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

Despite preventive vaccines for oncogenic human papillomaviruses (HPVs), cervical intraepithelial neoplasia (CIN) is common, and current treatments are ablative and can lead to long-term reproductive morbidity. We assessed whether VGX-3100, synthetic plasmids targeting HPV-16 and HPV-18 E6 and E7 proteins, delivered by electroporation, would cause histopathological regression in women with CIN2/3. Efficacy, safety, and immunogenicity of VGX-3100 were assessed in CIN2/3 associated with HPV-16 and HPV-18, in a randomised, double-blind, placebo-controlled phase 2b study. Patients from 36 academic and private gynaecology practices in seven countries were randomised (3:1) to receive 6 mg VGX-3100 or placebo (1 mL), given intramuscularly at 0, 4, and 12 weeks. Randomisation was stratified by age (<25 vs ≥25 years) and CIN2 versus CIN3 by computer-generated allocation sequence (block size 4). Funder and site personnel, participants, and pathologists were masked to treatment. The primary efficacy endpoint was regression to CIN1 or normal pathology 36 weeks after the first dose. Per-protocol and modified intention-to-treat analyses were based on patients receiving three doses without protocol violations, and on patients receiving at least one dose, respectively. The safety population included all patients who received at least one dose. The trial is registered at ClinicalTrials.gov (number NCT01304524) and EudraCT (number 2012-001334-33). Between Oct 19, 2011, and July 30, 2013, 167 patients received either VGX-3100 (n=125) or placebo (n=42). In the per-protocol analysis 53 (49·5%) of 107 VGX-3100 recipients and 11 (30·6%) of 36 placebo recipients had histopathological regression (percentage point difference 19·0 [95% CI 1·4–36·6]; p=0·034). In the modified intention-to-treat analysis 55 (48·2%) of 114 VGX-3100 recipients and 12 (30·0%) of 40 placebo recipients had histopathological regression (percentage point difference 18·2 [95% CI 1·3–34·4]; p=0·034). Injection-site reactions occurred in most patients, but only erythema was significantly more common in the VGX-3100 group (98/125, 78·4%) than in the placebo group (24/42, 57·1%; percentage point difference 21·3 [95% CI 5·3–37·8]; p=0·007). VGX-3100 is the first therapeutic vaccine to show efficacy against CIN2/3 associated with HPV-16 and HPV-18. VGX-3100 could present a non-surgical therapeutic option for CIN2/3, changing the treatment outlook for this common disease. Inovio Pharmaceuticals.

Background Currently, the role of human papillomavirus (HPV)-58 in southwestern China has been unexplored. Although there is some controversy, it is proposed that the viral load of HPV correlates with the severity of intraepithelial lesions. Methods We identified 7747 patients from south Sichuan and adjacent regions who were diagnosed with HPV between 2013 and 2017. The HR-HPV subtype distribution was analyzed and the patient’s viral loads were quantified using real-time RT-PCR. Results Among all 7747 patients screened for HPV genotypes, 1728 patients (22.31%) were identified as having HR-HPV subtypes. In patients without intraepithelial lesions (12.41%), HPV-52, HPV-16, and HPV-58 were the three most prevalent HR-HPV subtypes. Moreover, HPV-16, HPV-58, and HPV-33 were the most prevalent subtypes in patients with cervical intraepithelial neoplasia grade II (CINII) (42.86%) and grade III (CINIII) (59.81%), and accounted for the majority of invasive cervical cancer (ICC) (69.34%). Thus, viral loads of HPV-58, HPV-16, and HPV-33 positively correlated with the severity of cervical lesions ( P  < 0.001, P  = 0.016, P  = 0.026, respectively). Using receiver operating characteristic (ROC) curve analysis, the optimum thresholds for predicting severe intraepithelial lesions of cases (CINI, CINIII and ICC) with HPV-16, HPV-58, and HPV-33, respectively, were obtained, which were 1, 0.93, and 0.25, respectively. Conclusion In our study, we showed that HPV-16 was the most common carcinogenic HPV subtype in southwestern China followed by HPV-58 and HPV-33. Viral loads of these subtypes are associated with the severity of premalignant lesions in the cervix.

Background: Human papillomavirus (HPV) is a causal factor in virtually all cervical and a subset of oropharyngeal squamous cell carcinoma (OP-SCC), whereas its role in laryngeal squamous cell carcinoma (L-SCC) is unclear. Methods: Formalin-fixed paraffin-embedded ( N =154) and deep-frozen tissues ( N =55) of 102 L-SCC patients were analysed for the presence of 51 mucosal HPV types. HPV DNA-positive (HPV DNA+) cases were analysed for E6*I mRNA transcripts of all high risk (HR)/probably/possibly (p)HR-HPV identified, and for HPV type 16 (HPV16) viral load. Expression of p16 INK4a , pRb, cyclin D1 and p53 was analysed by immunohistochemistry. Results: Ninety-two patients were valid in DNA analysis, of which 32 (35%) had at least one HPV DNA+ sample. Among the 29 single infections, 22 (76%) were HPV16, 2 (7%) HPV56 and 1 each (4%) HPV45, HPV53, HPV70, HPV11 and HPV42. Three cases harboured HPV16 with HPV33 (twice) or HPV45. Only 32% of HPV DNA+ findings were reproducible. Among HPV16 DNA+ L-SCC, 2 out of 23 (9%) had high viral loads, 5 out of 25 (21%) expressed E6*I mRNA and 3 out of 21 (14%) showed high p16 INK4a and low pRb expression (all three HPV16 RNA-positive), immunohistochemical marker combination not identified in any other HPV DNA+ or HPV DNA-negative (HPV DNA−) L-SCC, respectively. Conclusion: HPV type 16 has a causative role in a small subgroup of L-SCC (<5% in this German hospital series).

A randomised trial designed to compare three and two doses of quadrivalent human papillomavirus (HPV) vaccine in adolescent girls in India was converted to a cohort study after suspension of HPV vaccination in trials by the Indian Government. In this Article, the revised aim of the cohort study was to compare vaccine efficacy of single dose to that of three and two doses in protecting against persistent HPV 16 and 18 infection at 10 years post vaccination. In the randomised trial, unmarried girls aged 10–18 years were recruited from nine centres across India and randomly assigned to either two doses or three doses of the quadrivalent HPV vaccine (Gardasil [Merck Sharp & Dohme, Whitehouse Station, NJ, USA]; 0·5 mL administered intramuscularly). After suspension of recruitment and vaccination, the study became a longitudinal, prospective cohort study by default, and participants were allocated to four cohorts on the basis of the number vaccine doses received per protocol: the two-dose cohort (received vaccine on days 1 and 180 or later), three-dose cohort (days 1, 60, and 180 or later), two-dose default cohort (days 1 and 60 or later), and the single-dose default cohort. Participants were followed up yearly. Cervical specimens were collected from participants 18 months after marriage or 6 months after first childbirth, whichever was earlier, to assess incident and persistent HPV infections. Married participants were screened for cervical cancer as they reached 25 years of age. Unvaccinated women age-matched to the married vaccinated participants were recruited to serve as controls. Vaccine efficacy against persistent HPV 16 and 18 infections (the primary endpoint) was analysed for single-dose recipients and compared with that in two-dose and three-dose recipients after adjusting for imbalance in the distribution of potential confounders between the unvaccinated and vaccinated cohorts. This trial is registered with ISRCTN, ISRCTN98283094, and ClinicalTrials.gov, NCT00923702. Vaccinated participants were recruited between Sept 1, 2009, and April 8, 2010 (date of vaccination suspension), and followed up over a median duration of 9·0 years (IQR 8·2–9·6). 4348 participants had three doses, 4980 had two doses (0 and 6 months), and 4949 had a single dose. Vaccine efficacy against persistent HPV 16 and 18 infection among participants evaluable for the endpoint was 95·4% (95% CI 85·0–99·9) in the single-dose default cohort (2135 women assessed), 93·1% (77·3–99·8) in the two-dose cohort (1452 women assessed), and 93·3% (77·5–99·7) in three-dose recipients (1460 women assessed). A single dose of HPV vaccine provides similar protection against persistent infection from HPV 16 and 18, the genotypes responsible for nearly 70% of cervical cancers, to that provided by two or three doses. Bill & Melinda Gates Foundation.

Background: The HPV16 E2 gene plays a crucial role in viral replication and oncogene regulation. This study aimed to assess the genetic variability of the E2 gene and to identify immunogenic epitopes of the E2 protein. Methods: The E2 gene was amplified and sequenced. T-cell epitope prediction and evaluation were performed using IEDB, NetMHCpan v4.0, NetMHCIIpan v4.1, VaxiJen, ToxNet, and pLM4Alg. Results: Phylogenetic analysis of 47 E2 sequences demonstrated co-circulation of the D (n = 4) and A (n = 43) HPV16 lineages in Cajamarca. Twenty-eight Single Nucleotide Polymorphism (SNPs) were identified in E2, 21 of which were nonsynonymous. Seventeen variations were associated with positive Papanicolaou (Pap) test results. Epitope prediction identified 2 MHC class I and 27 MHC class II epitopes classified as potentially antigenic, non-toxic, and non-allergenic, with an overall global population coverage across both MHC classes of 99.78%. Conclusions: The A HPV16 lineage predominated among the women studied. The identified SNPs indicate substantial variability in the E2 gene and a relationship with endocervical lesions. In total, 29 E2-derived T-cell epitopes with immunogenic potential were identified.

Infectious entry of human papillomaviruses into their host cells is an important step in the viral life cycle. For cell binding these viruses use proteoglycans as initial attachment sites. Subsequent transfer to a secondary receptor molecule seems to be involved in virus uptake. Depending on the papillomavirus subtype, it has been reported that entry occurs by clathrin- or caveolin-mediated mechanisms. Regarding human papillomavirus type 16 (HPV16), the primary etiologic agent for development of cervical cancer, clathrin-mediated endocytosis was described as infectious entry pathway. Using immunofluorescence and infection studies we show in contrast to published data that infectious entry of HPV16 occurs in a clathrin- and caveolin-independent manner. Inhibition of clathrin- and caveolin/raft-dependent endocytic pathways by dominant-negative mutants and siRNA-mediated knockdown, as well as inhibition of dynamin function, did not impair infection. Rather, we provide evidence for involvement of tetraspanin-enriched microdomains (TEMs) in HPV16 endocytosis. Following cell attachment, HPV16 particles colocalized with the tetraspanins CD63 and CD151 on the cell surface. Notably, tetraspanin-specific antibodies and siRNA inhibited HPV16 cell entry and infection, confirming the importance of TEMs for infectious endocytosis of HPV16. Tetraspanins fulfill various roles in the life cycle of a number of important viral pathogens, including human immunodeficiency virus (HIV) and hepatitis C virus (HCV). However, their involvement in endocytosis of viral particles has not been proven. Our data indicate TEMs as a novel clathrin- and caveolin-independent invasion route for viral pathogens and especially HPV16.

Background. Cervical cancer is caused by persistent infection with human papillomavirus (HPV). Most infections and associated lesions clear spontaneously. It is important to define the determinants and timing of clearance, so that viral persistence can be recognized and managed. Methods. We investigated HPV natural history among 4504 subjects from ALTS (Atypical Squamous Cells of Undetermined Significance/Low-Grade Squamous Intraepithelial Lesions Triage Study). A discrete-time Markov model was used to simultaneously describe the prevalence, incidence, and persistence of type-specific HPV infection over 24 months in women with equivocal or mildly abnormal cytological results. Interactions between multiple HPV types infecting the same woman were examined for incidence of new infection (after an HPV-16 infection) and persistence of a current infection within groups defined by phylogenetic relatedness or by carcinogenicity. Results. Ninety-one percent (95% credible interval [CI], 90%–92%) of prevalent HPV infections at enrollment cleared within 24 months. The probability that an infection would persist for a further 6 months increased with the duration of infection, from 37% (95% CI, 35%–39%) for a newly observed infection to 65% (95% CI, 61%–70%) for an infection that had already persisted for ⩾ 18 months. No consistent evidence of interactions was found between multiple HPV types regarding the incidence of new infection after an HPV-16 infection or regarding persistence of current HPV infection. Conclusion. Although virtually all HPV infections clear within 2 years, the remaining infections have a high potential for persistence and, by implication, progression to precancer and cancer. Once biological and behavioral determinants are controlled for, HPV infections with different types seem to be independent of each other.

Background In general, human papillomavirus (HPV) vaccines have demonstrated efficacy in young women worldwide, but there is limited evidence on the efficacy of the quadrivalent HPV6/11/16/18 vaccine in adult women and no evidence of its effectiveness in Japanese adult women in particular. This study aims to evaluate the efficacy of the quadrivalent HPV6/11/16/18 vaccine for persistent HPV16/18 infection in Japanese women aged 27–45 years. Methods This is an interventional, nonrandomized, non-double-blind prospective cohort study designed to compare the rates of persistent HPV16/18 infection between the vaccinated arm and unvaccinated arm. The subjects will consist of all women aged 27–45 years who have normal cytology results confirmed by cervical cancer screening from May 2019 to March 2021. The follow-up time is two years. The subjects will be divided into two groups: the vaccinated group and the unvaccinated group. The study will need to enroll 600 vaccinated participants (experimental arm) and 2200 unvaccinated participants (control arm). Discussion The findings of this trial (HAKUOH study) might provide the first local evidence on the subject and be significantly useful not only to medical academia but also to the Japanese Ministry of Health, Labour and Welfare. The findings could contribute to public health improvement by providing local supportive knowledge on the prevention of HPV infection through HPV vaccination in young adult women in Japan, where active recommendations have been suspended for a long time due to adverse effects. Trial registration Trial registration number: NCT04022148 . Registration began on December 1, 2019.

Long noncoding RNAs (lncRNAs) play diverse roles in biological processes, but their expression profiles and functions in cervical carcinogenesis remain unknown. By RNA-sequencing (RNA-seq) analyses of 18 clinical specimens and selective validation by RT-qPCR analyses of 72 clinical samples, we provide evidence that, relative to normal cervical tissues, 194 lncRNAs are differentially regulated in high-risk (HR)-HPV infection along with cervical lesion progression. One such lncRNA, lnc-FANCI-2, is extensively characterized because it is expressed from a genomic locus adjacent to the FANCI gene encoding an important DNA repair factor. Both genes are up-regulated in HPV lesions and in in vitro model systems of HR-HPV18 infection. We observe a moderate reciprocal regulation of lnc-FANCI-2 and FANCI in cervical cancer CaSki cells. In these cells, lnc-FANCI-2 is transcribed from two alternative promoters, alternatively spliced, and polyadenylated at one of two alternative poly(A) sites. About 10 copies of lnc-FANCI-2 per cell are detected preferentially in the cytoplasm. Mechanistically, HR-HPVs, but not low-risk (LR)-HPV oncogenes induce lnc-FANCI-2 in primary and immortalized human keratinocytes. The induction is mediated primarily by E7, and to a lesser extent by E6, mostly independent of p53/E6AP and pRb/E2F. We show that YY1 interacts with an E7 CR3 core motif and transactivates the promoter of lnc-FANCI-2 by binding to two critical YY1-binding motifs. Moreover, HPV18 increases YY1 expression by reducing miR-29a, which targets the 3′ untranslated region of YY1 mRNA. These data have provided insights into the mechanisms of how HR-HPV infections contribute to cervical carcinogenesis.