Persistent Human Papillomavirus Research Articles

Human papillomavirus, vaginal microbiota and metagenomics: the interplay between development and progression of cervical cancer

Persistent infection with oncogenic human papillomavirus (HPV) types, such as HPV 16 or 18, is a major factor in cervical cancer development. However, only a small percentage of infected women develop cancer, indicating that other factors are involved. Emerging evidence links vaginal microbiota with HPV persistence and cancer progression. Alterations in microbial composition, function, and metabolic pathways may contribute to this process. Despite the potential of metagenomics to explore these interactions, studies on the vaginal microbiota’s role in cervical cancer are limited. This review systematically examines the relationship between cervical microbiota, HPV, and cervical cancer by analyzing studies from PubMed, EBSCO, and Scopus. We highlight how microbial diversity influences HPV persistence and cancer progression, noting that healthy women typically have lower microbiota diversity and higher Lactobacillus abundance compared to HPV-infected women, who exhibit increased Gardenella, Prevotella, Sneathia, Megasphaera, Streptococcus, and Fusobacterium spp., associated with dysbiosis. We discuss how microbial diversity is associated with HPV persistence and cancer progression, noting that studies suggest healthy women typically have lower microbiota diversity and higher Lactobacillus abundance, while HPV-infected women exhibit increased Gardnerella, Prevotella, Sneathia, Megasphaera, Streptococcus, and Fusobacterium spp., indicative of dysbiosis. Potential markers such as Gardnerella and Prevotella have been identified as potential microbiome biomarkers associated with HPV infection and cervical cancer progression. The review also discusses microbiome-related gene expression changes in cervical cancer patients. However, further research is needed to validate these findings and explore additional microbiome alterations in cancer progression.

Impact of Hormonal Contraceptives on HPV Dynamics in Adolescent Girls and Young Women: Insights from a Randomized Controlled Sub-Study in South Africa.

Human papillomavirus (HPV) is the leading cause of cervical cancer, with adolescent girls and young women (AGYW) in sub-Saharan Africa carrying a disproportionately high burden of infection. Hormonal contraceptives may influence HPV acquisition, persistence, and clearance, but evidence remains inconclusive. This sub-study aimed to evaluate the impact of different hormonal contraceptives on HPV prevalence and genotype distribution in AGYW. Ninety-eight HIV-seronegative AGYW aged 15-19 years from South Africa were randomized to receive one of three hormonal contraceptive methods: norethisterone enanthate (Net-EN) injectable, combined oral contraceptive pills (COCPs), or the etonorgesterol/ethinyl estradiol combined contraceptive vaginal ring (CCVR). Cervical DNA samples were collected at baseline and after 16 weeks for HPV genotyping using the HPV Direct Flow Chip test. HPV prevalence, persistence, clearance, and acquisition were analyzed across contraceptive methods. At baseline, HPV prevalence was high (94.9%), with no differences among contraceptive arms. After 16 weeks, HPV prevalence remained high (89.5%) across groups. No significant differences were observed in overall HPV prevalence or genotype distribution by contraceptive method. Longitudinal analysis revealed that AGYW using Net-EN tended to have a higher cumulative number of high-risk HPV (HR-HPV) genotypes that cleared whereas those using CCVR acquired more HR-HPV types and had greater HR-HPV persistence compared to other groups. This study highlights the high burden of HPV among South African AGYW. However, different hormonal contraceptive methods did not significantly influence HR-HPV dynamics.

Decoding impact of human papillomavirus in gynecological oncology: a narrative review.

Human papillomavirus (HPV) is a key factor in gynecological oncology. This narrative review investigates the complex connection between HPV and various gynecological cancers. For a comprehensive exploration, we examined the association between persistent HPV infection and cervical cancer and its global prevalence. Beyond the cervix, we navigated the linkages between HPV and other gynecological malignancies, shedding light on vulvar, vaginal, anal, and oropharyngeal cancers. The narrative extends to discuss the critical role of HPV vaccination in preventing these cancers and exploring challenges, controversies, and future perspectives in the field. As we have described the impact of HPV, this review underscores the significance of ongoing research and public health endeavors in shaping the trajectory of gynecological oncology.

Persistence of HPV in cervical smears of vaccinated WLWH support for combined molecular testing and cytology screening

Background Human papillomavirus (HPV) infection profoundly affects women living with HIV (WLWH). This infection leads to cervical cancer (CC) and increased mortality. Methods This study monitored HPV infection in WLWH in Rio de Janeiro, Brazil, before (T1) and after (T2) 4 years of vaccination. HPV genotyping and the presence of intraepithelial lesions were investigated at both time points. Results Among the 156 WLWH who received the quadrivalent HPV vaccine (4vHPV) at T1, 30 (19.2%) were initially found to have HPV DNA. After vaccination, only three (7%) of those who were HPV-negative at T1 tested positive for HPV. Most women who tested positive for HPV DNA at T1 had normal Pap smear results. However, this cohort also demonstrated a significant increase in cases of atypical squamous cells of uncertain significance and cervical intraepithelial neoplasia in PCR-negative HPV DNA samples at T2 ( p < .01). Conversely, women who initially tested negative for HPV DNA continued to exhibit normal Pap smear results in 2018 ( p < .01). Conclusions This study highlights the persistence of HPV in WLWH despite vaccination and underscores the importance of continued molecular and cytologic screening. The findings enhance our understanding of vaccine effectiveness in this population and emphasize the need for tailored preventive strategies.

Risk factors for the onset of cervical intraepithelial neoplasia

BACKGROUND: Persistent human papillomavirus (HPV) infection is a well-established cause of cervical intraepithelial neoplasia (CIN). Epidemiological studies show that while HPV infection is common, it is far more prevalent than CIN itself. Consequently, HPV testing exhibits moderate specificity and positive predictive value for detecting high-grade CIN. Currently, there is no optimal strategy for identifying HPV-positive women at high risk of CIN. AIM: This study aims to assess the socioeconomic, behavioral, and comorbidity factors associated with an increased risk of developing cervical intraepithelial neoplasia. MATERIAL AND METHODS: The study included 121 women who presented to the Medical Research and Education Center of Moscow State University in the period from 2022 to 2023. Pap-smear revealed normal data in 66 women (Group 1, NILM), mild cervical intraepithelial neoplasia in 27 (Group 2, LSIL), and severe cervical intraepithelial neoplasia in 28 (Group 3, HSIL). A comparative analysis of clinical data and medical history, data of liquid cytology and HPV typing was performed in all patients. Statistical analysis was performed using the MedCalc software package. RESULTS: The analysis showed that the risk of severe cervical intraepithelial neoplasia increased 5.4-fold in patients aged 30 years, 3.4-fold in smokers, 9.9-fold in patients who had been sexually active for more than 10 years, 6.3-fold in patients who had ≥4 sexual partners, 4.1-fold in patients who used withdrawal method of contraception (coitus interruptus), 7.0-fold in patients who had ≥3 pregnancies, 4.7-fold in patients with HPV infection (in particular, 4.3-fold in women infected with HPV 16). Patients with cervical intraepithelial neoplasia had significantly greater probability to be infected with high-risk HPV types (88.9% in patients with LSIL and 85.7% in patients with HSIL vs. 56.1% in NILM women), in particular, HPV 16 was detected in more than half of patients with HSIL. CONCLUSION: In this study sample, the risk of cervical intraepithelial neoplasia was associated with age over 30 years, smoking, duration of the sexual activity 10 years, number of sexual partners (4), lack of barrier contraception, number of past pregnancies (3), and persisting high-risk HPV infection, especially HPV 16.

Mapping the HPV Landscape in South African Women: A Systematic Review and Meta-Analysis of Viral Genotypes, Microbiota, and Immune Signals

This systematic review and meta-analysis evaluate human papillomavirus (HPV) prevalence, genotype distribution, and associations with cervicovaginal microbiota and cytokine profiles among South African women, where cervical cancer ranks as the second most common cancer. PubMed, SCOPUS, and Web of Science were searched for studies on HPV infection up to 21 September 2024. The pooled prevalence was estimated using a random-effects model, with subgroup analyses by province, sample type, and HIV status. Publication bias was evaluated using funnel plots and Egger’s test. Of the 19,765 studies screened, 120 met the inclusion criteria, comprising 83,266 participants. Results indicate a high HPV burden, with a pooled prevalence of 58% (95% CI: 52–64%), varying regionally from 53% (95% CI: 41–65%) to 64% (95% CI: 55–73%), with some regions under-researched. Cervical samples had the highest HPV prevalence (60% (95% CI: 54–66%)), while non-genital samples were less studied. High-risk (HR) HPV types, notably HPV 16 (7.5%), HPV 35 (4.1%), and HPV 18 (3.9%), were prominent, with HPV 35 emphasizing the need for expanded vaccine coverage. HIV-positive women had a higher pooled HPV prevalence (63% (95% CI: 55–71%)). Funnel plot analysis and Egger’s test suggested a potential publication bias (p = 0.047). HPV-positive women exhibited lower Lactobacillus levels and an increase in Bacterial Vaginosis (BV)-associated species like Gardnerella, potentially supporting HPV persistence. Cytokine analysis showed elevated MIP-1α and MIP-1β in HPV infections, though cytokine profiles may depend on HPV genotypes. These findings underscore the need for research on HPV–microbiome-immune interactions and call for comprehensive HPV-prevention strategies, including vaccines targeting regional HPV types and tailored interventions for HIV-positive populations.

An exploration of the natural and acquired immunological mechanisms to high-risk human papillomavirus infection and unmasking immune escape in cervical cancer: A concise synopsis.

The most common STD that triggers cervical cancer is the human papillomavirus. More than 20 types of human papillomavirus (HPV) can induce uterine cervical cancer. Almost all women acquire genital HPV infection soon after their first intercourse, with most of them clearing the virus within 3 years. An immune response is necessary to clear. The first responders to HPV infection are the innate immune system elements composed of macrophages, keratinocytes, natural killer cells, and natural killer T-lymphocytic (NKT) cells. Cytotoxic T lymphocytes (CTLs) comprise the second line of defense and kill HPV16-infected cells expressing various peptides derived from their transforming early viral oncoproteins, mainly E2•E6. Even though HPV can manage to trick away our immune systems, first of all, it is important to emphasize that HPV replication does not kill the host cells. It does not replicate viral antigens or cause inflammation. The HPV16 E6 and E7 genes suppress host cell type 1 interferons (IFNs), which are detectable after infection. The patient may have immunological tolerance; hence, there are no costimulatory signals from inflammatory cytokines like IFNs during antigen recognition. Evidence shows that HlA class I generations have been inhibited by HPV16 E5, which could protect this tumor cell from CTL attack. HPV16 E7 is responsible for initiating immunotolerance and increasing regulatory T cells (Treg) to repress immunological regression. Evasion from immune system protection plays a critical role in the outcome of persistent HPV infection and the development of cervical cancer. Vaccination against HPV16 and 18 during adolescence is the most effective method for preventing cervical cancer in women, considering the immunological processes involved.

Genome-Wide Association Study of Persistent Anal Human Papillomavirus Infection Among HIV-Positive Males in Taizhou, China: A Cohort Study.

The determinants of persistent human papillomavirus (HPV) infection remain largely unknown, and existing studies have predominantly focused on the female population. Individual genetic background may influence the persistence of HPV infection, we the evidence overall and among human immunodeficiency virus (HIV)-positive males are very limited. We conducted a genome-wide association study (GWAS) to identify single nucleotide polymorphisms (SNPs) associated with anal HPV persistence, based on a cohort designed to study the natural history of anal HPV infection among HIV-positive males in Taizhou, China from 2016 to 2022. A total of 322 HIV-positive males with anal HPV infection, with a mean age of 43.0 (standard deviation [SD]: 13.8) years, were included in this GWAS. The median follow-up time was 1.8 (interquartile range [IQR]: 1.5-2.0) years. The persistence of any type of HPV infection was 53.4%. After adjusting for age and sexual orientation, there were 2 SNPs with p < 1 × 10-5 and 24 SNPs with p < 1 × 10-4. The most closely associated with HPV persistence in additive models were rs7359031 (LOC105370461, odds ratio [OR]T/C = 0.36, 95% confidence interval [CI]: 0.24-0.56; p = 6.67 × 10-6) located at 14q21.1, and rs11046048 (PYROXD1, ORC/A = 0.41, 95% CI: 0.28-0.60; p = 7.80 × 10-6) located at 12p12.1. Other SNPs were mainly located at 6q23.3 (HBS1L-MYB) and 6p21.33 (CCHCR1, PSORS1C3). LOC105370461, PYROXD1, HBS1L-MYB, CCHCR1, and PSORS1C3 may be susceptible genes for HPV persistence. We appeal further studies to validate these associations and examine the underlying mechanisms.

Fibroblasts regulate the transcriptional signature of human papillomavirus-positive keratinocytes.

Persistent human papillomavirus (HPV) infection is necessary but insufficient for viral oncogenesis. Additional contributing co-factors, such as immune evasion and viral integration have been implicated in HPV-induced cancer progression. It is widely accepted that HPV+keratinocytes require co-culture with fibroblasts to maintain viral DNA as episomes. How fibroblasts regulate viral episome maintenance is a critical knowledge gap. Here we present comprehensive RNA sequencing and proteomic analysis demonstrating that coculture with fibroblasts is supportive of the viral life cycle, and is confirmatory of previous observations. Novel observations suggest that errors in "cross-talk" between fibroblasts and infected keratinocytes may regulate HPV integration and drive oncogenic progression. Our co-culture models offer new insights into HPV-related transformation mechanisms.

Differential study on the relationship between HPV infection and vaginal microbiota composition in Uygur and Han women

ObjectiveTo analysis the differential composition in vaginal microbial communities following HPV infection in Uygur and Han women, and to Explore the correlation between these difference and the degree of Human Papillomavirus (HPV) infection in Uygur women compared to Han women. MethodsA total of 151 Uygur and Han women, with and without HPV, were studied at Xinjiang Uygur Autonomous Region People's Hospital (June 2021–June 2022). These participants were divided into six groups: Uygur control (CV), Uygur transient infection (TPV), Uygur persistent infection (PPV), Han control (CH), Han transient infection (TPH), Han persistent infection (PPH). Vaginal microbiota diversity and dominant bacteria with or without HPV infection were compared using 16S rDNA sequencing. ResultsAfter HPV infection, vaginal pH increased significantly in Uygur and Han women. Vaginal environment cleanliness decreased notably only in Han women (P < 0.05). In Han women, Lactobacillus and Gardnerella dominated both with or without HPV infection. Prevotella, Streptococcus, and Atopobium decreased, while Sneathia increased significantly in persistent HPV cases. Among Uygur women, Gardnerella, Streptococcus, Prevotella, and Shuttleworthia increased significantly in the TPV group, with lower Lactobacillus compared to CV and PPV groups. Bacterial diversity indices (Chao1, Shannon, Simpson) were significantly lower in TPH compared to CH (P < 0.05), with no significant difference in PPH compared to CH (P > 0.05). Chao1 index was significantly lower in TPH than TPV (P < 0.05), with no difference between PPH and PPV (P > 0.05). CV group's Chao1 index was significantly lower than CH (P < 0.01). PCoA and NMDS analyses showed distinct vaginal microbiota between TPH and TPV groups. LEfSe identified 20 differentially expressed taxa in CH-TPH-PPH comparison and 17 in CV-TPV-PPV. ConclusionOur study reveals ethnic-specific differences in vaginal microbial responses to HPV infection, with notable alterations in diversity and composition. The differential patterns observed between Uygur and Han women underscore the importance of considering host ethnicity in HPV-related microbial dysbiosis, emphasizing the need for tailored interventions targeting microbial signatures to enhance HPV prevention and management strategies.

Human umbilical cord mesenchymal stem cells small extracellular vesicles-derived miR-370-3p inhibits cervical precancerous lesions by targeting DHCR24

Abstract Background Cervical cancer is often caused by persistent high-risk human papillomavirus (HPV) infection, causing precancerous lesions. Human umbilical cord mesenchymal stem cells-derived small extracellular vesicles (hucMSC-sEV) exhibit diverse effects on tumors. This study investigates hucMSC-sEV, the impact and mechanisms on HPV-positive cervical precancerous lesion cells to provide new treatment insights. Materials and Methods We previously obtained hucMSC and hucMSC-sEV. In vitro experiments evaluated hucMSC-sEV effects on the proliferation and migration of S12 cells (derived from cervical precancerous lesions). Bioinformatics identified key microRNA components, and their impact on S12 cell proliferation and migration was investigated. The target gene of the microRNA component was predicted and confirmed via bioinformatics and dual-luciferase reporter assays. Lentiviral systems overexpressed target gene in S12 cells to examine the effects on microRNA impacts. SH-42 inhibitor was used to investigate target gene treatment potential. Immunohistochemistry assessed target gene expression in cervical precancerous lesions tissue. Results hucMSC-sEV significantly inhibited S12 cell proliferation and migration. Bioinformatics identified miR-370-3p as an effective cargo, which also suppressed S12 cell proliferation and migration. miR-370-3p was confirmed targeting DHCR24 (24-Dehydrocholesterol Reductase). DHCR24 overexpression reversed miR-370-3p’s inhibitory effects, while SH-42 counteracted DHCR24 overexpression’s promoting effects. Clinical specimen analysis supported these findings, demonstrating a positive correlation between DHCR24 protein expression and cervical precancerous lesions’ progression. Conclusions hucMSC-sEV inhibits S12 cell proliferation and migration, mediated by miR-370-3p targeting DHCR24 to regulate cellular cholesterol content. DHCR24 inhibition reduces the cholesterol level and cell functions, suggesting its potential as a therapeutic target in cervical precancerous lesions.

Abstract PR003: Preventing and treating HPV-related Cancer with mRNA Therapy Expressing A DC-targeting Antigen

Abstract Persistent human papillomavirus (HPV) infection is linked to several malignancies, highlighting the need for effective therapeutic vaccines. In this study, we tested a lipid nanoparticle-encapsulated mRNA vaccine expressing tHA-mE7-mE6. By mutating the E6 and E7 proteins to reduce their tumorigenicity and fusing them with a truncated influenza hemagglutinin protein (tHA) for better antigen uptake, we improved the vaccine’s efficacy. The tHA-mE7-mE6 mRNA vaccine showed superior results compared to mE7-mE6 mRNA, achieving complete tumor regression and preventing new tumors in an E6 and E7 positive model. It elicited a strong CD8+ T-cell response, with antigen-specific CD8+ T-cells found in the spleen, blood, and tumors. Additionally, the therapy increased DC and NK cell infiltration into tumors. Overall, this study demonstrates that the tHA-mE7-mE6 mRNA vaccine induces a potent anti-tumor immune response, showing promise for treating HPV-induced cancers and preventing recurrence. Citation Format: William Jia. Preventing and treating HPV-related Cancer with mRNA Therapy Expressing A DC-targeting Antigen [abstract]. In: Proceedings of the AACR Special Conference in Cancer Research: RNAs as Drivers, Targets, and Therapeutics in Cancer; 2024 Nov 14-17; Bellevue, Washington. Philadelphia (PA): AACR; Mol Cancer Ther 2024;23(11_Suppl):Abstract nr PR003.

Quadrivalent HPV (4vHPV) vaccine immunogenicity and safety in women using immunosuppressive drugs due to solid organ transplant.

Immunocompromised persons are at high risk of persistent Human Papilloma Virus (HPV) infection and associated diseases. Few studies evaluated HPV vaccines in immunocompromised persons. This study aimed to evaluate the quadrivalent HPV vaccine (4vHPV) immunogenicity and safety in solid organ transplant (SOT) recipients, in comparison to immunocompetent women (IC). Open-label clinical trial that enrolled SOT recipients and immunocompetent women aged 18 to 45 years. All participants received three doses of 4vHPV vaccine. Blood samples were drawn for evaluation of immune responses at baseline and one month after the third vaccination. Seroconversion rates and antibody geometric mean concentration (GMC) against HPV 6, 11, 16, 18, 31, 35, 52 and 58 were measured with in-house multiplexed serology assay (xMAP technology). Follow-up for the local and systemic adverse events (AEs) continued for seven days after each vaccination. Severe AEs were evaluated throughout the study. 125 SOT and 132 immunocompetent women were enrolled; 105 (84%) SOT and 119 (90%) immunocompetent women completed the study. At baseline, HPV seropositivity was not significantly different between groups. Seroconversion rates were significantly lower in SOT (HPV18, 57%; HPV6 and 16, 69%; and HPV11, 72%) than in immunocompetent women (100% seroconversion to all vaccine types) (p<0.001). Antibody GMCs of all four HPV vaccine types were also significantly lower in SOT (p<0.001). Pain in the injection site and headache were the most frequent adverse event in both groups. Local pain was more frequent in immunocompetent women than in SOT recipients. Rates of other AEs were comparable in both groups. 4vHPV vaccine was well-tolerated by SOT recipients. We found strong evidence of lower humoral immune responses to 4vHPV vaccine in SOT compared to immunocompetent women, which strengthen recommendation of routine cervical cancer screening in SOT recipients regardless of HPV vaccination status.

A Narrative Review of the Putative Etiologic Role and Diagnostic Utility of the Cervicovaginal Microbiome in Human Papillomavirus-Associated Cervical Carcinogenesis.

The cervicovaginal microbiome (CVM) may contribute to human papillomavirus (HPV)-associated cervical carcinogenesis. We summarized the literature on the CVM in cervical carcinogenesis by searching Medline, Web of Science, and Embase for articles that sequenced the CVM using metagenomics. Additionally, we identified studies assessing the diagnostic role of the CVM in cervical carcinogenesis by searching PubMed. We performed an environmental scan of Google and Google Scholar to review common CVM characterization techniques. Twenty-eight records presented or summarized associations between the CVM and HPV acquisition, prevalence, persistence, clearance, and cervical lesions or cancer, while three studies identified bacterial taxa detecting high-risk HPV prevalence or cervical lesions. The area under the curve ranged from 0.802 to 0.952. 16S ribosomal RNA gene sequencing and whole metagenome sequencing have sufficient resolution to study the CVM bacteriome. Bacterial communities may have important implications in cervical cancer; however, there is a need for methodological standardization for CVM characterization.

A prospective cohort study comparing efficacy of 1 dose of quadrivalent human papillomavirus vaccine to 2 and 3 doses at an average follow up of 12 years postvaccination.

While recommending a human papillomavirus (HPV) single-dose vaccination schedule in 2022, the World Health Organization highlighted the need for long-term follow-up studies to monitor waning of protection. We report on vaccine efficacy against HPV infections in 1-, 2-, and 3-dose schedules and protection against cervical precancers at a median follow-up of 12 years postvaccination. This randomized multicenter study in India was originally designed to vaccinate unmarried girls aged 10-18 years with either 2 or 3 doses of quadrivalent HPV vaccine. A ministerial decree to halt vaccination in trials resulted in the creation of cohorts receiving different doses, including just a single dose. Cohorts were assessed for incident and persistent infections by genotyping cervical samples collected yearly for 4 consecutive years after participants were married. Cervical screening with an HPV test was initiated at age 25 years for married participants. Age- and site-matched unvaccinated married women were recruited to be compared with vaccinated cohorts. Vaccine efficacy was assessed using proportional incidence ratios. The number of participants in the 1-, 2- (at 0 and 6 months), and 3-dose cohorts was 4949, 4980, and 4348, respectively. Of the recipients, 71%-82% in the different cohorts were eligible to provide samples for genotyping. Vaccine efficacy against persistent HPV 16 and 18 infection was 92.0% (95% confidence interval [CI] = 87.0% to 95.0%) in 3022 recipients of the single dose; and comparable with that observed in the 2-dose arm (94.8%, 95% CI = 90.0% to 97.3%) and the 3-dose arm (95.3%, 95% CI = 90.9% to 97.5%). No high-grade precancer associated with HPV 16 and 18 was detected among vaccinated participants compared with 8 precancers detected among the unvaccinated women. This observational cohort study has established that a single dose of HPV vaccine provides high protective efficacy against persistent HPV 16 and 18 infections and associated neoplasia 15 years postvaccination.

Long-Term Infection With a Particular Human Papillomavirus (HPV) Genotype, HPV Subtype, or HPV Genomic Variant Does not Significantly Influence the Clinical Course of Recurrent Respiratory Papillomatosis.

Recurrent respiratory papillomatosis (RRP) is caused by human papillomaviruses (HPV) 6 and 11, but the role of their genomic variants in the disease's clinical course is unclear. This study investigated whether long-term persistence of a particular HPV genotype, subtype or genomic variant influences the RRP clinical course. HPV genotyping was performed in paired baseline and follow-up RRP laryngeal tissue specimens of 59 patients. HPV6 and HPV11 genomic variants were determined in paired tissue specimens taken at least 10 years apart in 20 selected patients. HPV was identified in 58/59 patients, most commonly HPV6 (40/58), followed by HPV11 (17/58). The most prevalent HPV genomic variant was HPV11 A2. HPV6 A and HPV6 B1 were most frequent in aggressive RRP. In all patients, identical HPV genomic variants were identified in both paired specimens. RRP results from a long-term infection with the same HPV genomic variant that can be identified decades after disease onset. We report the longest duration of genetically confirmed persistent HPV infection in peer-reviewed literature, during a 44-year interval in a patient with HPB6 B1. This study suggests that infection with a particular HPV genotype, subtype, or genomic variant does not significantly influence the clinical course of RRP.

Modulation of epithelial homeostasis by HPV using Notch and Wnt

Highly conserved signalling pathways such as Notch and Wnt are essential in the regulation of differentiation and proliferation processes during adult tissue homeostasis. Human papillomaviruses (HPVs) have evolved with humans to manipulate these signalling pathways to establish a basal reservoir of infected cells by limiting HPV-infected keratinocyte differentiation whilst ensuring that differentiating cells are in a replication-competent state. Here, we focus on the canonical Notch and Wnt signalling pathways and their crosstalk to ensure cell-fate lineage determination during epithelial homeostasis. We then examine how HPVs use their E6 and E7 proteins to inhibit differentiation and maintain stem-like characteristics using Notch and Wnt in HPV-infected cells. Determining the functions of E6 and E7 in the maintenance of the infected cell reservoir, and the molecular crosstalk between Notch and Wnt is vital for our understanding of HPV persistence, and may represent an important factor in the development of therapeutic agents for HPV-associated disease.

Prospectives of developing therapeutic HPV vaccines

Human papillomavirus (HPV) represents one of the most serious global public health problems. Malignant female and male diseases mainly result from persistent HPV infection. Cancer belongs to a high mortality rate disease. It has been established that HPV infection causes about 70% vaginal cancer, 50% male genital cancer, 90% anal cancer and 60% head-and-neck cancer. Annually, a large number of people develop various HPV-caused cancer types, dominated by cervical cancer, one of the most common and aggressive types of cancer that threatens health holding the fourth place among most female common cancer worldwide. According to the World Health Organization (WHO), in 2020, about 600 cases of cervical cancer are recorded daily in different countries. Emergence of cervical cancer is closely related to factors such as long-term (persistent) HPV infection and somatic mutations of the host genome. Although HPV infection can be detected and cured early with highly effective screening methods and surgical procedures, the carcinogenic risk of HPV related diseases constantly increases, which elimination faces certain difficulties, especially in low- and mid-developed countries. The most acceptable solution to this is development and implementation of therapeutic vaccines for prevention and treatment of HPV related diseases. Three licensed HPV vaccines based on L1 type virus-like particles (L1-VLPs) technology are available globally: bivalent (HPV-2), quadrivalent (HPV-4) and nonavalent (HPV-9) vaccines. These vaccines demonstrated effectiveness in reducing HPV-related cervical cancer rate by up to 90% worldwide. However, the therapeutic effect of these vaccines on persistent HPV infection and lesions has not been observed. Therapeutic HPV vaccines candidates targeted Ye6/Ye7 cancer proteins activate cellular immunity that eliminates existing HPV infection. Here we review types, mechanisms of action and clinical effects of therapeutic HPV vaccines, as well as current and future developments in the field for prevention and treatment of HPV related diseases.

HPV Vaccines

Human papillomavirus (HPV) is a double-stranded DNA virus and a source of infection that primarily affects the skin and mucous membranes. It can be transmitted through sexual contact and contaminated surfaces. There are over 200 genotypes of HPV, approximately 40 of which infect the anogenital region. High-risk HPV types, such as HPV-16 and HPV-18, can lead to the development of various cancers, particularly cervical cancer. Factors that increase the risk of transmission include having multiple sexual partners, early initiation of sexual activity, and having an uncircumcised male partner. Low socioeconomic status, poor nutrition, immunosuppression, and co-infections with HIV, genital herpes, or chlamydia can result in persistent and severe HPV infection. Three types of vaccines have been developed against HPV: bivalent, quadrivalent, and nonavalent vaccines. The bivalent vaccine provides protection against HPV-16 and HPV-18; the quadrivalent vaccine is effective against HPV-16, HPV-18, as well as HPV-6 and HPV-11. The nonavalent vaccine offers the broadest protection, covering nine different types of HPV. All vaccines are approved for males and females aged 9 and older. Vaccination before the onset of sexual activity significantly increases protection against cervical cancer.

Design and antiviral assessment of a panel of fusion proteins targeting human papillomavirus type 16.

Cervical cancer ranks as the third most prevalent malignancy in women worldwide. The persistence of Human papillomavirus (HPV) infection stands out as the foremost risk factor for cervical cancer development. Among the numerous HPV subtypes, HPV16 infection emerges as the primary pathogenic determinant of cervical cancer. To date, no specific drugs have been approved. In this study, we engineered two high-affinity fusion protein targeting HPV16 L1 protein based on the alpaca-derived single-domain antibody 2C12 previously obtained in our laboratory. These two fusion proteins exhibited potent neutralizing activity against HPV16 pseudovirus with IC50 values of 7.8 nM and 6.5 nM, respectively. Molecular docking analysis revealed that 2C12 formed ten pairs of hydrogen bonds with HPV16 L1, among which Arg39 and Thr100 established multiple pairs of hydrogen bonds with HPV16 L1, indicating their crucial roles in antigen-antibody binding process. These structural and biological findings underscore the effective binding capacity of these fusion proteins to HPV16, leading to reduced viral load and providing valuable insights into therapeutic antibody and vaccine development against HPV 16 infection.