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High-risk human papilloma virus (HR-HPV) persistent infection is closely associated with the development of cervical cancer and squamous intraepithelial lesion (SIL).The α-9 HPVs, which is predominantly composed of HR-HPV types, account for 75% of HR-HPV infection in Sichuan. The oncoproteins E6 and E7 of HPV play a crucial role in tumor initiation and progression. Notably, HPV-35 is the only HR-HPV type within the α-9 genus that is not included in the nine-valent HPV prophylactic vaccine. Cervical cell samples obtained from Sichuan were collected for HPV detection and genotyping. Among the 406 HPV-positive samples, 31 HPV-35 were detected, 24 HPV-35 E6 and 26 E7 were successfully amplified and sequenced, five nucleotide mutations in E6 and three in E7 were detected, T232C, T434G of E6 (W78R, I145R) and C67T, G84T of E7 (H23Y, L28F) were non-synonymy mutation. PAML 4.8 server was used to detect positive selection sites of HPV-35 E6, E7, and E6 is W78R. Phyre2 were used to predict and analyze protein structures, W78R made influences on protein structure. IEDB were used to screen epitopes vaccine target for HPV-35 affection therapy, and 5 HPV-35 E6 and 3 HPV-35 E7 most potential epitopes were obtained, the most potential peptides for therapy vaccine design were 79-91YRYSVYGETLEKQ, 45-60FACYDLCIVREGQPY, 124-135RFHNIGGRWTGR of E6; 3-19GEITTLQDYVLDLEPEA, 38-47TIDGPAGQAK, 70-88VQSTHIDIRKLEDLLMGTF of E7 and W78R mainly decreased the epitopes affinity.Conclusions Amino acid substitution in the positive selection sites of HPV-35 E6 and E7 genes have been found to influence protein structure and to decrease the overall affinity of antigen epitopes. This observation aligns with the evolutionary significance of positive selection site, which may confer advantages to the virus by making infected cells more challenging for the immune system to detect, thereby enhancing HPV's adaptability to the host environment. The polymorphism analysis of HPV-35 E6, E7 contributes to the enrichment of α-9 HPV data in Sichuan China, which is instrumental in improving the effectiveness of clinical detection. Furthermore, these findings provide a relevant theoretical foundation for the prevention and treatment of HPV-related diseases., (© 2024. The Author(s).)

Human papillomavirus (HPV) type 81 has recently become one of the most common low-risk HPV types; however, literature focusing on it is limited. This study aimed to analyze the reasons for the increased detection rate of HPV81 and investigate its evolving pathogenicity. We analyzed the detection rates and trends of HPV81 in 229 061 exfoliated cervical cell samples collected from 2014 to 2023; collected samples of HPV81 single infections from two different time periods; and analyzed the allele frequencies, positive selection, viral load, persistent infection capacity, and pathogenicity of E6 and E7 genotypes. We found that the detection rate of HPV81 ranked first among the low-risk types in exfoliated cervical cells and exhibited a significantly increasing trend (p < 0.001). The frequency of the E6 prototype allele of HPV81 (n = 317) was significantly increased (p = 0.018) and demonstrated the strongest adaptive capacity. The viral load and persistent infection capacity of the E6 prototype were significantly higher than those of the mutants, thus serving as key drivers for increasing the detection rate of HPV81 and enhancing its pathogenicity. The viral load was positively correlated with persistent infection capacity and pathogenicity. Persistent infection was a crucial factor in the pathogenicity of HPV81. Successful adaptive evolution of HPV81 is accompanied by enhanced pathogenicity., (© 2024 Wiley Periodicals LLC.)

Background: Cervical cancer (CC) is a significant global public health concern, particularly in developing countries such as Colombia. The main risk factor involves high-risk HPV types (HR-HPV) infection, coupled with population-specific variables. The Caribbean region in Colombia lacks research on HR-HPV-type frequencies. Therefore, this study aims to establish the prevalence of type-specific HR-HPV and its association with sociodemographic factors among women undergoing cervical cytology screening., Methods: A cross-sectional study involving voluntary women who provided informed consent and completed a questionnaire capturing sociodemographic, clinical, and sexual behavior information was conducted. All participants underwent cervical cytology and molecular analysis. Generic HPV detection employed three simultaneous PCRs (GP5+/6+, MY09/11, and PU1R/2 M), and positive samples were genotyped using the Optiplex HPV Genotyping kit. The analysis encompassed the 12 types of high-risk HPV (HR-HPV-16,-18,-31,-33,-35,-39,-45,-51,-52,-56,-58, and - 59). Frequencies were reported based on geographic subregions within the Córdoba department, and disparities were made between single and multiple infections. Sociodemographic and clinical variables were subjected to ordinal logistic regression, with statistical significance at a p-value < 0.05. The statistical analyses utilized STATA 14® and R-Core Team-software., Results: We included 450 women, mean age 40 (SD±11.44). PCR analysis revealed 43% HPV-positive (n=192). GP5+/6+ detected the most positives at 26% (n=119), followed by PU1R/2 M at 22% (n = 100) and MY09/11 at 15% (n=69). Multiple infections occurred in 87.3% (n=142), primarily 2 to 4 types (47.37%, n=90). Dominant types were HPV-18 (15.6%, n=61), HPV-16 (14.9%, n=58), HPV-31 (13.0%, n = 51), and HPV-45 (11.5%, n=45). Logistic regression identified age above 60 as a risk for concurrent multiple types (OR=6.10; 95% CI 1.18-31.63). Menopause was protective (OR=0.31; 95% CI 0.11-0.89)., Conclusions: Our study reveals a notable prevalence of multiple (2-4) high-risk HPV infections among adult women engaged in CC detection initiatives. Predominantly, α7 species constitute the prevalent HR-viral types, with the Medio Sinú subregion showing elevated prevalence. Menopausal status confers protection against diverse HR-HPV infections. Nevertheless, advancing age, particularly beyond 60 years, is linked to an increased susceptibility to simultaneous infections by multiple HPV-types., (© 2024. The Author(s).)

Cervical cancer is closely linked to specific strains of human papillomavirus (HPV), notably HPV-33 and HPV-58, which exhibit a significant prevalence among women in China. Nevertheless, the codon usage bias in HPV-33 and HPV-58 is not well comprehended. The objective of this research is to analyze the codon usage patterns HPV-33 and HPV-58, pinpoint the primary factors that influence codon preference. The overall preference for codon usage in two HPV genotypes is not significant. Both HPV genotypes exhibit a preference for codons that end with A/U. The GC3 content for HPV-33 is 25.43% ± 0.35%, and for HPV-58, it is 29.44% ± 0.57%. Out of the 26 favored codons in HPV-33 and HPV-58 (relative synonymous codon usage (RSCU) > 1), 25 conclude with A/U. Principal component analysis (PCA) shows a tight clustering of the entire genome sequences of HPV-33 and HPV-58, suggesting a similarity in their RSCU preferences. Moreover, an examination of dinucleotide abundance indicated that translation selection influenced the development of a distinctive dinucleotide usage pattern in HPV-33 and HPV-58. Additionally, a combined analysis involving an effective number of codons plot, parity rule 2, and neutrality analysis demonstrated that, for HPV-33 and HPV-58, the primary determinant influencing codon usage preference is natural selection. HPV-33 and HPV-58 exhibit a restricted set of favored codons in common with humans, potentially mitigating competition for translation resources. Our discoveries could provide valuable perspectives on the evolutionary patterns and codon usage preferences of HPV-33 and HPV-58 viruses, contributing to the development and application of relevant HPV subtype vaccines., (© 2024 Wiley‐VCH GmbH.)

The authors compared the clinical performance of DH3 human papillomavirus (HPV) assay, which detects 14 high-risk HPVs with 16/18 genotyping based on hybrid capture technique, and Hybrid Capture 2 (HC2) test for women undergoing cervical cancer screening. A total of 7, 263 residual cytology specimens from an adjudicated cohort with 3-year follow-up were tested by the DH3 assay and the HC2 test. Assay results were compared with each other and to histology review. The overall agreement between the DH3 assay and the HC2 test was 99.2% (κ = 0.938). At baseline, DH3 had the equal sensitivity to that of HC2 for cervical intraepithelial neoplasia (CIN) grade 2 or higher (CIN2+, n  = 75) and CIN grade 3 or higher (CIN3+, n  = 45), 98.67% and 97.78%, respectively. After 3 years of follow-up, the sensitivity for CIN2+ ( n  = 133) and CIN3+ ( n  = 74) were both similar between DH3 and HC2 (95.49% vs 94.74%, 95.95% vs 95.95%, respectively, all P  > 0.05). The respective specificity for CIN2+ or CIN3+ did not differ between the two tests. A noninferiority test showed that both sensitivity and specificity of DH3 for CIN2+ and CIN3+ were noninferior to those of HC2 at baseline and after 3-year follow-up, respectively (all P  < 0.001). When used in primary screening strategy, the DH3 assay would yield an immediate sensitivity of 92% for CIN2+. DH3 HPV performs equally to HC2 for the detection of high-grade lesions in cervical cancer screening and has a potential advantage in primary screening strategy due to HPV16/18 genotyping. IMPORTANCE The benefits of testing for high-risk human papillomavirus (hrHPV) in cervical cancer screening have already been demonstrated. Hybrid Capture 2 (HC2) is the best validated HPV assay and has been considered the gold standard for hrHPV testing. However, HC2 cannot discriminate HPV16 and 18 from the other hrHPV types, which greatly limited the application of HC2 in cervical cancer screening. The DH3 human papillomavirus (HPV) is a recently developed assay based on hybrid capture technique like to HC2, which can specifically identify HPV 16/18 on the basis of detecting the 13 hrHPV types targeted by HC2 as well as HPV66. This comparative study of the two assays for detection of hrHPV infection in residual cytology samples from cervical cancer screening setting reveals that DH3 HPV provides a perfect alternative to HC2 in detecting hrHPV infection and identifying cervical precancer, while allowing concurrent HPV 16/18 genotyping.

HPV68 is a common HR-HPV, its persistent infection is closely related with the occurrence of cervical cancer. In this study, 2939 (27.60%, 2939/10650) positive samples were detected, and 174 (5.92%, 174/2939) were HPV68. 150 HPV68 E6-E7 were successful sequenced, 4 non-synonymous mutations were detected in E6, and E7 were 12. N133S non-synonymous mutations of HPV 68 E6 and C67G, T68 A/M of HPV68 E7 are E6, E7 positive selection sites, they all located in the key domains and major motifs of E6/E7 protein, the above amino-acid substitutions changed the protein structure, disturbed the interaction with other protein or cellular factors and make a difference in epitopes affinity, may affect the pathogenicity and adaptability of HPV68 to the environment. The enrichment of HPV68 data is of great significance for understanding the inherent geographical and biological differences of HPV68 in China., (Copyright © 2021. Published by Elsevier Inc.)

Human papillomaviruses (HPVs) are an ancient and highly successful group of viruses that have co-evolved with their host to replicate in specific anatomical niches of the stratified epithelia. They replicate persistently in dividing cells, hijack key host cellular processes to manipulate the cellular environment and escape immune detection, and produce virions in terminally differentiated cells that are shed from the host. Some HPVs cause benign, proliferative lesions on the skin and mucosa, and others are associated with the development of cancer. However, most HPVs cause infections that are asymptomatic and inapparent unless the immune system becomes compromised. To date, the genomes of almost 450 distinct HPV types have been isolated and sequenced. In this Review, I explore the diversity, evolution, infectious cycle, host interactions and disease association of HPVs., (© 2021. This is a U.S. government work and not under copyright protection in the U.S.; foreign copyright protection may apply.)

Human papillomavirus (HPV) is the most common sexually transmitted agent worldwide. Early prevention with HPV vaccination is a safe and effective method against this disease. HPV vaccines provided more protection against several oncogenic HPV strains. Three prophylactic HPV vaccines have been approved to target high-risk HPV types and protect against HPV-related disorders. These existing vaccines are based on the recombinant DNA technology and purified L1 protein that is assembled to form HPV empty shells. The prophylactic vaccines are highly immunogenic and can induce production of specific neutralizing antibodies. However, therapeutic vaccines are different from these prophylactic vaccines. They induced cell-mediated immunity against transformed cells, instead of neutralizing antibodies. The second generation of prophylactic HPV vaccines, made from alternative viral components using cost-effective production strategies, is undergoing clinical evaluation. The purpose of this review is to provide a complete and up-to-date review of the types of HPV vaccines and the efficiency of each of them for readers., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2022 Yousefi, Aria, Ghaedrahmati, Bakhtiari, Azizi, Bastan, Hosseini and Eskandari.)

The prevalence of HPV infection and its relationship with other sexually transmitted infections was analyzed in a cohort of 117 male partners of infertile couples from Cordoba, Argentina. Semen samples and urethral swabs were obtained and the infection with HPV, Chlamydia trachomatis, HSV1, HSV2, Mycoplasma hominis and Ureaplasma urealyticum was analyzed. A prevalence of HPV infection of 27.4% was found. Interestingly, infections by exclusively low risk HPV genotypes or high/intermediate risk HPV genotypes were present in 64.5% and 22.6% of cases, respectively. Low risk-HPV6 was the most frequently detected genotype. Remarkably, HPV and C. trachomatis infections were significantly associated to each other (OR: 11.55, 95% CI 1.14-117.06). No significant differences in sperm quality were found between HPV-positive and HPV-negative patients indicating that HPV male urogenital infection does not impair sperm quality. Our results show a high prevalence of HPV urogenital infection among male partners of infertile couples, and that HPV and C. trachomatis infections are reciprocal risk factors of their co-infection. Moreover, our results suggest that men constitute a reservoir for continued transmission of C. trachomatis and HPV to women highlighting the need for routine screening for these two pathogens in male partners of infertile couples., (© 2021. The Author(s).)

Background: Anal infection with high-risk human papillomavirus (HPV) genotypes 16 and 18 and anal cancer are overrepresented in men who have sex with men (MSM). This study investigated HPV prevalence in young MSM before and after the implementation of a school-based quadrivalent HPV (genotypes 6, 11, 16, and 18) vaccination programme for boys in Australia in 2013., Methods: In this repeated cross-sectional study, MSM aged 16-20 years were recruited from two successive birth cohorts via sexual health clinics and the community in Melbourne, Australia. The first cohort was before the implementation of gender-neutral vaccination (HYPER1 study, done in 2010-12, NCT01422356), and the second was the post-vaccination cohort (HYPER2 study, done in 2017-18, NCT03000933). Men who self-identified as being same-sex attracted were enrolled, and those recruited via the HYPER2 study had to be resident in Australia since 2013 to ensure eligibility. Study procedures were done in the Melbourne Sexual Health Centre. A clinician-collected anal swab and self-collected penile swab and oral rinse were tested for 28 HPV genotypes, and data on demographics and sexual health practices were collected via questionnaires. Only assessable samples were included in the analyses. We compared anatomical site-specific prevalence of HPV genotypes between cohorts by calculating the prevalence ratio, adjusting for age, circumcision, and sex with women. Herd protection was also assessed, by calculating the adjusted prevalence ratios by vaccination status., Findings: 400 MSM, 200 per cohort, were included in the study. In both cohorts, the median number of lifetime male partners was ten (IQR 5-25). The prevalence of any anal quadrivalent vaccine-preventable HPV genotype was higher in the pre-vaccination cohort (54 [28%] of 193) than in the post-vaccination cohort (14 [7%] of 193; adjusted prevalence ratio [PR] 0·24, 95% CI 0·14-0·42), largely driven by decreases in HPV6, followed by HPV11, 16, and 18. Nevertheless, there was also a significant reduction in anal HPV16 and 18 in the post-vaccination cohort from the pre-vaccination cohort (0·31, 0·14-0·68). The prevalence of any penile quadrivalent vaccine-preventable HPV genotype was also higher in the pre-vaccination cohort (21 [12%] of 177) than in the post-vaccination cohort (11 [6%] of 179; 0·48, 0·24-0·97), driven by decreases in HPV 6 and 11, but not by 16 and 18. The prevalence of any oral quadrivalent vaccine-preventable HPV genotype was higher in the pre-vaccination cohort (seven [4%] of 200) than in the post-vaccination cohort (one [1%] of 199; 0·10, 0·01-0·97); there were no cases of oral HPV6 or 11 detected in HYPER2. Comparing the pre-vaccinated cohort with the 149 confirmed vaccinated men from HYPER2 showed a reduction in any quadrivalent vaccine-preventable HPV genotype for anal (0·09, 0·03-0·25) and penile (0·18, 0·05-0·59) infection but not for oral infection (0·17, 0·03-1·08)., Interpretation: A reduction in anal, penile, and oral quadrivalent vaccine-targeted genotypes occurred in young MSM following the implementation of a school-based gender-neutral HPV vaccination programme. The fall in anal HPV16 and 18 may lead to a reduction in the incidence of anal cancer., Funding: Merck and the Australian Government Department of Health., Competing Interests: Declaration of interests EPFC is supported by an Australian National Health and Medical Research Council (NHMRC) Emerging Leadership Investigator Grant (GNT1172873). CKF and CSB are supported by an Australian NHMRC Leadership Investigator Grant (GNT1172900 and GNT1173361, respectively). EPFC and AMC have received educational grants from Seqirus Australia and bioCSL to assist with education, training, and academic purposes in the area of HPV, outside the submitted work. CKF has received research funding from CSL Biotherapies and owns shares in CSL Biotherapies. SMG has received advisory board fees and lecture fees from Merck for work in private time and through her institution (Royal Women's Hospital) funding for an investigator initiated grant from Merck for a young women's study on HPV, and is a member of the Merck Global Advisory Board for HPV vaccination. DAM reports educational grants from Seqirus to assist with education, training, and academic purposes in the area of HPV, and travel funding and honoraria to her institute from Merck, outside of the submitted work. She is also an investigator on a genital warts surveillance grant funded by Seqirus. She also reports grants from Commonwealth Department of Health during the conduct of the study. AMC reports grants from Australian Government of Health National HPV Monitoring Program during the conduct of the study. CSB reports grants from SpeeDx outside the submitted work. EPFC, MYC, CKF, SNT, SMG, and AMC received the investigator initiated grant to conduct the HYPER2 study from Merck. All other authors have no competing interests to declare., (Copyright © 2021 Elsevier Ltd. All rights reserved.)

Competing Interests: We declare no competing interests.

Nonmelanoma skin cancer (NMSC) has a greatly increased incidence among the immunosuppressed and the DNA of human papillomavirus (HPV) is commonly found in these tumors. To investigate if there are any actively transcribed HPV infections in these tumors, we identified all skin cancers diagnosed after solid organ transplantation in Sweden during 1964-2011 (n = 7614 NMSCs) and requested the diagnostic tumor blocks from the corresponding pathology archives. For the present study, we selected diagnostic specimens from 345 NMSC and performed whole genome transcriptome analysis using NovaSeq (Illumina), in comparison with three cervical cancers. Although we obtained an abundance of high-quality paired reads per sample (median of 35 million reads), only 15 NMSC specimens contained HPV transcription. Three specimens had transcription of oncogenic anogenital HPVs (HPV16 and 56), six tumors had transcription of HPVs from the beta-2 species (three HPV38, two with HPV23 and one with HPV107) and then there was one observation each of transcription of HPVs 3, 26, 57, 147, 158, 168 and of two nonestablished HPV types belonging to the gamma genus. In conclusion, transcription of specific HPV types can be found in NMSC among the immunosuppressed, but this is not common., (© 2021 The Authors. International Journal of Cancer published by John Wiley & Sons Ltd on behalf of UICC.)

This paper aimed to investigate the characteristics of female HPV infection in the Shangcheng District, Hangzhou city, China. The retrospective study was designed to analyze the HPV prevalence rate of 22,382 women receiving physical examinations from 2016 to 2020 in the Shangcheng District of Hangzhou city in China. A commercial kit was designed to detect the HPV genotypes. Trends were examined for age-specific groups (≤ 30 years, 31-44 years, 45-54 years, 55-64 years,  ≥ 65 years). A receiver operating characteristic (ROC) analysis was used to assess the correlation of age classification in high risk HPV (HR-HPV) infection. 22.41% (5015/22,382) of samples were HPV positive, 91.28% (4578/5015) of HPV positive women were infected by HR-HPV. The most prevalent HR-HPV genotypes were 16, 52, 18, 58, 56, and 51. The trend of HPV prevalence showed the significant differences in age-specific groups (χ 2  = 164.70, P < 0.001). Moreover, the areas under ROC curve (AUC) was 0.712 in 55-64 years group which showed a strong contribution of age classification for HR-HPV infection. This study provided baseline data on the prevalence characteristics of HPV infection and the critical age group of HR-HPV prevalence rate was 55-64 y among the samples receiving physical examinations., (© 2021. The Author(s).)

Background: The data with regards to the regional variants of distinct HPV types is of great value. Accordance with this, this study aimed to investigate the sequence variations of E6 gene and long control region of HPV 39 among normal, premalignant and malignant cervical samples in order to characterize the frequent HPV 39 variants circulating in Tehran, Iran., Methods: In total, 70 cervical samples (45 normal, 16 premalignant, and 9 malignant samples) infected with HPV 39 were analyzed by nested-PCR and sequencing., Results: Our results revealed that all samples belonged to A lineage. Almost all sequences (98.6%) were classified in A1 sublineage and only one sample (1.4%) was A2 sub lineage., Conclusions: Our findings showed that lineages A, sublineage A1, is dominant in Tehran, Iran. However, the small sample size was the most important limitations of this study. Further studies with larger sample size from different geographical regions of Iran are necessary to estimate the pathogenicity risk of HPV 39 variants in this population., (© 2021. The Author(s).)

Human papillomavirus (HPV) infection is one of the most commonly reported sexually transmitted infections. Persistent infection is associated with the development of cervical cancer. Men may serve as a medium for HPV transmission among women, and much remains unknown about the prevalence and genotypes of HPV infection among men in Yunnan Province. This study was designed to investigate these parameters among men in this region. Clinical information was collected from January 2015 to May 2020, and 369 men who wished to undergo tests for HPV were included in this study. HPV screening was performed using the HPV GenoArray Test Kit, and the anatomical site of sample collection was the urethra. The mean age was 36.15 ± 9.08 years. Our results revealed that the prevalence of HPV infection among men was 23.85% in Yunnan Province, and there was no association between age and HPV prevalence in men. There were 72 (81.81%) individuals positive for a single HPV type, and 16 (18.19%) positive for multiple HPV types. The most prevalent oncogenic HPV types were found to be 52, 51, and 16. The most prevalent types of HPV infection were similar between men and women in this region, though the prevalence of HPV in men was relatively high.

As part of the human papillomavirus (HPV) vaccination strategy in South Africa, it is essential to have information on HPV prevalence, and HPV types distribution among the unvaccinated population. Information on the prevalence of HPV and the distribution of HPV types in adolescents and young women in South Africa's Eastern Cape Province is minimal. Therefore, this study investigates the prevalence, distribution of HPV types, and factors associated with HPV infection amongst unvaccinated female learners. A sample composed of 213 sexually active female learners attending high schools in the Eastern Cape Province of South Africa; median age 18 years, who provided self-collected vaginal specimens. Roche Linear Array HPV genotyping assay that detects 37 HPV genotypes was used to detect HPV infection. HPV infection was detected in 76.06% (162/213) of participants. Of these 14.55% (31/213) were positive for HPV types targeted by the Cervarix® HPV vaccine (HPV-16 and/or 18), 20.66% (44/213) by Gardasil®4 (HPV-6, -11, -16 and/or -18) and 37.09% (79/213) by Gardasil®9 (HPV-6, -11, -16, -18, -31, -33, -45, -52 and/or -58). HPV-35, commonly detected in cervical cancer cases among women of African ancestry, was frequently detected (9.40%). Participants who reported to have ever consumed alcohol had a significantly higher risk of HPV infection (OR: 2.91, 95% CI: 1.38-6.11, p = 0.005). High HPV prevalence was observed among participants. The high prevalence of HPV types targeted by the Gardasil®9 vaccine encourages the introduction of the Gardasil®9 vaccine. Data from this study will inform both vaccination campaigns and monitor the impact on HPV types after vaccination., Competing Interests: The authors have declared that no competing interests exist.

Human papillomaviruses (HPV) cause a subset of head and neck cancers (HNSCC). HPV16 predominantly signs responsible for approximately 10% of all HNSCC and over 50% of tonsillar (T)SCCs. Prevalence rates depend on several factors, such as the geographical region where patients live, possibly due to different social and sexual habits. Smoking plays an important role, with non-smoking patients being mostly HPV-positive and smokers being mostly HPV-negative. This is of unparalleled clinical relevance, as the outcome of (non-smoking) HPV-positive patients is significantly better, albeit with standard and not with de-escalated therapies. The results of the first prospective de-escalation studies have dampened hopes that similar superior survival can be achieved with de-escalated therapy. In this context, it is important to note that the inclusion of p16 INK4A (a surrogate marker for HPV-positivity) in the 8th TMN-classification has only prognostic, not therapeutic, intent. To avoid misclassification, highest precision in determining HPV-status is of utmost importance. Whenever possible, PCR-based methods, still referred to as the "gold standard", should be used. New diagnostic antibodies represent some hope, e.g., to detect primaries and recurrences early. Prophylactic HPV vaccination should lead to a decline in HPV-driven HNSCC as well. This review discusses the above aspects in detail.

The goal of this study was to identify human papillomavirus (HPV) type 52 genetic and epigenetic changes associated with high-grade cervical precancer and cancer. Patients were selected from the HPV Persistence and Progression (PaP) cohort, a cervical cancer screening program at Kaiser Permanente Northern California (KPNC). We performed a nested case-control study of 89 HPV52-positive women, including 50 cases with predominantly cervical intraepithelial neoplasia grade 3 (CIN3) and 39 controls without evidence of abnormalities. We conducted methylation analyses using Illumina sequencing and viral whole genome Sanger sequencing. Of the 24 CpG sites examined, increased methylation at CpG site 5615 in HPV52 L1 region was the most significantly associated with CIN3, with a difference in median methylation of 17.9% (odds ratio (OR) = 4.8, 95% confidence interval (CI) = 1.9-11.8) and an area under the curve of 0.73 (AUC; 95% CI = 0.62-0.83). Complete genomic sequencing of HPV52 isolates revealed associations between SNPs present in sublineage C2 and a higher risk of CIN3, with ORs ranging from 2.8 to 3.3. This study identified genetic and epigenetic HPV52 variants associated with high risk for cervical precancer, improving the potential for early diagnosis of cervical neoplasia caused by HPV52.

Objective: The aim of this study was to evaluate the diagnostic accuracy and efficiency of p16/ki-67 dual stain in the identification of CIN2+ lesions, in Greek women with ASCUS or LSIL cytology., Methods: A total of 200 women, 20 to 60 years old, were enrolled in the study. All samples were cytologically evaluated and performed for p16/ki-67 and high-risk HPV (HR-HPV) test. All patients were referred to colposcopy for biopsy and histological evaluation. Three cervical cancer (CC) screening strategies were designed and the total direct medical costs of the procedures during our clinical trial were evaluated, from a healthcare perspective., Results: HPV 16 as expected was the most common HR-HPV type followed by HPV 31 and HPV 51. The risk for CIN2+ was significantly higher in HPV 16/18 positive cases. p16/ki-67 demonstrated a high sensitivity for CIN2+ identification in both ASCUS and LSIL groups (90.4% and 95%, respectively). HR-HPV test with sensitivity 52.3% and 65.5%, as well as colposcopy with sensitivity 14.3% and 36% respectively in ASCUS and LSIL group, showed inferior results compared to p16/ki-67. The specificity of p16/ki-67 for ASCUS and LSIL was 97.2% and 95.2% respectively, inferior only to colposcopy: 100% and 100%, lacking however statistical significance. HR-HPV test instead, presented the lowest specificity: 76.4% and 71.4% respectively in comparison to the other two methods. From a healthcare perspective, the costs and benefits of the tests implementation for the annual screening and triaging, in three CC screening strategies, were also calculated and discussed., Conclusions: The results of the study indicate that p16/ki-67 is a safe and rapid assay that could be used to detect CIN2+ among women with mild cervical lesions, presenting both high sensitivity and specificity and could minimize the psychological and economic burden of HPV screening., Competing Interests: The authors have declared that no competing interests exist. Roche Diagnostics (Hellas) S.A partially supported the statistical analysis of the current study (No 16742). This does not alter our adherence to PLOS ONE policies on sharing data and materials.

Cervical cancer is the fourth most common malignant tumor in women worldwide and is closely related to human papillomavirus (HPV). Women have the highest susceptibility to HPV-52 type in Jingzhou, China. In this study, E6-E7 sequences of 183 HPV-52 positive samples were amplified by a polymerase chain reaction and sequenced. HPV-52 E6-E7 gene variations were analyzed. The phylogenetic tree was constructed using the Kimura 2-parameter method. The secondary structure of the protein was analyzed. The selective pressure to E6-E7 genes was estimated using PAML. In addition, the B cell epitopes of the E6-E7 sequences in HPV-52 were predicted by the ABCpred server. In E6 sequences, 15 single nucleotide variants were observed, including 6 nonsynonymous variants and 9 synonymous variants. In E7 sequences, 19 single nucleotide variants occurred, including 10 nonsynonymous variants and 9 synonymous variants. Six amino acid variants, including 3 nonconservative substitutions, were found in sequences encoding the alpha helix. Eight amino acid variants, including three nonconservative substitutions, occurred in sequences encoding the strand. Through phylogenetic analysis, the E6-E7 sequences were mainly distributed in B lineage. In HPV-52 E6-E7 sequences, no positively selected site was found. The nonconservative substitutions, such as K93R, K93E in E6, T37I, and D38N in E7, affected multiple hypothetical epitopes in the B cell. This study provides information for the investigation of HPV epidemic characters. The discovery of new variants of HPV-52 may lay the basis for the development of the virus diagnosis, further study of cervical cancer, and vaccine design in Central China., (© 2020 Wiley Periodicals LLC.)

Serum antibody levels can be used to measure the humoral immune response against human papillomaviruses (HPV). We developed and validated a rapid, technically simple and relatively inexpensive multiplex non-competitive Luminex-based immunoassay (ncLIA) to measure total IgG antibody levels against four HPV types. For the assay's solid phase, virus-like particles (VLPs) of HPV6, 11, 16 and 18 were bound to heparin-coated beads. HPV serum antibody levels binding to the VLPs were quantified using a phycoerithrin-conjugated secondary polyclonal donkey anti-human IgG antibody. Standardization and validation of the ncLIA were performed using 96 paired serum and genital samples from participants in the HITCH cohort study, including young women (aged 18-24 years) and their male sexual partners (aged 18+) in Montreal, Canada. Results from the ncLIA were compared to a validated Luminex immunoassay from PPD laboratories using Pearson's correlation coefficients, receiver operating characteristic curves and logistic regression. Our assay had good inter- and intra-assay variability. The correlation of serum antibody levels between the ncLIA and validation assay was highest for HPV16 and HPV11 ( r =0.90), followed by HPV6 ( r =0.86) and HPV18 ( r =0.67). The ncLIA was better able to predict HPV DNA positivity in genital samples than the validation assay for HPV16 [area under the curve (AUC) 0.65 versus 0.52, P =0.001] and HPV18 [AUC 0.71 versus 0.57, P =0.024]. AUCs for HPV6 and HPV11 were similar between the two assays (0.70 versus 0.71, P =0.59, and 0.88 versus 0.96, P =0.08, respectively). The developed ncLIA is useful for measuring total IgG antibody response following natural infection or vaccination against four HPV VLPs included in the quadrivalent vaccine.

Objective: The term ''Human Papillomavirus'' or ''HPV'' has become synonymous with uterine cervical cancer leading to feminisation of all the preventive measures, especially immunisation. Taking into consideration the rising number of HPV associated cancers among men in many developed countries and the risk of transmission to women, male HPV infection is a serious concern. A systematic review and meta-analysis of literature was performed to determine the global prevalence of HPV among men with oropharyngeal and anogenital cancers., Methods: A systematic review and meta-analysis of literature was performed searching electronic databases for published articles in English between January 1984- April 2020 based on standard systematic review guidelines. The meta-analysis component was modified appropriately for the synthesis of prevalence study results. National Institutes of Health checklist for observational, cohort and cross-sectional studies was used to assess the quality of the studies selected after the abstract and content review. The meta-analysis was performed in STATA version 13.0 (College Station, Texas 77,845 USA) and the forest plots were constructed using metan package in STATA., Results: Through the electronic search of databases, 3486 original articles were screened for eligibility. Fifty-eight articles were systematically reviewed and 42 articles were qualified for meta-analysis including 4,250 men with oropharyngeal, penile and prostate cancers. The pooled prevalence of HPV DNA in oropharyngeal cancers was 45% (95%CI 24.0%-66.0%). Meanwhile the pooled prevalence rates of 48% (CI 40.0%- 57.0%) and 19% (CI 10.0%-29.0%) were observed in penile and prostate cancers respectively. Even though, articles regarding HPV prevalence in anal cancers were systematically reviewed, none of the studies were qualified for meta-analysis., Conclusion: Higher pooled prevalence of HPV DNA was observed among men with oropharyngeal and penile cancers. Multicentric molecular studies investigating the prevalence of HPV in prostate cancers have to be planned in future.

Background: Oropharyngeal cancers associated with high-risk human papillomavirus (HR-HPV) infection are increasing in the United States, especially among men. We evaluated the prevalence and predictors of concurrent (genital and oral) and concordant (same-type) HR-HPV infections in the United States., Methods: We used the National Health and Nutrition Examination Survey from 2009 to 2016. Predictors were assessed via multivariable logistic regression., Results: Among 10 334 respondents, 172 (2.1%) had concurrent infections (109 [3.5%] men and 63 [0.76%] women]. Ninety-three (1.0%) had concordant infections (54 [1.6%] men and 39 [0.5%] women). Predictors of concurrence in men included the following: no longer married versus married (odds ratio [OR], 2.3; 95% confidence interval [CI], 1.3-4.9), living with a partner versus married (3.0; 1.2-7.5), and having 2-5 lifetime oral sex partners (3.0; 1.2-7.5). In women they included the following: no longer married versus married (3.6; 1.3-10.3), ≥2 recent sex partners (4.6; 1.4-15.6 for 2-5 partners and 3.9; 1.1-14.3 for ≥6 partners), and marijuana use (2.2; 1.0-4.5). The predictor of concordance in men and women was no longer married versus married (3.5; 1.2-9.9 in men and 3.2; 1.1-9.4 in women)., Conclusions: Concurrent and concordant HR-HPV infections occur at a high rate, especially among men, and are associated with behavioral factors. This underscores the importance of HPV vaccination, screening, and education in men., (© The Author(s) 2020. Published by Oxford University Press for the Infectious Diseases Society of America. All rights reserved. For permissions, e-mail: journals.permissions@oup.com.)

Oral infection with human papillomavirus (HPV) is likely to underpin the rapidly rising incidence of oropharyngeal squamous cell carcinoma; however, there are few data describing the natural history of oral HPV infection. We recruited 704 participants aged 20 to 70 years from worksites, universities and primary care practices in Brisbane, Australia. Participants completed questionnaires at baseline, 12 and 24 months and donate four saliva samples at baseline, 6, 12 and 24 months for HPV polymerase chain reaction testing and typing. We estimated the prevalence of oral HPV infection at baseline, incidence of new infections among those HPV-negative at baseline, clearance rate and persistent infections. At baseline, 10.7% of participants had oral HPV infections from 26 different HPV types. Sexual behaviours were associated with oral HPV infection, including more partners for passionate kissing (29 or more; odds ratio [OR] 3.4, 95% confidence interval [CI] 1.5-8.0), and giving and receiving oral sex (16 or more; OR 5.4, 95% CI 1.6-17.7 and OR 5.6, 95% CI 1.6-18.7, respectively). Of 343 participants, HPV-free at baseline and with subsequent saliva samples, 87 (25%) acquired new infections over the 24 months. Sixty-eight of 87 people included in the clearance analysis (78%) cleared their oral HPV infections. Clearance was associated with being a nonsmoker (OR 12.7, 95% CI 1.3-122.8), and no previous diagnosis of a sexually transmitted infection (OR 6.2, 95% CI 2.0-19.9). New oral infections with HPV in this sample were not rare. Although most infections were cleared, clearance was not universal suggesting a reservoir of infection exists that might predispose to oropharyngeal carcinogenesis., (© 2020 UICC.)

Objectives: Human papillomaviruses (HPV) are the main etiology of invasive cervical cancer. Together HPV and viral hepatitis account for the cause of 25% of cancers in developing countries. To evaluate the association between population movements and the spread of HPV, this study looked at prevalence, genotypes, and phylogenetic assessment of HPV in Great Khorasan, a pilgrimage-tourism province in northeast Iran., Methods: From March 2013 to July 2018, 567 samples were collected from three groups in Khorasan: Razavi and North Khorasan provinces (highly mobile population); South Khorasan province (conservative and desert); and diverse group (tourists)., Results: HPV prevalence was 48.4% in Razavi and North Khorasan (first group); 19.9% in South Khorasan (second group); and 33.6% in the diverse group. The four most common HPV genotypes were HPV-6, 11, 51 and 16, in the first group; HPV-6, 11, 16 and 58 in the second group; and HPV-6, 11, 16 and 53/89 in the diverse group. The most frequent genotypes that are known as high risk for cervical cancer were HPV-51 in the first group, HPV-16 in the second group and the diverse group. Among low-risk genotypes, HPV-6, and HPV-11 were more frequent in all groups. DNA sequencing and phylogenetic analysis of 20 HPV-positive samples showed that the distributions of the HPV genotypes were HPV-6 (50%), 11 (10%), 67 (5%), 16 (15%), 31 (10%), 54 (5%), and 89 (5%)., Conclusions: The findings show that areas associated with population movement should be frequently monitored for infectious diseases, while conservative and less populated areas have less risk for virus spread and endemicity. Health authorities should focus more on the establishment of HPV diagnostic facilities, screening, vaccination, and enhancement of public knowledge in these regions., (Copyright © 2020 The Author(s). Published by Elsevier Ltd.. All rights reserved.)

In Ethiopia, cervical cancer is the second leading cause of morbidity and mortality from all cancers in women. Persistent infection with human papillomaviruses (HPV) plays a key role in the development of cervical intraepithelial neoplasia and invasive cervical cancer. To establish baseline data on the population-based prevalence of HPV infection and genotype distribution, we investigated cervical HPV epidemiology among rural women. This population-based study was conducted among rural women aged 30-49 years in Butajira, south-central Ethiopia. A total of 893 samples were tested from 1020 screened women. A self-sampling device (Evalyn Brush, Rovers, Oss, The Netherlands) was used and HPV presence and genotype was determined using multiplexed genotyping (MPG) by BSGP5+/6+ PCR with Luminex read out. The HPV positivity rate was 23.2% (95% CI: 23.54-22.86%) and 20.5% (95% CI = 20.79-20.21) and 10.3% (95% CI = 10.52-10.08) women were high-risk (hr- and low-risk (lr-) HPV positive, respectively. Fifty five (7.2%) of the women showed multiple hr-HPV infections. Age-specific hr-HPV infection peaked in the age-group 30- to 34 years old (58.6%) and decreased in 35-39, 40-44 and 45-49 years to 20.4%, 4.5% and 3.8% respectively. The top five prevalent hr-HPV genotypes were HPV16 (57.1%), 35 (20.3%), 52 (15.8%), 31 (14.1%), and 45 (9.6%) in the Butajira district. As a first population-based study in the country, our results can serve as valuable reference to guide nationwide cervical cancer screening and HPV vaccination programs in Ethiopia., (© 2020 Union for International Cancer Control.)

High-throughput HPV typing assays with increased automation, faster turnaround and type-specific digital readout would facilitate studies monitoring the impact of HPV vaccination. We evaluated the NanoString nCounter ® platform for detection and digital readout of 48 HPV types in a single reaction. NanoString (NS) used proprietary software to design CodeSets: type-specific probe pairs targeting 48 HPV types and the globin gene. We tested residual DNA extracts from epidemiologic specimens and defined samples (HPV plasmids at 10 to 10 4 copies/reaction) directly (No-PCR) as well as after L1 consensus PCR of 45 (PCR-45) or 15 cycles (PCR-15). Assay and interpretation followed NS recommendations. We evaluated analytic performance by comparing NanoString results for types included in prior assays: Roche Linear Array (LA) or HPV TypeSeq assay. No-PCR results on 40 samples showed good type-specific agreement with LA (k = 0.621) but sensitivity was 65% with lower limit of detection (LOD) at 10 4 plasmid copies. PCR-45 results showed almost perfect type-specific agreement with LA (k = 0.862), 82% sensitivity and LOD at 10 copies. PCR-15 results on 75 samples showed substantial type-specific agreement with LA (k = 0.796, 92% sensitivity) and TypeSeq (k = 0.777, 87% sensitivity), and LOD at 10 copies of plasmids. This proof-of-principle study demonstrates the efficacy of the NS platform with HPV CodeSet for type-specific detection using a low number of PCR cycles (PCR-15). Studies are in progress to evaluate assay reproducibility and analytic validation with a larger number of samples.

Increasing evidences indicate that high-risk HPV variants are heterogeneous in carcinogenicity and ethnic dispersion. In this work, we identified genetic signatures for convenient determination of lineage/sublineage of HPV16, 18, 52 and 58 variants. Using publicly available genomes, we found that E2 of HPV16, L2 of HPV18, L1 and LCR of HPV52, and L2, LCR and E1 of HPV58 contain the proper genetic signature for lineage/sublineage classification. Sets of hierarchical signature nucleotide positions were further confirmed for high accuracy (>95%) by classifying HPV genomes obtained from Chinese females, which included 117 HPV16 variants, 48 HPV18 variants, 117 HPV52 variants and 89 HPV58 variants. The circulation of HPV variants posing higher cancer risk in Eastern China, such as HPV16 A4 and HPV58 A3, calls for continuous surveillance in this region. The marker genes and signature nucleotide positions may facilitate cost-effective diagnostic detections of HPV variants in clinical settings., (Copyright © 2020 The Authors. Published by Elsevier Inc. All rights reserved.)

Background: Recent publications from a single research group have suggested that aldehyde-based high-level disinfectants (HLDs), such as ortho-phthalaldehyde (OPA), are not effective at inactivating HPVs and that therefore, patients may be at risk of HPV infection from medical devices. These results could have significant public health consequences and therefore necessitated evaluation of their reproducibility and clinical relevance., Methods: We developed methods and used standardised controls to: (1) quantify the infectious levels of clinically-sourced HPVs from patient lesions and compare them to laboratory-derived HPVs, (2) evaluate experimental factors that should be controlled to ensure consistent and reproducible infectivity measurements of different HPV genotypes, and (3) determine the efficacy of select HLDs., Findings: A novel focus forming unit (FFU) infectivity assay demonstrated that exfoliates from patient anogenital lesions and respiratory papillomas yielded infectious HPV burdens up to 2.7 × 10 3 FFU; therefore, using 2.2 × 10 2 to 1.0 × 10 4 FFU of laboratory-derived HPVs in disinfection assays provides a relevant range for clinical exposures. RNase and neutralising antibody sensitivities were used to ensure valid infectivity measures of tissue-derived and recombinant HPV preparations. HPV infectivity was demonstrated over a dynamic range of 4-5 log 10 ; and disinfection with OPA and hypochlorite was achieved over 3 to >4 log 10 with multiple genotypes of tissue-derived and recombinant HPV isolates., Interpretation: This work, along with a companion publication from an independent lab in this issue, address a major public health question by showing that HPVs are susceptible to HLDs., Funding: Advanced Sterilization Products; US NIH (R01CA207368, U19AI084081, P30CA118100)., Competing Interests: Declaration of Competing Interest M.A.O. reports grants, personal fees, and non-financial support from Advanced Sterilization Products, grants from U.S. National Institutes of Health, during the conduct of the study; A.G.W. reports personal fees and non-financial support from ASCCP, non-financial support from ACOG, non-financial support from Loktal Medical Electronics, personal fees and non-financial support from CSCCP (Chinese Society for colposcopy and cervical pathology, personal fees and non-financial support from Henan People's Regional Hospital, personal fees from Southcentral Foundation (Alaska Native Corp), non-financial support from FECOLSOG (Colombian colposcopy society), non-financial support from COMEGIC (Mexican colposcopy society), non-financial support from Doctors Hospital at Renaissance, non-financial support from MD Anderson, non-financial support from Univ Texas Rio Grande Valley, non-financial support from Global Coalition against Cervical Cancer, non-financial support from AIDS Malignancy Consortium, personal fees and non-financial support from Deaconess Beth Israel Hospital, personal fees and non-financial support from Texas Tech University, personal fees and non-financial support from ABPTGIC (Brazilian colposcopy society), outside the submitted work. V.B., N.A.P, R.T.S., E.C.B. and R.M. have nothing to disclose. A.S., J.Y. and M.R. are employees of Advanced Sterilization Products. G.E. is an employee and shareholder of Johnson & Johnson, which was the parent company for Advanced Sterilization Products and Janssen Pharmaceutica NV at the time the research was conducted., (Copyright © 2020 The Authors. Published by Elsevier B.V. All rights reserved.)

Large scale human papillomavirus (HPV) vaccination against the most oncogenic high-risk human papillomavirus (HPV) types 16/18 is rapidly reducing their incidence. However, attempts at assessing if this leads to an increase of nonvaccine targeted HPV types have been hampered by several limitations, such as the inability to differentiate secular trends. We performed a population-based serological survey of unvaccinated young women over 12 years. The women were under 23-years-old, residents from 33 communities which participated in a community-randomised trial (CRT) with approximately 50% vaccination coverage. Serum samples were retrieved pre-CRT and post-CRT implementation. Seropositivity to 17 HPV types was assessed. HPV seroprevalence ratios (PR) comparing the postvaccination to prevaccination era were estimated by trial arm. This was also assessed among the sexual risk-taking core group, where type replacement may occur more rapidly. In total, 8022 serum samples from the population-based Finnish Maternity Cohort were retrieved. HPV types 16/18 showed decreased seroprevalence among the unvaccinated in communities only after gender-neutral vaccination (PR 16/18A = 0.8, 95% CI 0.7-0.9). HPV6/11 and HPV73 were decreased after gender-neutral vaccination (PR 6/11A = 0.8, 95% CI 0.7-0.9, PR 73A = 0.7, 95% CI 0.6-0.9, respectively) and girls-only vaccination (PR 6/11B = 0.8, 95% CI 0.7-0.9, PR 73B = 0.9, 95% CI 0.8-1.0). HPV68 alone was increased but only after girls-only vaccination (PR 68B = 1.3, 95% CI 1.0-1.7, PR core68B = 2.8, 95% CI 1.2-6.3). A large-scale, long-term follow-up found no type replacement in the communities with the strongest reduction of vaccine HPV types. Limited evidence for an increase in HPV68 was restricted to girls-only vaccinated communities and may have been due to secular trends (ClinicalTrials.gov number: NCT00534638)., (© 2020 The Authors. International Journal of Cancer published by John Wiley & Sons Ltd on behalf of UICC.)

In recent years, next generation sequencing (NGS) technology has been widely used for the discovery of novel human papillomavirus (HPV) genotypes, variant characterization and genotyping. Here, we compared the analytical performance of NGS with a commercial PCR-based assay (Anyplex II HPV28) in cervical samples of 744 women. Overall, HPV positivity was 50.2% by the Anyplex and 45.5% by the NGS. With the NGS, we detected 25 genotypes covered by Anyplex and 41 additional genotypes. Agreement between the two methods for HPV positivity was 80.8% (kappa = 0.616) and 84.8% (kappa = 0.652) for 28 HPV genotypes and 14 high-risk genotypes, respectively. We recovered and characterized 243 complete HPV genomes from 153 samples spanning 40 different genotypes. According to phylogenetic analysis and pairwise distance, we identified novel lineages and sublineages of four high-risk and 16 low-risk genotypes. In total, 17 novel lineages and 14 novel sublineages were proposed, including novel lineages of HPV45, HPV52, HPV66 and a novel sublineage of HPV59. Our study provides important genomic insights on HPV types and lineages, where few complete genomes were publicly available.

Background and Aim: Data on type-specific human papillomavirus (HPV) are needed to investigate HPV-based screening tests and HPV vaccines. However, Chinese relevant data are insufficient. Therefore, this meta-analysis aimed to summarize and demonstrate the prevalence and distribution of HPV genotypes in cervical intraepithelial neoplasia (CIN) and compensate for the shortage of HPV vaccines in China., Methods: The Medline, Embase, and the Cochrane Library databases, as well as references cited in the selected studies, were systematically searched for studies investigating the prevalence and distribution of HPV genotypes between January 2000 and April 2019 in China., Results: A total of 8 studies were identified, which comprised 2950 patients with CIN1 and 5393 with CIN2/3. The overall HPV infection rate was 84.37%. The HPV infection rate was significantly higher in the CIN2/3 group (87.00%) than in the CIN1 group (79.56%) (χ 2  = 80.095, P < 0.001). The most common HPV types in CIN1 in order of decreasing prevalence were as follows: HPV52 (20.31%), HPV16 (16.81%), HPV58 (14.44%), HPV18 (6.44%), and HPV53 (5.76%). However, in the CIN2/3 group, HPV16 (45.69%) was the predominant type, followed by HPV58 (15.50%), HPV52 (11.74%), HPV33 (9.35%), and HPV31 (4.34%)., Conclusions: This study suggested that HPV16, HPV52, and HPV58 were the top three types of CIN in China. The findings might provide a reference for future HPV-based cervical cancer screening tests, treatment of HPV infection, and application of HPV vaccines in China.

Objective: This study aimed to evaluate the incidence of and factors associated with persistence and clearance of oral human papillomavirus (HPV) infections., Method: A prospective cohort study invited 458 subjects (231 HPV-positive and 227 HPV-negative at baseline) to attend follow-ups at 12 months. Those 231 HPV-positive subjects and 10 new infections were invited to reassessment at 24 months. We used next-gen sequencing for detection and genotyping of HPV., Results: α-HPV infections showed higher persistence rates than β/γ-HPV (22.7% vs 9.2% at 12 months [P < .05], 10.6% vs 6.8% at 24 months [P = .30]). Clearance rates of α-HPV were lower than β/γ-HPV at 12 months (31.8% vs 45.1%; P = .05) and higher at 24 months (7.6% vs 4.8%; P = .36). Persistence of β/γ-HPV was positively associated with males (crude odds ratio [COR] = 3.8, 95% confidence interval [CI] = 1.3-11.2), elderly (51-65 vs 16-50 years; COR = 5.1, 95% CI = 1.2-22.3), and smoking (COR = 4.3, 95% CI = 1.9-9.6). Drinking (COR = 0.5, 95% CI = 0.3-0.9), handwashing less than 90% of times before meals (COR = 0.6, 95% CI = 0.3-0.9), and using public bath more than once per month (COR = 0.5, 95% CI = 0.2-0.9) were risk factors hindering β/γ-HPV clearance., Conclusions: This study identified factors associated with persistence and clearance of oral HPV infections among Chinese. Studies on other ethnogeographic groups may further inform prevention strategies of oral HPV infection and immunization programmes., (© 2020 Wiley Periodicals LLC.)

Human papillomavirus (HPV) causes not only most cervical cancers but also cancers of the vagina, vulva, penis, anus, rectum, and oropharynx. Every year, 200,000 women die of cervical cancer in the world, and China accounts for about 10%. HPV vaccines are effective in preventing HPV infections thus HPV-related cancers worldwide. Studies on the clinical trials of the 2v Cervarix™ and the 4v Gardasil® have suggested that immunization with either of these vaccines provided some level of protection against other HPV types that are closely related to the types contained in the vaccines. Here we conducted a preliminary evaluation on the ability to induce cross-neutralizing antibodies in rhesus monkeys by a 3v HPV vaccine that targets HPV16, 18, and 58 and it is specifically designed for Chinese women. We found that this vaccine is no less than Gardasil® in terms of the ability to induce NAbs against non-vaccine types of HPV in rhesus macaques. These results provided evidence from the immunogenicity point of view that the KLWS 3v HPV vaccine is a strong competitor to the imported 2v and 4v HPV vaccines currently available on the market., (Copyright © 2020 The Authors. Published by Elsevier B.V. All rights reserved.)

To study the interaction between HIV and other carcinogenic infections in conjunctival squamous cell carcinoma (SCC), we evaluated the presence of a broad spectrum of human viruses in conjunctiva specimens. Beta Human papillomavirus (HPV; n = 46), gamma HPV (n = 52), polyomaviruses (n = 12) and herpes viruses (n = 3) was determined in DNA extracted from 67 neoplastic and 55 non-neoplastic conjunctival tissues of HIV-positive and HIV negative subjects by Luminex-based assays. Next-generation sequencing (NGS) was also used to further characterize the presence of cutaneous HPVs. Detection of beta-2 HPV infections was associated with the risk of neoplasia (adjusted odds ratio [aOR] 3.0; 95% confidence interval [CI] 1.3-6.8), regardless of HIV status (HIV positive, aOR 2.6, 95% CI 0.9-7.7; HIV negative, aOR 3.5, 95% CI 0.9-14.4). EBV was strongly associated with the risk of neoplasia (aOR 12.0, 95% CI 4.3-33.5; P < .01) mainly in HIV individuals (HIV positive, aOR 57.5; 95% CI: 10.1-327.1; HIV negative aOR 2.6; 95% CI: 0.2-34.7). NGS allowed to identify 13 putative novel HPVs in cases and controls. Our findings suggest a role of beta HPV types and EBV, in conjunctival SCC. However, additional studies of viral expression in tumor tissue are required to confirm the causal association., (© 2020 UICC.)

Objectives: To explore male human papillomavirus (HPV) contemporary genotyping epidemiology and correlations to peniscopy, cytology, and histopatology., Methods: Medical records of patients who had been submitted to HPV infection screening with genotyping, peniscopy, cytology, and histopathology in a period of 2 years were reviewed. Frequency analysis and correlations between the diagnostic tools were established., Results: Genotype of 1132 men resulted in 69.2% (784) positivity for HPV DNA, 78% classified as high risk of oncogenesis. Co-infections occurred in 429 (54.7%) and the most frequently identified types were HPV-6, HPV-42, and HPV-16, in 133 (17%), 94 (12%), and 86 (11%) patients, respectively. Positive/negative predictive values of peniscopy, cytology, and histopathology were 83/31%, 92/32%, and 87/33%, respectively. As a result, though significant, the correlations between genotype and non-molecular tests were poor., Conclusions: In the current contemporary representative male cohort, over two thirds are positive for human HPV DNA, 78% of high risk and with over half co-infections. Though significant, its correlation with non-molecular tests is poor and while the positive predictive values of peniscopy, cytology, and histopatology are between 83% and 92%, their negative predictive values are as low as 31% to 33%., (© 2020 Wiley Periodicals LLC.)

Background: During 2013 and 2016 the region of Skåne, Sweden started to analyse human papillomavirus (HPV) and cytology in postmenopausal women 60-65 years of age. Our aim was to evaluate high-risk (HR) HPV mRNA testing for the triage of HPV DNA-positive postmenopausal women with normal cytology., Methods: A total of 271 women, 60-65 years of age, underwent liquid-based cytology (LBC) and HPV testing by using the HR-HPV DNA MGP-PCR-Luminex assay. HR-HPV DNA-positive women with normal cytology underwent complimentary HPV mRNA testing (Aptima, Hologic Inc.). Over a period of 49 months (SD 11.0) the women received regular follow-ups at intervals of 12-18 months. Women with abnormal cytology and/or a positive HR-HPV DNA and/or mRNA result at two subsequent visits were scheduled for colposcopy and clinical examination., Results: Over the surveillance period, 3.6% (10/271) of the HR-HPV DNA-positive women developed histologically confirmed high-grade squamous intraepithelial lesions (HSILs) or worse. The cumulative incidence rates (CIR) were 29.7% (CI 24.8-30.1) for HSIL or worse among HPV mRNA-positive women at enrolment (39.5% 107/271) and 0% among HPV mRNA-negative women (60.5%, 164/271), (p = 0.002)., Conclusions: Postmenopausal women with normal cytology testing positive for HR-HPV mRNA are at increased risk for the development of high-grade cervical intraepithelial neoplasia (CIN), in contrast to women with a negative HR-HPV mRNA outcome. The HR-HPV mRNA APTIMA assay detecting 14 HR-HPV types may be a useful triage method among HPV DNA-positive postmenopausal women with normal cytology.

Objective: To define the human papillomavirus (HPV) subtypes seen in a large adult population with traditionally defined recurrent respiratory papillomatosis., Study Design: Retrospective review., Setting: Tertiary care laryngology practice., Subjects and Methods: All patients had a firm diagnosis of recurrent respiratory papillomatosis defined by (1) visually obvious papillomas, (2) recurrence requiring multiple surgeries, and (3) pathology diagnosis of "papilloma." Each patient had also undergone HPV subtyping. Age, sex, presence of malignancy, and HPV subtypes were tabulated and correlated with long-term patient outcomes., Results: A total of 184 patients were identified who fulfilled the above criteria. In total, 87.0% (160) had a low risk subtype; 9.2% had an alternative subtype. These consisted of subtypes 16, 18, 31, 44, 45, 55, and 70. Four patients (2.2%) had combinations of subtypes, with 1 patient with HPV 11 and 16, 1 patient with HPV 11 and 76, 1 patient with 11 and 84, and 1 patient with 18 and 45. Finally, 3.8% of patients were HPV negative, despite fulfilling all 3 criteria listed above., Conclusion: In the patient population above, almost 10% of patients had an HPV subtype other than 6 and 11. This suggests that traditionally defined recurrent respiratory papillomatosis (RRP) can be caused by HPV subtypes other than 6 and/or 11. In addition, the clinical course of persons with this definition of RRP appears to vary by subtype, and this information may offer the ability to nuance follow-up instructions, reducing in particular the burden placed upon patients who have RRP caused by subtypes 6 and 11.

Immunosuppression is a risk factor of persistent human papillomavirus (HPV) infections, which might lead to development of (pre)malignant lesions of the cervix and lower anogenital tract. Results of HPV DNA testing using cervicovaginal self-samples are comparable to those that are clinician-obtained and therefore might be used in cervical screening. The aim of this study was to assess the prevalence of high-risk HPV (hrHPV) infections, their risk factors and the genotypes distribution among women undergoing immunosuppressive therapy. Women undergoing immunosuppressive therapy for at least three months due to solid organ transplantation or autoimmune disorders were asked to self-collect samples for HPV testing using cervicovaginal brushes and complete questionnaires regarding cervical cancer risk factors. HPV DNA detection and genotyping were performed using Genotyping kit HPV GP version 2. hrHPV was detected in 26/90 (28.9%) specimens. Genotyping revealed a broad range of hrHPV, with type 16 being the most common genotype (11/26). The components of bivalent/quadrivalent or nonavalent vaccines cover all genotypes present in 4.4% and 17.8% women, respectively, and occur as a co-infection with other types in 12.2% and 23.3% of women, respectively. The only feature significantly associated with being hrHPV-positive was having at least two lifetime sexual partners. The high prevalence of hrHPV infections among immunosuppressed women emphasizes the need for regular cervical cancer screening with HPV DNA testing, which might be performed on self-collected specimen.

Both mucosal and cutaneous Human Papillomaviruses (HPVs) can be detected in the oral cavity, but investigations regarding the epidemiology of cutaneous HPVs at this site are scarce. We assessed mucosal (alpha) and cutaneous (beta and gamma) HPV infection in oral samples of HIV-infected and uninfected men who have sex with men (MSM). Oral rinse-and-gargles were collected from 310 MSM. Alpha HPVs were detected using the Linear Array, whereas beta and gamma HPVs were detected using multiplex PCR and Luminex technology. An amplicon-based next-generation sequencing (NGS) protocol was applied to a subset of samples collected from 30 HIV-uninfected and 30 HIV-infected MSM. Beta HPVs were significantly more common than alpha types (53.8% vs. 23.9% for HIV-infected subjects, p < 0.0001; 50.3% vs. 17.1% for HIV-uninfected subjects, p < 0.0001). Gamma HPVs were also frequently detected (30.8% and 25.9% in HIV-infected and uninfected MSM, respectively). NGS produced 2,620,725 reads representative of 146 known HPVs (16 alpha-PVs, 53 beta-PVs, 76 gamma-PVs, one unclassified) and eight putative new HPVs, taxonomically assigned to the beta genus. The oral cavity contains a wide spectrum of HPVs, with beta types representing the predominant genus. The prevalence of beta and gamma HPVs is high even in immunorestored HIV-infected individuals. NGS confirmed the abundance of cutaneous HPVs and identified some putative novel beta HPVs. This study confirms that cutaneous HPVs are frequently present at mucosal sites and highlights that their pathological role deserves further investigation since it may not be limited to skin lesions.

The beta human papillomaviruses (HPVs) are subdivided into 5 species (beta-1 to beta-5), and they were first identified in the skin. However, the beta-3 species appears to be more highly represented in the mucosal epithelia than in the skin. Functional studies have also highlighted that beta-3 HPV49 shares some functional similarities with mucosal high-risk (HR) HPV16. Here, we describe the characterization of the in vitro transforming properties of the entire beta-3 species, which includes three additional HPV types: HPV75, HPV76, and HPV115. HPV49, HPV75, and HPV76 E6 and E7 (E6/E7), but not HPV115 E6 and E7, efficiently inactivate the p53 and pRb pathways and immortalize or extend the life span of human foreskin keratinocytes (HFKs). As observed for HR HPV16, cell cycle deregulation mediated by beta-3 HPV E6/E7 expression leads to p16 INK4a accumulation, whereas no p16 INK4a was detected in beta-2 HPV38 E6/E7 HFKs. As shown for HPV49 E6, HPV75 and HPV76 E6s degrade p53 by an E6AP/proteasome-mediated mechanism. Comparative analysis of cellular gene expression patterns of HFKs containing E6 and E7 from HR HPV16, beta-3 HPV types, and beta-2 HPV38 further highlights the functional similarities of HR HPV16 and beta-3 HPV49, HPV75, and HPV76. The expression profiles of these four HPV HFKs show some similarities and diverge substantially from those of beta-3 HPV115 E6/E7 and beta-2 HPV38 E6/E7 HFKs. In summary, our data show that beta-3 HPV types share some mechanisms with HR HPV types and pave the way for additional studies aiming to evaluate their potential role in human pathologies. IMPORTANCE Human papillomaviruses are currently classified in different genera. Mucosal HPVs belonging to the alpha genus have been clearly associated with carcinogenesis of the mucosal epithelium at different sites. Beta HPV types have been classified as cutaneous. Although findings indicate that some beta HPVs from species 1 and 2 play a role, together with UV irradiation, in skin cancer, very little is known about the transforming properties of most of the beta HPVs. This report shows the transforming activity of E6 and E7 from beta-3 HPV types. Moreover, it highlights that beta-3 HPVs share some biological properties more extensively with mucosal high-risk HPV16 than with beta-2 HPV38. This report provides new paradigms for a better understanding of the biology of the different HPV types and their possible association with lesions at mucosal and/or cutaneous epithelia., (Copyright © 2020 Minoni et al.)

Background: Human papillomaviruses (HPVs), a group of non-enveloped small viruses with double-stranded circular DNA which lead to multiple skin diseases such as benign warts, are commonly seen in clinics. The current HPV detection systems aim mainly at mucosal HPVs, however, an efficient clinical approach for cutaneous HPVs detection is lacking., Objectives: To establish a rapid detection system for cutaneous HPVs using a colorimetric loop-mediated isothermal amplification (LAMP) with hydroxynaphthol blue (HNB) dye in combination with microfluidic technology., Methods: L1 DNA sequences of the 30 cutaneous HPVs were chemically synthesized, and LAMP primers against L1 DNA were designed with use of an online LAMP designing tool. Isothermal amplification was performed with use of a water bath and the amplification results were inspected with the naked eye. Using PCR sequencing as a control method, the specificity and sensitivity of the new detection system were obtained by detecting clinical samples., Results: The lower detection limit of the LAMP assay was 10 7 viral DNA copies/μl when tested on synthesized L1 DNA sequences, which was better than the conventional PCR. Compared to PCR sequencing, the sensitivity of HPV27, HPV2, HPV1, HPV57, HPV3, HPV4, HPV7 and HPV75 genotypes detections were 100%, whereas the specificity was 34.55, 45.12, 95.83, 98.59 and 97.62% respectively, when tested on clinical samples., Conclusions: The new cutaneous type HPV detection system is characterized by both a good sensitivity and specificity compared to conventional methods.

Purpose: HPV is involved in the development of some head and neck squamous-cell carcinomas (HNSCC). It was suggested that only transcriptionally active virus can induce carcinogenesis, therefore, the aim of our study was to analyze the frequency of active HPV infection, virus type, and its prognostic role in HNSCC patients., Methods: Status of active HPV infection was assessed for 155 HNSCC patients based on p16 expression and HPV DNA presence. Univariate and multivariate analyses with Cox proportional regression model were performed to select independent prognostic factors., Results: Active HPV infection was detected in 20.65% of patients. We identified 16.0, 40.9 and 1.7% of HPV positive oral cavity, oropharyngeal, and laryngeal cancer cases, respectively. HPV16 was dominant (81.25%) followed by HPV35 (9.38%) and double infections with HPV16 and 35 (6.25%) or HPV35 and 18 (3.12%). Patients with active HPV infection demonstrated significantly higher survival than HPV negative ones (OS 80.89% vs. 37.08%, p = 0.000; DFS 93.0% vs. 53.35%, p = 0.000, respectively). Longer OS and DFS were maintained for infected patients when oropharyngeal and non-oropharyngeal cases were analyzed separately. Interestingly, all patients infected with other than HPV16 types survived 5 years without cancer progression. In the analyzed group of 155 patients the strongest independent favourable prognostic factor for both OS and DFS was HPV presence., Conclusions: High prevalence of HPV-driven HNSCC (mostly within oropharynx) was detected, with HPV16 type the most frequent, followed by HPV35 and HPV18. The presence of active HPV infection improved survival of both oropharyngeal and non-oropharyngeal cancer patients and should be taken into account in treatment planning.

We use all the currently known 405 Papillomavirus (PV) sequences, 343 curated PV sequences from both humans and animals from the PAVE data base, to analyse the recombination dynamics of these viruses at the whole genome levels. After showing some evidence of human and non-human primate PV recombination, we report a comprehensive recombination analysis of all currently known 82 Alphapapillomaviruses (Alpha-PVs). We carried out an exploratory study and found novel recombination events between High-Risk HPV Types and Macaca fascicularis PV1 (MfPV1), Macaca Fuscata PV2 (MfuPV2) and Pan Paniscus PV1 (PpPV1) Papillomaviruses. This is the first evidence of interactions between PVs from different hosts and hence postulates the likelihood of ancient host switching among Alpha-PVs. Notwithstanding these results should be interpreted with caution because the major and minor parents indicated by RDP4 program are simply the sequences in the alignment that most closely resemble the actual parents. We found statistically significant differences between the phylogenies of the PV sequences with recombination regions and PV sequences without recombination regions using the Shimodaira-Hasegawa phylogenetic incongruence testing. We show that not more than 76MYA Alpha-PVs were in the same biological niche, a pre-requisite for recombination, and as the hosts evolved and diversified, the viruses adapted to specific host niches which eventually led to coevolution with specific hosts before speciation of primate species. Thus providing evidence that in ancient times no earlier than the Cretaceous period of the Mesozoic age, Alpha-PVs recombined and switched hosts, but whether this host switching is occurring currently is unknown. However, a clearer picture of the PVs evolutionary landscape can only be achieved with the incremental discovery of PV sequences, especially from the animal kingdom.

We recently developed a test based on the Agilent SureSelect target enrichment system capturing genomic fragments from 191 human papillomaviruses (HPV) types for Illumina sequencing. This enriched whole genome sequencing (eWGS) assay provides an approach to identify all HPV types in a sample. Here we present a machine learning algorithm that calls HPV types based on the eWGS output. The algorithm based on the support vector machine (SVM) technique was trained on eWGS data from 122 control samples with known HPV types. The new algorithm demonstrated good performance in HPV type detection for designed samples with 25 or greater HPV plasmid copies per sample. We compared the results of HPV typing made by the new algorithm for 261 residual epidemiologic samples with the results of the typing delivered by the standard HPV Linear Array (LA). The agreement between methods (97.4%) was substantial (kappa= 0.783). However, the new algorithm identified additionally 428 instances of HPV types not detectable by the LA assay by design. Overall, we have demonstrated that the bioinformatics pipeline is an accurate tool for calling HPV types by analyzing data generated by eWGS processing of DNA fragments extracted from control and epidemiological samples.

A human papillomavirus type plays an important role in the early diagnosis of cervical cancer. Most of the prediction methods use protein sequence and structure information, but the reduced amino acid modes have not been used until now. In this paper, we introduced the modes of reduced amino acids to predict high-risk HPV. We first reduced 20 amino acids into several nonoverlapping groups and calculated their structure and physicochemical modes for high-risk HPV prediction, which was tested and compared with the existing methods on 68 samples of known HPV types. The experiment result indicates that the proposed method achieved better performance with an accuracy of 96.49%, indicating that the reduced amino acid modes might be used to improve the prediction of high-risk HPV types., Competing Interests: The authors declare that they have no conflicts of interest., (Copyright © 2020 Xinnan Xu et al.)

High risk human Papillomavirus (HPV) infections ultimately cause cervical cancer. Human Immunodeficiency Virus (HIV) infected women often present with multiple high-risk HPV infections and are thus at a higher risk of developing cervical cancer. However, information on the circulating high-risk HPV genotypes in Kenya in both HIV-infected and HIV-uninfected women is still scanty. This study is aimed at determining the phylogeny and the HPV genotypes in women with respect to their HIV status and at correlating this with cytology results. This study was carried out among women attending the Reproductive Health Clinic at Kenyatta National Hospital, a referral hospital in Nairobi, Kenya. A cross-sectional study recruited a total of 217 women aged 18 to 50 years. Paired blood and cervical samples were obtained from consenting participants. Blood was used for serological HIV screening while cervical smears were used for cytology followed by HPV DNA extraction, HPV DNA PCR amplification, and phylogenetic analysis. Out of 217 participants, 29 (13.4%) were HIV seropositive, while 68 (31.3%) were positive for HPV DNA. Eight (3.7%) of the participants had abnormal cervical cytology. High-risk HPV 16 was the most prevalent followed by HPV 81, 73, 35, and 52. One participant had cervical cancer, was HIV infected, and had multiple high-risk infections with HPV 26, 35, and 58. HPV 16, 6, and 81 had two variants each. HPV 16 in this study clustered with HPV from Iran and Africa. This study shows the circulation of other HPV 35, 52, 73, 81, 31, 51, 45, 58, and 26 in the Kenyan population that play important roles in cancer etiology but are not included in the HPV vaccine. Data from this study could inform vaccination strategies. Additionally, this data will be useful in future epidemiological studies of HPV in Nairobi as the introduction or development of new variants can be detected., Competing Interests: The authors declare that there is no conflict of interest regarding the publication of this paper., (Copyright © 2020 Agnes Omire et al.)