rare, late and the route to cancer.

The HPV-specific mechanism rests on two proteins. E6 of the high-risk types recruits a cellular ubiquitin ligase, E6-associated protein, to mark p53 for destruction, removing the cell’s response to DNA damage, and separately switches on telomerase to grant replicative immortality. E7 binds and inactivates the retinoblastoma protein, releasing the E2F transcription factors and driving the cell into unscheduled division; the cell’s compensatory rise in the p16 protein is the basis of the p16 stain used diagnostically. The E5 protein adds to this by sustaining growth-factor signalling and reducing immune visibility. In benign lesions the viral genome stays episomal, but progression to cancer is typically accompanied by integration of the viral DNA into the host chromosome in a way that disrupts the E2 gene; because E2 normally represses the E6/E7 promoter, its loss releases the two oncoproteins to be expressed without restraint.

Why the process is so slow is explained by the same biology. The virus does not lyse cells, never enters the blood, replicates without inflammation and downregulates interferon signalling, so it provokes little immune response and persists under the radar. Most infections are nonetheless cleared by cell-mediated immunity, and the risk of cancer tracks the persistence of a high-risk type, not the fact of acquisition. Host factors that impair clearance, above all HIV infection, accordingly raise the risk most.

Epidemiology

HPV is endemic everywhere, without epidemic or strongly seasonal behaviour. Genital infection is so common that a large majority of sexually active people acquire it at some point, with prevalence peaking in women under 25 and multiple concurrent types being usual. Transmission of the genital types is by sexual contact, though penetrative sex is not required because the virus spreads by skin-to-skin contact; the cutaneous wart types spread by direct contact and fomites; and perinatal transmission of HPV6 and HPV11 from the maternal genital tract can seed recurrent respiratory papillomatosis in the child. Anogenital warts are the commonest clinical manifestation, and cutaneous warts are very common in children.

The cancer burden is what gives HPV its importance. High-risk HPV causes close to 5 per cent of all human cancers, and the attributable fractions are high across several sites.

Cancer	Roughly HPV-attributable
Cervix	Essentially all
Anus	Around 90 per cent
Vagina	Around 75 per cent
Vulva, penis	Around 40 to 50 per cent
Oropharynx	Around 30 per cent, and rising in high-income countries

The risk of persistence and progression is increased by HIV and other immunosuppression, by smoking, by high parity and by early and frequent sexual exposure. Men who have sex with men, transgender women and people living with HIV carry far higher rates of anogenital, especially anal, HPV, and people living with HIV clear the virus poorly and carry multiple types at higher load. The global distribution mirrors access to vaccination and screening, with the highest cervical cancer rates in sub-Saharan Africa.

Natural history

The incubation period is ill-defined; cutaneous warts appear over a few months and anogenital warts at a median of around three months. The great majority of infections are transient: about half become undetectable within nine months and roughly 90 per cent within two years, with high-risk types persisting somewhat longer than low-risk ones and HPV16 the most persistent of all. A minority, perhaps a fifth, persist, and it is this persistent fraction that carries clinical consequence; there is emerging evidence that the virus may never be fully cleared at the molecular level but is instead controlled.

When a high-risk infection persists, the cervical epithelium passes through graded change: low-grade squamous intraepithelial lesions, most of which regress, then high-grade lesions (cervical intraepithelial neoplasia grades 2 and 3), and finally, in a fraction and typically over years to decades, invasive cancer. Squamous cell carcinoma accounts for around 90 per cent of cervical cancer and adenocarcinoma for most of the rest. The long, detectable precancerous phase is exactly what makes screening effective. Cofactors such as HIV and smoking shorten the journey.

Clinical presentations and complications

Cutaneous warts

Common warts (verruca vulgaris) on the hands and knees, plantar warts on the feet and flat warts are caused mostly by HPV types 1, 2, 27 and 57. They are benign and often resolve spontaneously, around half within a year, though they can be persistent and troublesome, particularly in the immunosuppressed.

Anogenital warts

Condylomata acuminata, the commonest clinical HPV disease, are caused by the low-risk types 6 and 11 and occur anywhere in the anogenital area, with onset peaking in the twenties. They are not premalignant, but they recur frequently and carry considerable psychosexual morbidity. Treatment is directed at the lesions, by patient-applied topical agents such as imiquimod or podophyllotoxin or by clinician-delivered ablation, none of it reliably curative because the surrounding epithelium stays infected. The clearest preventive gain in HPV medicine outside cancer has been here: in countries with high uptake of the quadrivalent or nonavalent vaccine, which include types 6 and 11, anogenital warts have fallen sharply in vaccinated cohorts and, through herd protection, in unvaccinated people too.

Recurrent respiratory papillomatosis

HPV6 and HPV11 cause papillomas of the larynx and airway, a rare but serious disease. Its onset is bimodal, affecting young children and young adults but not the elderly. The juvenile-onset form is acquired at birth from a mother with genital warts, and the classic risk profile is a firstborn child delivered vaginally to a young, often teenage, mother with condylomata; the risk that such a child develops the disease is estimated at between roughly 1 in 80 and 1 in 500 deliveries through an infected canal. The adult-onset form is thought to follow oral acquisition of the virus. Diagnosis is made at laryngoscopy or bronchoscopy, with biopsy and HPV typing. The papillomas regrow persistently and can obstruct the airway, so management rests on repeated surgical removal (microdebridement or laser) to keep the airway patent, while tracheostomy is avoided because it can seed disease into the lower airway. Severe or rapidly recurring disease is increasingly treated with adjuvant therapy: the antiviral cidofovir injected into lesions and, for aggressive disease, the anti-angiogenic antibody bevacizumab. HPV vaccination reduces incidence. Malignant transformation, usually linked to HPV11 or to distal pulmonary spread, is rare.

Epidermodysplasia verruciformis

This rare inherited disorder leaves the skin unable to control the beta papillomaviruses that most people carry harmlessly. It is usually autosomal recessive, caused most often by mutations in the EVER1 (TMC6) or EVER2 (TMC8) genes, and presents from childhood with widespread flat warts and reddish or pityriasis-versicolor-like plaques. The cardinal danger is malignancy: up to two-thirds of patients develop cutaneous squamous cell carcinoma, typically from early adulthood and on sun-exposed skin, with the beta types HPV5 and HPV8 found in most of these tumours, so ultraviolet light acts as a co-carcinogen. Diagnosis rests on the characteristic lifelong eruption, the histology and the demonstration of beta HPV types, supported increasingly by genetic testing. There is no cure, so management centres on lifelong rigorous photoprotection and regular skin surveillance with prompt excision of carcinomas, with topical agents and systemic retinoids used for the warty lesions on limited evidence. An acquired form with the same susceptibility occurs in people with profound T-cell immunodeficiency, most importantly advanced HIV.

HPV-associated cancers

Persistent infection with a high-risk type causes cancer at several sites, each preceded by a gradable precancerous phase of intraepithelial neoplasia, graded as low-grade or high-grade squamous intraepithelial lesions, the high-grade lesion being the immediate precursor of cancer. That precancerous phase is the single most important fact in HPV medicine, because it is long, detectable and treatable, which is what makes the disease screenable and largely preventable.

Cervical cancer is by far the most important HPV disease and the reason the virus matters at population scale. It is the fourth commonest cancer in women worldwide, with around 660,000 new cases and 350,000 deaths in 2022, and the burden falls overwhelmingly on lower-income countries that lack screening and vaccination. Screening works by finding and treating the high-grade precancerous lesion before it becomes invasive. The historic tool was cervical cytology, the Papanicolaou smear, which detects the koilocytotic and dyskaryotic cells of an established lesion; programmes are now moving to primary high-risk HPV DNA testing, which detects the cause before the cells change and is more sensitive, with cytology kept as a triage test and visual inspection with acetic acid used where laboratory testing is unavailable. A positive screen leads to colposcopy and, where a high-grade lesion is confirmed, to local excision or ablation. Combined with vaccination, screening makes cervical cancer in principle an eliminable disease.

The other anogenital cancers, of the vulva, vagina, penis and anus, follow the same persistent-infection-to-neoplasia sequence, though organised screening for them is far less developed. Anal cancer is rising in men who have sex with men and in people living with HIV, and the ANCHOR trial showed that treating anal high-grade lesions reduces progression to cancer, which supports anal screening in these groups. HPV-positive oropharyngeal cancer has become a distinct and rising entity, especially in high-income countries: driven mainly by HPV16, arising in the tonsil and base of tongue and linked to oral sexual exposure, it carries a markedly better prognosis than the tobacco-related, HPV-negative cancers it is overtaking, and p16 immunostaining identifies it.

Diagnosis

Warts are diagnosed clinically and rarely need a test. There is no routine viral culture and no useful serology, so laboratory diagnosis of infection rests on detecting the viral genome. High-risk HPV DNA testing, with partial genotyping, is the primary tool of cervical screening, and E6/E7 mRNA testing identifies transcriptionally active, higher-risk infection. Cytology (the Papanicolaou smear) shows the koilocyte, a squamous cell with a perinuclear halo and an enlarged irregular nucleus, that is the morphological signature of productive infection, along with the dyskaryosis of higher-grade disease. Histology grades intraepithelial neoplasia, and p16 immunostaining serves as a surrogate marker of transforming high-risk infection, used to resolve equivocal cervical lesions and to confirm that an oropharyngeal cancer is HPV-driven. Colposcopy with acetic acid, and high-resolution anoscopy with anal cytology in high-risk groups, localise lesions for biopsy and treatment.

Management

There is no specific antiviral against HPV, so treatment is directed at the lesion. Warts, cutaneous and anogenital, are removed by ablative or destructive means (cryotherapy, electrocautery, laser, curettage or excision) or treated topically (with agents such as imiquimod, podophyllotoxin, salicylic acid or trichloroacetic acid); none is reliably curative and recurrence is common. High-grade intraepithelial lesions are treated by excision or ablation, for example large loop excision of the transformation zone for cervical high-grade disease, which both treats and provides tissue for histology. Invasive cancers are managed multimodally with surgery, radiotherapy and chemotherapy according to site and stage. The immune checkpoint inhibitor pembrolizumab has a growing role in advanced cervical and HPV-positive head and neck cancer, and therapeutic vaccines intended to clear established infection are in trials but not yet in use. Prophylactic vaccination after treatment of a high-grade lesion reduces the risk of recurrence.

Prevention and public health

Vaccination

The prophylactic vaccines are built from the L1 capsid protein, which self-assembles into virus-like particles that present the natural capsid surface to the immune system and raise high titres of type-specific neutralising antibody; the particles contain no viral DNA and cannot cause infection. Because the response is type-specific, the vaccines have been broadened over successive generations to cover more types.

Vaccine	Valency	Types	Notes
Cervarix	Bivalent	16, 18	AS04 adjuvant; cross-protects against 31, 33 and 45
Gardasil	Quadrivalent	6, 11, 16, 18	Adds protection against anogenital warts
Gardasil 9	Nonavalent	6, 11, 16, 18, 31, 33, 45, 52, 58	Covers the types behind about 90 per cent of cervical cancer

Given before sexual debut the vaccines almost completely prevent vaccine-type persistent infection and the precancerous lesions that follow, and national programmes have produced large real-world falls in cervical precancer and cancer, and, where the wart types are included, in anogenital warts. The vaccines are prophylactic, not therapeutic: they prevent new infection but do not clear established infection. Three developments define current practice. A single dose is now accepted by WHO as giving protection comparable to two in those aged 9 to 20, which greatly eases the cost and logistics of programmes, while immunocompromised people are still given a multi-dose schedule. Programmes are increasingly gender-neutral, vaccinating boys as well as girls to prevent the warts, anal, penile and oropharyngeal disease of males and to improve herd protection. And vaccination is recommended for higher-risk groups including men who have sex with men and people living with HIV.

Elimination and eradication

WHO has set the elimination of cervical cancer as a public health problem, defined as an incidence below 4 per 100,000 women, as a global goal. Its 90-70-90 strategy for 2030 requires that 90 per cent of girls are fully vaccinated by age 15, that 70 per cent of women are screened with a high-performance test by 35 and again by 45, and that 90 per cent of women with cervical disease are treated. Screening, increasingly by primary high-risk HPV testing rather than cytology, is the second pillar of this strategy alongside vaccination.

South African context

South Africa carries one of the highest cervical cancer burdens in the world, and it is a leading cause of cancer death in South African women. The defining local factor is the HIV epidemic: the high prevalence of HIV drives greater HPV acquisition, poorer clearance, faster progression and more multi-type and anal disease, so cervical cancer and HPV-related anogenital disease weigh especially heavily on women living with HIV. South Africa was an early adopter of school-based HPV vaccination, introduced for young girls in 2014, and it is moving its cervical screening programme from cytology to primary high-risk HPV testing in line with the WHO elimination targets.

References and recommended reading

• Bonnez W. Papillomaviruses. In: Richman DD, Whitley RJ, Hayden FG (eds.), Clinical Virology, 4th edition. ASM Press; 2016. The readable backbone for the virology, the clinical spectrum and the natural history.
• McBride AA, Howley PM; Schiller JT, Lowy DR. Papillomaviridae: The Viruses and Their Replication; Papillomaviruses. In: Fields Virology, 7th edition, Volume 2, Chapters 2 and 3. Wolters Kluwer; 2022. The molecular reference for the genome, the differentiation-coupled replication cycle and transformation.
• McBride AA. Human papillomaviruses: diversity, infection and host interactions. Nature Reviews Microbiology 2022;20(2):95-108. DOI 10.1038/s41579-021-00617-5. The current source for the modern classification and the life cycle.
• Kohli M, Bunker CB, Kravvas G. Human papillomavirus: an update. Clinics in Dermatology 2026;44(1):54-66. DOI 10.1016/j.clindermatol.2025.09.012. The current source for epidemiology, the clinical spectrum and the vaccine landscape.