More than 200 types of human papillomavirus have been identified, and they split into two broad camps based on what they do inside the body: roughly a dozen “high-risk” types that can cause cancer, and a larger group of “low-risk” types that cause warts and other benign growths but almost never turn malignant. The distinction matters because the type you carry shapes your screening needs, your treatment path, and your actual risk of serious disease. But the simple label of “high-risk” or “low-risk” hides a more complicated picture, from how these viruses hijack cells to why most infections never cause problems at all.
The High-Risk Types and What They Actually Cause
About 14 HPV types are classified as high-risk, meaning they have a demonstrated ability to cause cancer. The biggest players are HPV 16 and HPV 18, which together account for the majority of HPV-related cancers worldwide. High-risk HPV is behind virtually all cervical cancers, most vaginal and anal cancers, and a meaningful fraction of vulvar cancers.1PubMed. The risk of vaginal, vulvar and anal precancer and cancer according to high-risk HPV status in cervical cytology samples Other high-risk types include HPV 31, 33, 35, 39, 45, 51, 52, 56, 58, 59, 66, and 68. Each of these carries some cancer-causing potential, though their individual contributions are smaller than HPV 16 and 18.
To illustrate how dominant HPV 16 and 18 are: in a study of 200 cervical cancer tissue samples from Yemen, HPV 16 was found in 37% of cases and HPV 18 in 16%, with some patients carrying both.2PubMed Central. Prevalence of Human Papillomavirus subtypes 16 and 18 among Yemeni Patients with Cervical Cancer Those numbers vary by region and population, but the overall pattern holds globally: HPV 16 is the single most common type found in cervical cancers, and HPV 18 comes second.
How High-Risk HPV Turns Cells Cancerous
Carrying a high-risk type does not mean you will get cancer. In most people, the immune system brings the infection under control. Cancer only develops when the virus persists for years and its genetic material becomes entangled with the host cell’s DNA. When high-risk HPV DNA integrates into a cell’s genome, it tends to disrupt two viral genes called E1 and E2, which normally help regulate the virus. Losing that regulation is considered a risk factor for the chain of events that leads to malignancy.3PubMed Central. Disruption Events in the HPV18 E1 and E2 Genes in Precancerous Cervical Lesions
With E2 disrupted, the virus ramps up production of two proteins, E6 and E7, that are the real engines of cancer. These proteins interfere with the cell’s normal growth controls. E6 and E7, along with a third protein called E5, collectively push infected cells toward uncontrolled division and help them resist the signals that would normally trigger cell death.4PubMed Central. The Not-So-Good, the Bad and the Ugly: HPV E5, E6 and E7 Oncoproteins in the Orchestration of Carcinogenesis Because E6 and E7 are produced continuously in infected and precancerous tissue, they have become the primary targets for both diagnostic testing and experimental treatments.
Low-risk types also have versions of these proteins, but they interact with the cell’s machinery differently and much less aggressively, which is why low-risk infections stay benign.
Low-Risk Types and the Conditions They Cause
The two most important low-risk types are HPV 6 and HPV 11. Together they are responsible for about 90% of genital warts.5PubMed Central. Genital warts: a comprehensive review Genital warts are common, often distressing, and can recur, but they are not a cancer risk. The benign lesions caused by low-risk HPV types are biologically distinct from the precancerous changes caused by high-risk types.6PubMed. Annual disease burden due to human papillomavirus (HPV) 6 and 11 infections in Finland
HPV 6 and 11 also cause a condition called recurrent respiratory papillomatosis (RRP), in which wart-like growths develop in the airway, usually the larynx. RRP comes in two forms. The juvenile-onset version is typically picked up during birth from a mother with an active genital HPV infection. The adult-onset form is usually linked to sexual transmission. Both are predominantly caused by HPV 6, with HPV 11 playing a secondary role.7PubMed. Recurrent respiratory papillomatosis: Recent advances in HPV-6/HPV-11-targeted immunotherapy RRP can be serious: the growths can obstruct breathing and tend to come back after surgical removal, sometimes requiring dozens of procedures over a lifetime. In a survey of patients living with RRP, the vast majority of those who reported their birth delivery method were born vaginally, and all respondents with a known maternal history of genital warts at the time of delivery had juvenile-onset disease.8PubMed Central. The Patient Perspective of Living With Recurrent Respiratory Papillomatosis
Warts on the hands and feet are caused by other low-risk HPV types (types 1, 2, 4, and others), which are genetically distinct from the genital types and spread through skin contact rather than sexual activity.
Most HPV Infections Disappear on Their Own
Whether high-risk or low-risk, the majority of HPV infections become undetectable within a year or two. For a long time, this was described as the body “clearing” the virus. The updated understanding is more nuanced: what looks like clearance on a test may actually reflect the immune system clamping down hard enough that viral activity drops below detectable levels, without necessarily eliminating every last viral particle.9PubMed. An updated understanding of the natural history of cervical human papillomavirus infection-clinical implications Similarly, what looks like a new infection on a follow-up test can sometimes be a previously suppressed infection flickering back to life, or even virus deposited from a recent sexual contact without establishing a true new infection.
Not all types are equally good at persisting. In a Brazilian cohort of HPV-positive women followed for two years, about 60% had persistent infections while roughly 40% had apparent clearance. Among high-risk types, HPV 16, 33, and 59 were particularly likely to persist, while HPV 31, 45, and 58 cleared more readily. Among the low-risk types, HPV 6 was associated with clearance, whereas HPV 11 tended to stick around.10PubMed Central. Persistence or Clearance of Human Papillomavirus Infections in Women in Ouro Preto, Brazil The vaginal microbiome also plays a role: inflammation and shifts in bacterial communities have emerged as potential drivers of high-risk HPV persistence and progression to more severe disease.11PubMed Central. Role of Immunity and Vaginal Microbiome in Clearance and Persistence of Human Papillomavirus Infection
How HPV Hides From the Immune System
HPV is unusually good at staying under the radar. Unlike many viruses that trigger immediate alarm bells in the body, HPV infects only the outermost layer of skin or mucous membranes, a compartment the immune system monitors less aggressively than the bloodstream. The virus also actively suppresses immune signaling. Its oncoproteins E5, E6, and E7 interfere with the pathways cells use to flag themselves as infected, making it harder for immune cells to detect and destroy them.12PubMed Central. Evasion of host immune defenses by human papillomavirus HPV also dampens the activity of a key immune signaling molecule, which further helps it avoid triggering an effective response.13PubMed Central. Mechanisms of virus immune evasion lead to development from chronic inflammation to cancer formation associated with human papillomavirus infection
Even after the immune system gets the upper hand and visible lesions disappear, viral DNA can linger in a latent state within a small number of long-lived cells at the base of the skin. Animal studies show that immune memory cells in the surrounding tissue keep the virus in check, restricting its gene activity without fully wiping out the viral genome.14PubMed Central. The biology of papillomavirus latency These latent infections can potentially reactivate if the immune system is weakened by illness, medication, or even local tissue damage like wounding or UV exposure.15PubMed. Latent papillomavirus infections and their regulation This explains why genital warts can recur months or years after treatment, and why immunosuppressed people face a higher risk of HPV-related disease.
HPV Beyond the Cervix
High-risk HPV, especially type 16, is increasingly recognized as a major driver of cancers in the throat, specifically oropharyngeal squamous cell carcinoma (OPSCC). This cancer affects the tonsils and the base of the tongue and has been rising in incidence in many countries even as smoking-related oral cancers decline. In a US study of 240 OPSCC patients, about 62% of male cases and 56% of female cases were HPV-positive. The proportion of HPV-driven cases climbed sharply over the study period, roughly doubling for both sexes.16British Journal of Cancer. Human papillomavirus as a driver of head and neck cancers French population data tells a similar story: cancers at HPV-associated sites have been increasing at a faster rate than cancers at sites unrelated to HPV, a pattern consistent with a growing role for the virus.17PubMed Central. Incidence trends for potentially human papillomavirus-related and -unrelated head and neck cancers in France using population-based cancer registries data: 1980-2012
HPV-positive oropharyngeal cancers tend to respond better to treatment and carry a better prognosis than HPV-negative oral cancers driven by tobacco and alcohol. This distinction has practical consequences: oncologists now test for HPV status in throat cancers because it can influence treatment decisions. For the average person, the takeaway is that HPV’s reach extends well beyond the reproductive tract, and that oral sex is a recognized route of HPV transmission to the throat.
Screening Tests and How They Differ
Two main types of HPV tests are used in cervical cancer screening. HPV DNA tests detect whether viral genetic material is present. HPV E6/E7 mRNA tests go a step further by detecting whether the virus is actively producing the proteins that drive precancerous change. The mRNA approach tends to be more specific, meaning it is better at distinguishing infections that are truly progressing from harmless, transient ones. One study found that combining mRNA testing with cytology had a specificity of about 86% for detecting high-grade precancerous lesions, compared to roughly 83% for the DNA-plus-cytology approach.18PubMed. HPV E6/E7 mRNA vs. HPV DNA in co-testing with ThinPrep cytology for cervical cancer screening: a prospective observational diagnostic accuracy study of methylation biomarkers In populations with borderline cytology results, the higher specificity of mRNA testing can help avoid unnecessary biopsies and reduce patient anxiety.19PubMed. HPV E6/E7 mRNA versus HPV DNA biomarker in cervical cancer screening of a group of Macedonian women
Self-sampling is gaining ground as a way to bring screening to people who do not attend regular clinic-based exams. Self-collected vaginal swabs have been shown to be as accurate as clinician-collected samples for HPV detection when paired with modern testing methods.20PubMed Central. Self-Sampling for Human Papillomavirus Testing: Increased Cervical Cancer Screening Participation and Incorporation in International Screening Programs A systematic review and meta-analysis found that vaginal self-sampling had a pooled sensitivity of about 91% and specificity of about 87% for high-risk HPV, while urine-based sampling, though slightly less accurate, still performed well enough to be a useful option for populations that are difficult to reach.21PubMed Central. Diagnostic Accuracy of Urine and Vaginal Self-Sampling for Detection of High-Risk Human Papillomavirus: A Systematic Review and Meta-Analysis Acceptability is high: in a study of women in rural Senegal, nearly all participants used the self-sampling device correctly, and the sample quality was satisfactory in every case.22PubMed Central. Feasibility, Acceptability, and Accuracy of Vaginal Self-Sampling for Screening Human Papillomavirus Types in Women from Rural Areas in Senegal Several countries have already incorporated or are trialing self-sampling in their national screening programs.
How Vaccines Cover Multiple Types
Current HPV vaccines were designed around the types that cause the most disease. The nonavalent vaccine (Gardasil 9) targets nine types: HPV 6, 11, 16, 18, 31, 33, 45, 52, and 58. The two low-risk types protect against most genital warts and RRP, while the seven high-risk types cover the strains responsible for the bulk of HPV-related cancers.
An important bonus of vaccination is cross-protection. Vaccines can partially protect against HPV types not directly included in their formulation, because some types are genetically similar enough that antibodies raised against one also neutralize close relatives. Data from the Costa Rica Vaccine Trial showed that the bivalent vaccine (targeting only HPV 16 and 18) provided partial cross-protection against HPV 31, 33, and 45.23PubMed Central. Cross-protection of the Bivalent Human Papillomavirus (HPV) Vaccine Against Variants of Genetically Related High-Risk HPV Infections The cross-protection was strongest for lineages most closely related to the vaccine types: vaccine effectiveness against HPV 31 overall was about 80%, but it climbed above 94% for one lineage that was most genetically similar to the vaccine strain.24npj Vaccines. Differential long-term bivalent HPV vaccine cross-protection by variants in the Costa Rica HPV vaccine trial A larger study confirmed modest cross-protection against persistent infections with HPV 45, 31, and 52, suggesting the benefits extend to several types beyond what the label lists.25PubMed. Human papillomavirus vaccines and the potential for cross-protection between related HPV types
One of the most consequential recent developments in HPV vaccination is the evidence that a single dose may be enough. A trial among young women in Africa found that one dose of HPV vaccine was effective, which could drastically simplify vaccination programs in lower-resource settings.26PubMed Central. Efficacy of single-dose HPV vaccination among young African women Moving from a two-dose or three-dose schedule to a single dose would cut costs roughly in half and make it far easier to reach girls in remote areas, which is where vaccination coverage tends to be lowest.
Therapeutic Vaccines for People Already Infected
Preventive vaccines work by training the immune system to block infection before it starts, which is why they are most effective when given before sexual debut. They do not treat existing infections. That gap has fueled research into therapeutic vaccines designed to help the immune system attack cells already harboring HPV. These experimental vaccines train immune cells to recognize and destroy cells producing the E6 and E7 proteins, which are expressed in precancerous and cancerous tissue driven by high-risk HPV.27Expert Opinion on Biological Therapy. Therapeutic human papillomavirus vaccines: Current clinical trials and future directions
Several therapeutic vaccine candidates have progressed through early-stage clinical trials. Approaches tested include DNA-based vaccines, protein-based vaccines, and live-vector vaccines that use a harmless virus to deliver HPV antigens. A systematic review of DNA therapeutic vaccines targeting E6 and E7 found that five different candidates were well tolerated and produced measurable immune responses, with some showing regression of precancerous cervical lesions.28PubMed Central. The Efficacy of Therapeutic DNA Vaccines Expressing the Human Papillomavirus E6 and E7 Oncoproteins for Treatment of Cervical Cancer: Systematic Review None has yet been approved for routine use, but the field is active, with multiple strategies being refined and combined to boost effectiveness.29PubMed Central. Therapeutic vaccines for high-risk HPV-associated diseases If any of these vaccines succeeds in larger trials, it could offer a non-surgical option for treating early cervical lesions and potentially even advanced disease caused by persistent high-risk infections.
An Ancient Evolutionary Relationship
HPV types did not emerge recently. The virus has been co-evolving with humans and our ancestors for hundreds of thousands of years. Genetic analyses of HPV 16 show that the major lineages of this virus diverged from a common ancestor roughly half a million years ago, around the same time that archaic Neanderthals and modern humans split from their shared ancestor. The timescale of HPV divergence is nearly three times longer than the divergence of modern human populations from one another.30PubMed Central. Niche adaptation and viral transmission of human papillomaviruses from archaic hominins to modern humans This deep evolutionary history helps explain why there are so many distinct HPV types and why some lineages of the same type behave differently in terms of cancer risk and vaccine responsiveness. It also means that HPV is not a recent plague but a deeply embedded feature of human biology, one we have been carrying and adapting to far longer than recorded history.