Human Papillomavirus (HPV): Warts, Cervical Cancer, and the Vaccine

A woman in her thirties feels completely well, but a routine cervical screening test comes back abnormal. She has no symptoms, no pain, nothing she could have noticed.

Years earlier she acquired a common sexually transmitted virus that most people clear without ever knowing they had it. In her case it did not clear, and it has been quietly altering the cells of her cervix ever since.

The virus is human papillomavirus, and the story of how a usually harmless infection becomes cervical cancer, slowly and silently, is what makes HPV one of the most important viruses in medicine.

Human papillomavirus (HPV) is a common virus with a split personality. Most infections cause nothing at all, or at most a harmless wart. Yet a subset of HPV types, infecting the wrong place and persisting for years, cause cervical cancer and several other cancers. Understanding HPV means understanding that difference: which types, in which tissue, doing what to the cell.

What HPV is

HPV is a small, non-enveloped virus with a circular double-stranded DNA genome, belonging to the family Papillomaviridae. (Older texts group it in the "papovaviruses," a now-obsolete family that combined papillomaviruses with polyomaviruses; the two are now separate families.) Because it has no envelope, HPV is relatively stable in the environment and resistant to drying, which contributes to its transmissibility.

There are more than 200 HPV types, distinguished by their DNA sequence and numbered (HPV-6, HPV-16, and so on). They infect epithelial cells, the surface-lining cells of skin and mucous membranes, and this tissue preference is the key to everything HPV does. HPV cannot be grown in ordinary cell culture, which shaped how it is diagnosed (by cytology and DNA testing, not culture).

The single most important division among the types is high-risk versus low-risk.

High-risk and low-risk types: the central split

HPV types fall into two groups by their cancer-causing potential, and holding this split clear organizes the whole topic.

Low-risk types (for example HPV-6 and HPV-11) cause benign growths. They produce genital warts (condylomata acuminata) and, less commonly, laryngeal (respiratory) papillomas. They rarely progress to cancer.

High-risk (oncogenic) types (for example HPV-16 and HPV-18) are the ones that cause cancer. HPV-16 and HPV-18 together account for about 70% of cervical cancers. High-risk types also cause anal, penile, vulvar, vaginal, and a growing share of oropharyngeal (throat) cancers.

The practical consequence: a wart is almost always a low-risk type and is not a cancer risk, while the dangerous infections are usually invisible high-risk infections of the cervix that produce no wart at all. What you can see is mostly harmless; what is dangerous is mostly unseen.

How HPV causes cancer: the E6 and E7 oncoproteins

This is the heart of HPV as a medically important virus, and it is worth understanding as a mechanism rather than memorizing, because it explains why only high-risk types cause cancer and why persistence matters.

Every cell has natural brakes on uncontrolled division, above all two tumor-suppressor proteins: p53 (which halts the cell cycle and triggers repair or self-destruction when DNA is damaged) and Rb (retinoblastoma protein, which holds the cell in a resting state until it is safe to divide). High-risk HPV types make two oncoproteins that disable exactly these two brakes:

• E6 targets p53. E6 binds p53 and marks it for destruction (degradation by the cell's ubiquitin-proteasome system). With p53 gone, the cell loses its ability to stop the cycle and repair DNA damage, so mutations accumulate unchecked.
• E7 targets Rb. E7 binds Rb and releases the transcription factor E2F that Rb normally holds back. The cell is pushed into continuous division.

With both brakes disabled, the infected cell divides continuously and accumulates genetic damage it can no longer repair. Over years, this can progress through precancerous change (cervical intraepithelial neoplasia, CIN) to invasive cancer.

Two further points complete the mechanism and explain the clinical behavior:

• Why only high-risk types. The E6 and E7 proteins of low-risk types bind p53 and Rb weakly or not at all. Same gene names, very different binding strength. That difference in the oncoproteins, not a difference in where the virus goes, is what separates a wart-causer from a cancer-causer.
• Why persistence and integration matter. In most infections the virus stays separate from the host chromosome (episomal) and the immune system clears it within a couple of years. Cancer arises from the minority of infections that persist, and it is strongly associated with the viral DNA integrating into the host genome. Integration typically disrupts the viral E2 gene, which normally restrains E6 and E7, so integration switches the oncoproteins into overdrive. This is why cancer develops only after years of persistent infection, not from a transient one.

This mechanism is the reason HPV is the textbook example of a virus causing cancer by direct genetic damage. For how HPV sits among the other cancer-causing infections, see infectious causes of cancer.

Diseases caused by HPV

Organized by the high-risk/low-risk split:

Benign disease (low-risk types)

• Genital warts (condylomata acuminata): soft, cauliflower-like growths on the genitals and perianal area, usually HPV-6 or HPV-11. Common and benign, but distressing and transmissible.
• Recurrent respiratory papillomatosis: warts in the larynx, which can occur in children exposed during birth. Rare but difficult to treat.
• Cutaneous warts: common warts, plantar warts, and flat warts on the skin are caused by other HPV types, spread by ordinary skin contact rather than sexually. These are benign and are mentioned here for completeness; the medically weighty HPV disease is the genital and oncogenic disease above.

Malignant and premalignant disease (high-risk types)

• Cervical cancer and its precursor, cervical intraepithelial neoplasia (CIN). This is the most important HPV-related disease worldwide and the reason cervical screening exists.
• Other anogenital cancers: anal, penile, vulvar, and vaginal.
• Oropharyngeal cancer: cancer of the throat, tonsils, and base of tongue, a rising share of which is HPV-driven (chiefly HPV-16), acquired through oral exposure.

Koilocytes: the cytological signature

The microscopic hallmark of HPV infection, and the finding this virus is known for on a cervical smear, is the koilocyte.

A koilocyte is a squamous epithelial cell altered by HPV: it has a large, irregular, darkly staining (hyperchromatic) nucleus surrounded by a clear, sharply defined halo in the cytoplasm (a perinuclear cavity, from which the name derives, "koilos" meaning hollow). Seeing koilocytes on a Pap smear is direct cytological evidence of HPV infection. Like clue cells for bacterial vaginosis, the koilocyte is the "what does this infection look like down the microscope" finding worth committing to memory.

Laboratory diagnosis

HPV cannot be grown in routine culture, so diagnosis rests on cytology and molecular testing rather than isolation.

• Cytology (the Pap smear). A sample of cervical cells is stained and examined for the cellular changes of HPV infection and precancer: koilocytes, and the abnormal cells of CIN (dyskaryosis). The Pap smear has been the backbone of cervical cancer screening for decades because it detects precancerous change early, when it is curable.
• HPV DNA and mRNA testing (molecular). Nucleic acid tests detect high-risk HPV types directly, and testing for E6/E7 mRNA indicates active oncogenic expression. Screening programs have increasingly moved toward primary HPV DNA testing, because detecting the high-risk virus is more sensitive than cytology for identifying women at risk; cytology is then used to triage those who test positive. This shift, from looking at the cells to looking for the virus, is the major change in cervical screening.
• Colposcopy and biopsy confirm and grade disease when screening is abnormal.
• Visual diagnosis is sufficient for typical genital warts; biopsy is reserved for atypical lesions.

Because there is no spoke article for cervical cytology yet, the essentials are given here; the Pap smear method itself is a candidate for its own future article.

The HPV vaccine

The HPV vaccine is one of the clearest success stories in cancer prevention, and its design follows directly from the virus's structure.

• What it is. The vaccine is made of virus-like particles (VLPs): the L1 major capsid protein of HPV, self-assembled into empty shells that look like the virus to the immune system but contain no viral DNA. Because there is no genome, the vaccine cannot cause infection or cancer; it simply raises strong neutralizing antibody against the capsid.
• Which types. Vaccines have progressed from bivalent (HPV-16 and 18) and quadrivalent (adding the wart types 6 and 11) to the nonavalent vaccine, which covers nine types (16, 18, 6, 11 and five additional high-risk types), broadening the cancers prevented.
• Prophylactic, not therapeutic. This is the key point. The vaccine prevents new infection; it does not clear an infection already present or treat existing disease. That is why it is given before the likely age of exposure, ideally to adolescents before first sexual activity, when it gives the greatest benefit.
• Impact. Vaccination, combined with screening, has produced large falls in high-risk HPV infection, precancerous lesions, and, increasingly, cervical cancer itself in vaccinated populations.

Prevention also includes cervical screening (which catches precancer regardless of vaccination) and barrier protection, which reduces but does not eliminate transmission because HPV infects skin not covered by a condom.

How to remember

Two jobs, two type groups. Low-risk HPV (6, 11) makes warts; high-risk HPV (16, 18) makes cancer. "6 and 11 for the warts you can see, 16 and 18 for the cancer you cannot." That single pairing carries most of the exam value.

E6 eats p53, E7 eats Rb. The two high-risk oncoproteins each disable one tumor-suppressor brake. A memory hook: E6 and p53 (think "6" and the "5" in 53) go together; E7 takes Rb. With both brakes gone, the cell divides unchecked. This is the mechanism of HPV cancer in one line.

The dangerous infection is the invisible one. Warts are benign and visible; cervical cancer starts from a silent, symptomless high-risk infection. What you can see is usually harmless; what is unseen is what kills. This is why screening exists.

The vaccine is a shield, not a cure. It is made of empty capsid shells (L1 VLPs) with no DNA, so it cannot cause infection, and it only prevents new infection. Give it before exposure; it does nothing for an infection already there.

Koilocyte = hollow cell. The HPV-infected cell on a Pap smear has a clear halo around a dark nucleus. "Koilos" means hollow. See the halo, think HPV.

Key exam facts

Where students get confused

• High-risk versus low-risk is about cancer, not severity of symptoms. Low-risk types cause visible warts but not cancer; high-risk types often cause no visible lesion yet drive cancer. The visible disease is the benign one. Do not equate "I can see it" with "it is dangerous."
• E6/E7 exist in low-risk types too, but they are weak. It is not that only high-risk types have these genes; it is that the high-risk E6 and E7 bind and disable p53 and Rb strongly, while the low-risk versions barely do. The difference in binding strength is the difference between a wart and a cancer.
• The vaccine does not treat existing infection or disease. It is purely preventive. A person already infected, or with existing warts or CIN, is not cured by vaccination. This is why timing (before exposure) matters so much.
• Most HPV infections clear on their own. Acquiring HPV, even a high-risk type, does not mean cancer. The immune system clears most infections within about two years. Cancer comes from the minority that persist. The infection raises risk; it does not equal cancer.
• A Pap smear and an HPV test are not the same thing. The Pap smear looks at the cells for abnormal change; the HPV test looks for the virus itself. Modern screening increasingly leads with the HPV DNA test and uses cytology to triage positives.
• HPV is a virus. It sounds obvious, but because HPV is discussed alongside bacterial and parasitic causes of cancer, students sometimes misfile it. It is a DNA virus.

References

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5. World Health Organization. Human papillomavirus vaccines: WHO position paper (2022 update). Wkly Epidemiol Rec. 2022;97(50):645-672.