Co-expression of low-risk HPV E6/E7 and EBV LMP-1 leads to precancerous lesions by DNA damage.

BACKGROUND: Low-risk human papillomavirus (HPV), such as types 6 and 11, is considered non-oncogenic, but these types have been detected in oral cancer tissue samples, suggesting their possible involvement in oral carcinogenesis. Because double infection of high-risk HPV and Epstein-Barr virus (EBV) is known to be involved in oral carcinogenesis, we hypothesized that low-risk HPV and EBV co-infection can transform the oral cells. To verify our hypothesis, we evaluated the transformation activity of cell lines expressing both low-risk HPV E6/E7 and EBV LMP-1. METHODS: We transduced HPV6, 11 and 16 E6/E7 genes and EBV LMP-1 gene into primary mouse embryonic fibroblasts. The cell lines were examined for indices of transformation activity such as proliferation, induction of DNA damage, resistance to apoptosis, anchorage-independent growth, and tumor formation in nude mice. To evaluate the signaling pathways involved in transformation, NF-κB and p53 activities were analyzed. We also assessed adhesion signaling molecules associated with anchorage-independent growth such as MMP-2, paxillin and Cat-1. RESULTS: Co-expression of low-risk HPV6 E6 and EBV LMP-1 showed increased cell proliferation, elevated NF-κB activity and reduced p53 induction. Moreover, co-expression of low-risk HPV6 E6 and EBV LMP-1 induced DNA damage, escaped from apoptosis under genotoxic condition and suppression of DNA damage response (DDR). Co-expression of low-risk HPV11 E6/E7 and EBV LMP-1 demonstrated similar results. However, it led to no malignant characteristics such as anchorage-independent growth, invasiveness and tumor formation in nude mice. Compared with the cells co-expressing high-risk HPV16 E6 and EBV LMP-1 that induce transformation, co-expression of low-risk HPV6 E6 and EBV LMP-1 was associated with low MMP-2, paxillin and Cat-1 expression. CONCLUSIONS: The co-expression of low-risk HPV E6/E7 and EBV LMP-1 does not induce malignant transformation, but it allows accumulation of somatic mutations secondary to increased DNA damage and suppression of DDR. Thus, double infection of low-risk HPV and EBV could lead to precancerous lesions.

Prevalence and sociodemographic correlates of anogenital Human Papillomavirus (HPV) carriage in a cross-sectional, multi-ethnic, community-based Asian male population.

BACKGROUND: Addressing the burden of HPV-associated diseases among men is increasingly becoming a public health issue. The main objective of this study was to determine HPV prevalence among a healthy community-based Malaysian men. METHOD: This was a cross-sectional study that recruited 503 healthy males from 3 community-based clinics in Selangor, Malaysia. Genital and anal samples were collected from each participant for 14 high risk and 2 low risk HPV DNA detection and genotyping. All participants responded to a set of detailed sociodemographic and sexual behaviour questionnaire. RESULTS: The median age at enrolment was 40 years old (IQR: 31-50). The anogenital HPV6/11 prevalence was 3.2% whereas high risk HPV prevalence was 27.1%. The genital HPV prevalence for HPV6/11 was 2.9% while high risk HPV was 18.8%. HPV6/11 prevalence in the anal canal was 1.6% and high risk HPV was 12.7%. HPV 18 was the most prevalent genotype detected in the anogenital area. There was a significant independent association between genital and anal HPV infections. CONCLUSION: Anogenital HPV infection is common among Malaysian men. These findings emphasize the ubiquity of HPV infection and thus the value of population-wide access to HPV prevention.

Autophagy is induced in human keratinocytes during human papillomavirus 11 pseudovirion entry.

Human papillomavirus type 11 (HPV11) is one of the main causes of condyloma acuminatum, a widespread sexually transmitted disease. During infection of its primary target cell, keratinocytes, it is likely to encounter the autophagy pathway, which is an intracellular maintenance process that is also able to target invading pathogens. It is currently unknown whether HPV11 is targeted by autophagy or whether it is able to escape autophagy-mediated killing. Here, we investigated the autophagy response during HPV11 pseudovirion (PsV) entry in human keratinocytes. Transmission electron microscopy showed that intracellular PsVs were sequestered in lumen of double-membrane autophagosomes that subsequently appeared to fuse with lysosomes, while confocal microscopy showed induction LC3 puncta, the hallmark of induced autophagy activity. Furthermore, quantitative infection assays showed that high autophagy activity resulted in reduced HPV11 PsV infectivity. Therefore, the autophagy pathway seemed to actively target invading HPV11 PsVs for destruction in the autolysosome. Western analysis on the phosphorylation state of autophagy regulators and upstream pathways indicated that autophagy was activated through interplay between Erk and Akt signaling. In conclusion, autophagy functions as a cellular protection mechanism against intracellular HPV11 and therefore therapies that stimulate autophagy may prevent recurrent condyloma acuminatum by helping eliminate latent HPV11 infections.

Sex differences in the prevalence and determinants of HPV-related external genital lesions in young adults: a national cross-sectional survey in Brazil.

BACKGROUND: External genital lesions (EGL) are the most common sexually transmitted infections (STIs). We aimed to evaluate the prevalence, determinants and sex differences in EGL among young adults from Brazil. METHODS: Overall, 7694 participants (aged 16 to 25 years) underwent an interview, genital examination and sampling for HPV genotyping. RESULTS: The prevalence of EGL was 4.08% (234) and is more frequent in men (5.72%) than women (2.31%) (p <  0.001). Genital lesions were significantly associated with male sex, infection by high-risk and multiple HPV types, having more than two sexual partners in the last year, smoking status and the presence of other STI. While alcohol use was associated with a higher prevalence of EGL in women, same-sex sexual relationship increase the prevalence in men. In the EGL group, 67.79% (p = 0.032) were positive for HPV infection and the types HPV6 and HPV11 were the most prevalent ones. CONCLUSION: The prevalence of EGL in young adults was consistently high, and most cases were associated with genital HPV infection and STIs. Although men have a higher prevalence, both sexes share most genital lesion determinants. The promotion of sexual education and vaccination especially focus in young men, who are usually outside the targets of primary health care programmes, can prevent EGL in Brazilian young adults.

Implication of low risk human papillomaviruses, HPV6 and HPV11 in laryngeal papillomatosis in Burkina Faso.

PURPOSE: Laryngeal papillomatosis is the most common benign tumor of the larynx of children. It is characterized by the development of exophytic proliferative lesions in the mucosa of the airways. Human papillomavirus (HPV) has been recognized as a causal agent among which HPV types 6 and 11 are the most frequently implicated. This disease affects the vocal cords and other important functions of the child. The difficulty of treatment is related to the high recurrence of papilloma growth after surgical removal. The objective of this study was to describe the implication of HPV6 and HPV11 in cases of laryngeal papillomatosis histologically confirmed in Ouagadougou. MATERIALS AND METHODS: This was a descriptive cross-sectional study based on histologically diagnosed archival tissue; obtained in the last ten years (2007 to 2017) in the anatomy and cyto-pathology laboratories in Burkina Faso. These fixed and paraffin-embedded tissues were deparaffinized with xylene before HPV DNA extraction; then HPV6 and HPV 11 were identified by real-time multiplex PCR. RESULTS: The prevalence of low-risk HPV infection (HPV-LR) was 54.84% in histologically confirmed laryngeal papillomatosis in Ouagadougou. Among the HPV-LR positive samples, HPV6 and HPV11 genotype prevalence's were respectively 41.17% and 35.3% while the HPV6 / HPV11 co-infection was 23.53%. CONCLUSIONS: The results show the implication of HPV6 and HPV11 in laryngeal papillomatosis in Burkina Faso with a high prevalence.

Prevalence and incidence of genital warts and cervical Human Papillomavirus infections in Nigerian women.

BACKGROUND: Genital warts are important causes of morbidity and their prevalence and incidence can be used to evaluate the impact of HPV vaccination in a population. METHODS: We enrolled 1020 women in a prospective cohort study in Nigeria and followed them for a mean (SD) of 9 (4) months. Nurses conducted pelvic examinations and collected ectocervical samples for HPV testing. We used exact logistic regression models to identify risk factors for genital warts. RESULTS: The mean age of study participants was 38 years, 56% (535/962) were HIV-negative and 44% (427/962) were HIV-positive. Prevalence of genital warts at enrolment was 1% (4/535) among HIV-negative women, and 5% (23/427) among HIV-positive women. Of 614 women (307 HIV negative and 307 HIV positive women) for whom we could compute genital wart incidence, it was 515 (95% CI:13-2872) per 100,000 person-years in HIV-negative and 1370 (95% CI:283-4033) per 100,000 person-years in HIV-positive women. HIV was associated with higher risk of prevalent genital warts (OR:7.14, 95% CI:2.41-28.7, p < 0.001) while higher number of sex partners in the past year was associated with increased risk of incident genital warts (OR:2.86, 95% CI:1.04-6.47. p = 0.04). HPV11 was the only HPV associated with prevalent genital warts in this population (OR:8.21, 95% CI:2.47-27.3, p = 0.001). CONCLUSION: Genital warts are common in Nigeria and our results provide important parameters for monitoring the impact of future HPV vaccination programs in the country. HIV infection and number of sexual partners in past year were important risk factors for prevalent and incident genital warts respectively.

Development of a human papillomavirus type 6/11 vaccine candidate for the prevention of condyloma acuminatum.

Condyloma acuminatum (CA) represents a significant human papillomavirus (HPV) disease burden worldwide, resulting in substantial healthcare costs and loss of life quality in both genders. To address this problem, we tried to develop a bivalent HPV6/11 virus-like particle (VLP) vaccine targeting CA. HPV6/11 VLPs were generated in Hansenula polymorpha, and a disassembly and reassembly (D/R) treatment was further conducted to improve the stability and monodispersity of the VLPs. The HPV6/11 VLPs were identified by transmission electron microscopy (TEM), high performance liquid chromatography (HPLC), mass spectrum (MS) and dynamic light scattering (DLS), and were evaluated for their immunogenicity in both mice and cynomolgus monkeys. The results showed that the HPV6/11 L1 proteins were correctly expressed and assembled into HPV6/11 VLPs, and the HPV6/11 VLPs formulated with aluminum phosphate induced vigorous production of specific neutralizing antibodies against HPV6/11 VLPs in mice and cynomolgus monkeys. These data indicated that the Hansenula polymorpha-derived HPV6/11 VLPs could be formulated into a bivalent vaccine used in prevention of CA.

Papilomatosis respiratoria recurrente con compromiso pulmonar y de la pared torácica: una rara complicación en un adolescente / Recurrent respiratory papillomatosis with lung and chest wall involvement: A rare complication in an adolescent

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Recurrent respiratory papillomatosis: A state-of-the-art review.

Recurrent respiratory papillomatosis (RRP) is a benign disease of the upper aero-digestive tract caused by human papillomavirus (HPV) infection, which affects children and young adults. The aim of this review is to describe the main etiological, epidemiological, clinical, diagnostic, and treatment aspects of RRP. Most infections in children occur at birth, during passage through the birth canals of contaminated mothers. In adults, HPV is transmitted sexually. Papillomas usually appear as exophytic nodules, primarily in the larynx, but occasionally involving the nasopharynx, tracheobronchial tree, and pulmonary parenchyma. The disease course is unpredictable, ranging from spontaneous remission to aggressive persistent or recurrent disease. Although it occurs rarely, RRP has the potential for malignant transformation to squamous cell carcinoma. Clinically, RRP usually presents with nonspecific symptoms of airway involvement, including chronic cough, hoarseness, wheezing, voice change, stridor, and chronic dyspnea. Helical computed tomography (CT) is highly accurate for the identification and characterization of focal or diffuse airway narrowing caused by nodular vegetant lesions. The typical CT pattern of lung papillomatosis consists of numerous multilobulated nodular lesions of various sizes, frequently cavitated, scattered throughout the lungs. Bronchoscopy is the most reliable method for the diagnosis of RRP; it enables direct visualization of lesions in the central airways and collection of biopsy samples for histopathological diagnosis, and is also useful for therapeutic planning. The definitive diagnosis of RRP is based on histopathological analysis. Currently, no definitive curative treatment for RRP is available; despite the availability of adjunctive treatments, surgery remains the mainstay of treatment.

Disfonía infantil precoz como síntoma de alerta de la papilomatosis laríngea juvenil / Early infantile dysphonia as an alert symptom of juvenile laryngeal papillomatosis

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Role of histological findings and pathologic diagnosis for detection of human papillomavirus infection in men.

Early HPV infection in males is difficult to detect clinically and pathologically. This study assessed histopathology in diagnosing male genital HPV. External genital lesions (n = 352) were biopsied, diagnosed by a dermatopathologist, and HPV genotyped. A subset (n = 167) was diagnosed independently by a second dermatopathologist and also re-evaluated in detail, tabulating the presence of a set of histopathologic characteristics related to HPV infection. Cases that received discrepant diagnoses or HPV-related diagnoses were evaluated by a third dermatopathologist (n = 163). Across dermatopathologists, three-way concordance was fair (k = 0.30). Pairwise concordance for condyloma was fair to good (k = 0.30-0.67) and poor to moderate for penile intraepithelial neoplasia (k = -0.05 to 0.42). Diagnoses were 44-47% sensitive and 65-72% specific for HPV 6/11-containing lesions, and 20-37% sensitive and 98-99% specific for HPV 16/18. Presence of HPV 6/11 was 75-79% sensitive and 35% specific for predicting pathologic diagnosis of condyloma. For diagnosis of penile intraepithelial neoplasia, HPV 16/18 was 95-96% specific but only 40-64% sensitive. Rounded papillomatosis, hypergranulosis, and dilated vessels were significantly (P < 0.05) associated with HPV 6/11. Dysplasia was significantly (P = 0.001) associated with HPV 16/18. Dermatopathologists' diagnoses of early male genital HPV-related lesions appear discordant with low sensitivity, while genotyping may overestimate clinically significant HPV-related disease. Rounded papillomatosis, hypergranulosis, and dilated vessels may help establish diagnosis of early condyloma.

Vacunas frente al VPH / No disponible

Esta revisión se centra en publicaciones de los ensayos clínicos de fase II y III llevados a cabo con dos vacunas profilácticas frente al VPH: Gardasil(R) (Merck & Co., Inc., Whitehouse Station, NJ, Estados Unidos), una vacuna cuadrivalente que contiene partículas similares a virus (VLPs) de la región L1 de los tipos del VPH 6, 11, 16 y 18, y CervarixTM (GlaxoSmithKline Biologicals, Rixensart, Bélgica), una vacuna bivalente que contiene VLPs de los tipos del VPH 16 y 18. En la actualidad, los análisis de fin de estudio de los ensayos clínicos de fase III de estas vacunas ya se han completado y se dispone de un amplio tiempo de seguimiento desde su inicio en los años 2000-1. La evidencia científica sobre el perfil de seguridad, inmunogenicidad y eficacia de las dos vacunas VPH está bien establecida. Ambas vacunas obtuvieron resultados excelentes de seguridad. Los efectos adversos más frecuentes fueron reacciones leves a moderadas en el lugar de la inyección sin diferencias significativas en la aparición de efectos adversos sistémicos graves y no graves en los grupos vacunados respecto a los grupos control. Altamente inmunogénicas, ambas vacunas inducen títulos elevados de anticuerpos en virtualmente todos los vacunados y constantes a lo largo de los años. Ambas vacunas han demostrado ser altamente eficaces y presentar eficacias similares para prevenir un amplio abanico de variables clínicas en mujeres jóvenes (15 a 26 años): desde infecciones persistentes cervicales hasta CIN3 en mujeres naïve para el tipo de VPH correspondiente en el momento de la vacunación. Hasta la fecha no hay signos de disminución de la protección a lo largo del tiempo. Ambas vacunas también presentan protección cruzada parcial frente a infección y enfermedad causadas por un número limitado de VPHs no vacunales relacionados filogenéticamente. La infección por un tipo de VPH vacunal no inhibe la prevención para el resto de tipos de VPH vacunales. Sin embargo, las vacunas no tienen acción terapéutica para inducir regresión o prevenir la progresión de infecciones ya establecidas. Gardasil(R) también ha demostrado alta protección frente a verrugas genitales y neoplasia vulvar/vaginal asociada a los tipos de VPH vacunales. En otros ensayos, Gardasil(R) ha demostrado también protección frente a infección incidente y CIN en mujeres de 25 a 45 años. Gardasil(R) también ha demostrado protección en hombres frente a infección incidente, verrugas genitales y AIN por los tipos de VPH vacunales. Por su lado, Cervarix(R) también ha demostrado protección frente a infecciones anales y de la cavidad oral por los tipos de VPH incluidos en la vacuna. Los estudios puente de immunogenicidad y seguridad en niñas y niños adolescentes muestran excelentes respuestas immunitarias y de seguridad. Estos resultados de noinferioridad de respuesta a las mujeres jóvenes prevén una gran efectividad para los programas de vacunación adolescente. Los excelentes resultados de estos estudios han llevado a las agencias reguladoras nacionales de numerosos países a autorizar el uso de Gardasil(R) y Cervarix(R) y a la financiación pública de amplias campañas de vacunación en mujeres preadolescentes y en algunos países en mujeres adolescentes, adultas jóvenes y/o hombres. Los primeros datos de impacto poblacional nos presentan un futuro muy optimista. Las vacunas VPH han presentado una efectividad muy alta frente a las verrugas genitales en países que han implementado programas de vacunación sistemática con altas coberturas. Las verrugas genitales son el primer resultado clínico evaluable debido al intervalo corto de tiempo entre infección incidente y progresión a enfermedad clínica. Sin embargo, todavía faltan unos años para poder evaluar completamente la efectividad de esta intervención y en todo el espectro de enfermedad relacionada con el VPH. Múltiples estudios post-autorización están en curso y el seguimiento de las cohortes vacunadas en los grandes ensayos de fase III continúa

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Number of external anogenital warts is associated with the occurrence of abnormal cervical cytology.

BACKGROUND: Anogenital warts (AGWs) are common results of sexually transmitted infection (STI). Human papillomavirus (HPV) types 6 and 11, which are non-oncogenic types, account for 90% of the clinical manifestations. Although the quadrivalent HPV vaccine has been launched, AGW remains prevalent in some countries and shows association with abnormal cervical cytology. OBJECTIVES: To study the prevalence of abnormal cervical cytology (low grade squamous intraepithelial lesions or worse; LSIL+) in immunocompetent Thai women newly presenting with external AGWs. MATERIALS AND METHODS: Medical charts of all women attending Siriraj STI clinic during 2007-2011 were reviewed. Only women presenting with external AGWs who were not immunocompromised (pregnant, human immunodeficiency virus positive or being on immunosuppressant drugs) and had not been diagnosed with cervical cancer were included into the study. Multivariate analysis was used to determine the association between the characteristics of the patients and those of AGWs and LSIL+. RESULTS: A total of 191 women were eligible, with a mean age of 27.0±8.9 years; and a mean body mass index of 20.6±8.9 kg/m2. Half of them finished university. The most common type of AGWs was exophytic (80.1%). The posterior fourchette appeared to be the most common affected site of the warts (31.9%), followed by labia minora (26.6%) and mons pubis (19.9%). The median number of lesions was 3 (range 1-20). Around 40% of them had recurrent warts within 6 months after completing the treatment. The prevalence of LSIL+ at the first visit was 16.3% (LSIL 12.6%, ASC-H 1.1%, HSIL 2.6%). After adjusting for age, parity and miscarriage, number of warts ≥ 5 was the only factor associated with LSIL+ (aOR 2.65, 95%CI 1.11-6.29, p 0.027). CONCLUSIONS: LSIL+ is prevalent among immunocompetent Thai women presenting with external AGWs, especially those with multiple lesions.

Recombination-dependent oligomerization of human papillomavirus genomes upon transient DNA replication.

We describe the extensive and progressive oligomerization of human papillomavirus (HPV) genomes after transfection into the U2OS cell line. The HPV genomic oligomers are extrachromosomal concatemeric molecules containing the viral genome in a head-to-tail orientation. The process of oligomerization does not depend on the topology of the input DNA, and it does not require any other viral factors besides replication proteins E1 and E2. We provide evidence that oligomerization of the HPV18 and HPV11 genomes involves homologous recombination. We also demonstrate oligomerization of the HPV18 and HPV11 genomes in SiHa, HeLa, and C-33 A cell lines and provide examples of oligomeric HPV genomes in clinical samples obtained from HPV-infected patients.

Quadrivalent HPV vaccine efficacy against disease related to vaccine and non-vaccine HPV types in males.

A small number of HPV types are related to a majority of HPV-related neoplastic lesions in humans. High-risk types such as HPV 16 and 18 are most often implicated, although other oncogenic and non-oncogenic HPV types can cause disease in men. The efficacy of the quadrivalent HPV vaccine (qHPV) against external genital lesions and intra-anal disease related to HPV in men has been demonstrated. This report examines the vaccine's efficacy against disease due to 10 additional non-vaccine HPV types, as well as efficacy regardless of HPV detection. The data presented suggest that vaccinating males against HPV 6, 11, 16 and 18 protects them against most vaccine HPV-type related anogenital disease. However, significant efficacy against disease due to non-vaccine HPV types was not seen. In addition, the data do not provide any evidence that vaccination with qHPV vaccine will increase the likelihood of disease caused by non-vaccine types in the short term.

Laser capture microdissection shows HPV11 as both a causal and a coincidental infection in cervical cancer specimens with multiple HPV types.

AIMS: To identify, by laser capture microdissection (LCM), the cellular localization of HPV11 when present with carcinogenic HPV in invasive cervical cancer (ICC) specimens, and to relate this to p16(INK) (4a) expression. METHODS AND RESULTS: Three squamous cell ICC specimens showing coinfection with HPV11 and carcinogenic HPV16 or HPV31 were selected from the Institut Català d'Oncologia international survey of anogenital carcinomas, and coinfection was confirmed by SPF10 -DEIA-LiPA25 analysis. In two cases LCM-PCR identified HPV11 in low-grade and high-grade squamous intraepithelial lesions (SILs) adjacent to the ICC, and HPV16 or HPV31 in the ICC. In one case, HPV11 was the only genotype found in the ICC. P16(INK) (4a) expression was diffuse in ICC associated with carcinogenic HPV, but focal in ICC with HPV11. CONCLUSIONS: Our results confirm that a single cervical, cancerous or precancerous lesion is associated with a single HPV type. Detecting low-risk HPV as a coinfection in whole tissue from ICC does not prove a causal association. HPV11 may be found only in an adjacent SIL with carcinogenic HPV in the ICC. It is also found alone in carcinoma. LCM-PCR and differential P16(INK) (4a) expression can clarify the causal role of each type when multiple HPVs are present in whole tissue from carcinomas.

Genomic differences in the background of different severity in juvenile-onset respiratory papillomatoses associated with human papillomavirus type 11.

This study aimed to compare complete genome sequences of human papillomavirus (HPV) type 11 from two solitary papillomas (considered minimally aggressive), two moderately (six and nine episodes) and two highly aggressive (30 and 33 episodes) juvenile-onset respiratory papillomatoses. Genomic regions were sequenced using the Sanger method; sequences were compared to available GenBank genomes. Activity of the long control region (LCR) was assessed in HEp-2 cell line using luciferase assays and compared to that of the reference (GenBank Accession Number M14119). Site-directed mutagenesis was performed to confirm the association of polymorphisms with differences in LCR activity. Eleven alterations resulted in amino acid changes in different open reading frames. A72E in E1 and Q86K in E2 proteins were exclusively present in a moderately aggressive disease, L1 alterations A476V and S486F were unique to a severe papillomatosis. HPV11s in both solitary papillomas had identical LCRs containing a T7546C polymorphism, which strongly attenuated LCR activity, as confirmed by site-directed mutagenesis. This strong attenuator polymorphism was also present in the other four genomes showing significantly higher activities, but in these other alterations with demonstrable but statistically not significant attenuating (A7413C, 7509 T deletion) or enhancing (C7479T, T7904A) effect on transactivating potential (as demonstrated by site-directed mutagenesis) were also detected. LCR activities corresponded well to severity, excepting the highly aggressive papillomatosis with the L1 alterations. Presence of intratypic variants cannot explain differences in severity of respiratory papillomatoses associated with HPV11; virulence seems to be determined by the interaction of multiple genetic differences.

Human papillomavirus and cervical cancer.

Cervical cancer is caused by human papillomavirus infection. Most human papillomavirus infection is harmless and clears spontaneously but persistent infection with high-risk human papillomavirus (especially type 16) can cause cancer of the cervix, vulva, vagina, anus, penis, and oropharynx. The virus exclusively infects epithelium and produces new viral particles only in fully mature epithelial cells. Human papillomavirus disrupts normal cell-cycle control, promoting uncontrolled cell division and the accumulation of genetic damage. Two effective prophylactic vaccines composed of human papillomavirus type 16 and 18, and human papillomavirus type 16, 18, 6, and 11 virus-like particles have been introduced in many developed countries as a primary prevention strategy. Human papillomavirus testing is clinically valuable for secondary prevention in triaging low-grade cytology and as a test of cure after treatment. More sensitive than cytology, primary screening by human papillomavirus testing could enable screening intervals to be extended. If these prevention strategies can be implemented in developing countries, many thousands of lives could be saved.