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ObjectiveDue to long lag time between infection/cancer diagnoses human papillomavirus (HPV) vaccination programs will deliver vaccine efficacy (VE) estimates against cancer end-points late. Cancer registry follow-up of population-based, randomised trial cohorts of vaccinated and unvaccinated women was undertaken for the estimation of VE against cervical intraepithelial neoplasia grade three and invasive cancer (CIN3+).MethodsWe report interim results with 98 561 person years of Finnish Cancer Registry -based follow-up of individually and/or cluster randomised cohorts of HPV-16/18 vaccinated and unvaccinated adolescent women enrolled in June 2003/2005, and between May 2004 and April 2005, respectively. The cohorts comprised 15 627 18- to 19-year-old unvaccinated women (NCT01393470), and 2 401 and 64 16- to 17-year-old HPV-16/18 vaccinated women participating the PATRICIA (NCT00122681) and HPV-012 (NCT00169494) trials, respectively. The age-aligned passive follow-up started 6 months after the clinical trials’ end.ResultsDuring the follow-up of 4.5 to 10 years post enrolment we identified 75 cases of cervical intraepithelial neoplasia grade 3 (CIN3) and 4 cases of invasive cervical cancer (ICC) in the unvaccinated cohort, and 4 CIN3 cases in the HPV-16/18 vaccinated women. Diagnostic blocks were available for HPV typing from 87% of the cases. CIN3+ lesions were detectable in 54 cases. HPV16 was found in 26 of 50 unvaccinated CIN3+ cases, and in 3 CIN3+ cases in the HPV-16/18 vaccinated women. The latter were all baseline positive for cervical HPV16 DNA. Baseline data was not available for the unvaccinated women. Intention-to-treat VE against any CIN3+ was 66% (95% CI 8, 88).ConclusionsTen years post vaccination the AS04-adjuvanted HPV-16/18 vaccine shows continued efficacy against CIN3+ irrespectively of HPV type. Vaccine efficacy was not observed in baseline HPV16 DNA positive subjects.Trial registration numberNCT01393470.

Human papillomavirus (HPV) infection is the leading cause of cervical cancer world-wide. Here, we show that native HPV particles produced in a differentiated epithelium have developed different strategies to infect the host. Using biochemical inhibition assays and glycosaminoglycan (GAG)-negative cells, we show that of the four most common cancer-causing HPV types, HPV18, HPV31, and HPV45 are largely dependent on GAGs to initiate infection. In contrast, HPV16 can bind and enter through a GAG-independent mechanism. Infections of primary human keratinocytes, natural host cells for HPV infections, support our conclusions. Further, this renders the different virus types differentially susceptible to carrageenan, a microbicide targeting virus entry. Our data demonstrates that ordered maturation of papillomavirus particles in a differentiating epithelium may alter the virus entry mechanism. This study should facilitate a better understanding of the attachment and infection by the main oncogenic HPV types, and development of inhibitors of HPV infection.

To clarify E1^E4's role during high-risk HPV infection, the E4 proteins of HPV16 and 18 were compared side by side using an isogenic keratinocyte differentiation model. While no effect on cell proliferation or viral genome copy number was observed during the early phase of either virus life cycle, time-course experiments showed that viral genome amplification and L1 expression were differently affected upon differentiation, with HPV16 showing a much clearer E4 dependency. Although E4 loss never completely abolished genome amplification, its more obvious contribution in HPV16 focused our efforts on 16E4. As previously suggested, in the context of the virus life cycle, 16E4s G2-arrest capability was found to contribute to both genome amplification success and L1 accumulation. Loss of 16E4 also lead to a reduced maintenance of ERK, JNK and p38MAPK activity throughout the genome amplifying cell layers, with 16E4 (but not 18E4) co-localizing precisely with activated cytoplasmic JNK in both wild type raft tissue, and HPV16-induced patient biopsy tissue. When 16E1 was co-expressed with E4, as occurs during genome amplification in vivo, the E1 replication helicase accumulated preferentially in the nucleus, and in transient replication assays, E4 stimulated viral genome amplification. Interestingly, a 16E1 mutant deficient in its regulatory phosphorylation sites no longer accumulated in the nucleus following E4 co-expression. E4-mediated stabilisation of 16E2 was also apparent, with E2 levels declining in organotypic raft culture when 16E4 was absent. These results suggest that 16E4-mediated enhancement of genome amplification involves its cell cycle inhibition and cellular kinase activation functions, with E4 modifying the activity and function of viral replication proteins including E1. These activities of 16E4, and the different kinase patterns seen here with HPV18, 31 and 45, may reflect natural differences in the biology and tropisms of these viruses, as well as differences in E4 function.

Recently long non‐coding RNAs were identified as new factors involved in gene expression regulation. To gain insight into expression pattern of these factors related to E7 HPV18 oncogene, this study uses HeLa cell culture transfected with E7‐siRNA. Gene expression profile was investigated using microarray analysis. After analysing the microarray results, we identified 15,387 RNA species differentially expressed in E7‐siRNA‐transfected cells compared with controls (fold change >2). The expression profiles of lncRNA species highlighted 731 lncRNAs and 203 lincRNAs. We selected two lincRNAs (LINC01101 and LINC00277) and we evaluated the expression profile in HPV‐induced neoplasia. Both lincRNAs investigated display a significantly reduced pattern of expression in cervical lesions and cancer, associated with clinical parameters. A connection between HPV presence and lincRNAs was noted. hrHPV‐positive samples exhibit significantly reduced LINC01101 and LINC00277 expression level (P < 0.05). These results provide new insights into involvement of lncRNA in HPV‐induced cervical cancer, enriching our understanding of their potential role in this pathology.

High-risk human papillomavirus (HPV) types are associated with cervical cancer. It is well established that individual HPV types vary in oncogenicity, but current data on their prognostic implication remain controversial. We examined the association between HPV types/species and the survival of 236 Chinese women aged 26-87 (mean 54.4) years after receiving primary treatment for cervical cancer. Overall, 45.8% were of FIGO stage I, 41.9% stage II, and 12.3% stage III. The four most prevalent types found were HPV-16 (60.2%), HPV-18 (21.6%), HPV-52 (11.9%), and HPV-58 (9.3%). Overall, 19.5% of patients had multiple-type infections, 78.4% harboured one or more alpha-9 species, and 28.8% harboured one or more alpha-7 species. After a median follow-up of 8.0 years, 156 (66.1%) patients survived. The 3-year overall survival rate was 75.5%. Factors independently associated with a poorer 3-year overall survival were age >60 years, tumour size >4 cm, lymph node involvement and treatment with radiotherapy+/-chemotherapy. Univariate analysis showed HPV-16 single-type infection was associated with a marginally poorer disease-specific survival (71.6% vs. 87.0%, HR: 1.71, 95% CI = 1.01-2.90), whereas non-HPV-16 alpha-9 species was associated with a better disease-specific survival (90.0% vs. 76.2%, HR: 0.36, 95% CI = 0.16-0.79). However, on multivariate analysis, HPV infection status irrespective of different grouping methods, including individual types, species, single-type or co-infection, did not carry any significant prognostic significance. In conclusion, we did not observe any association between infection with a particular HPV type/species and survival. An HPV type-based stratification in treatment and follow-up plan could not be recommended.

Most DNA viruses associate with, and reorganize, nuclear domain 10 (ND10) bodies upon entry into the host nucleus. In this study, we examine the roles of the ND10 components PML, Sp100, and Daxx in the establishment of human papillomavirus type 18 (HPV18) infection of primary human keratinocytes. HPV18 DNA or HPV18 quasivirus was introduced into primary human keratinocytes depleted of each ND10 protein by small interfering RNA technology, and genome establishment was determined by using a quantitative immortalization assay and measurements of viral transcription and DNA replication. Keratinocyte depletion of Sp100 resulted in a substantial increase in the number of HPV18-immortalized colonies and a corresponding increase in viral transcription and DNA replication. However, Sp100 repressed viral transcription and replication only during the initial stages of viral establishment, suggesting that Sp100 acts as a repressor of incoming HPV DNA. IMPORTANCE The intrinsic immune system provides a first-line defense against invading pathogens. Host cells contain nuclear bodies (ND10) that are important for antiviral defense, yet many DNA viruses localize here upon cell entry. However, viruses also disrupt, reorganize, and modify individual components of the bodies. In this study, we show that one of the ND10 components, Sp100, limits the infection of human skin cells by human papillomavirus (HPV). HPVs are important pathogens that cause many types of infection of the cutaneous and mucosal epithelium and are the causative agents of several human cancers. Understanding how host cells counteract HPV infection could provide insight into antimicrobial therapies that could limit initial infection. The intrinsic immune system provides a first-line defense against invading pathogens. Host cells contain nuclear bodies (ND10) that are important for antiviral defense, yet many DNA viruses localize here upon cell entry. However, viruses also disrupt, reorganize, and modify individual components of the bodies. In this study, we show that one of the ND10 components, Sp100, limits the infection of human skin cells by human papillomavirus (HPV). HPVs are important pathogens that cause many types of infection of the cutaneous and mucosal epithelium and are the causative agents of several human cancers. Understanding how host cells counteract HPV infection could provide insight into antimicrobial therapies that could limit initial infection.

Telomerase is a ribonucleoprotein comprising an RNA template, the telomerase-associated protein and its catalytic subunit, human telomerase reverse transcriptase (hTERT). Telomerase activation is a critical step in cellular immortalisation and development of cancer. Enhanced telomerase activity has been demonstrated in cervical cancer. In the present study telomerase activity and hTERT mRNA expression were evaluated and correlated with the presence of human papillomavirus (HPV) infection and cytological changes in the cervical lesions. Telomerase activity was assayed by telomeric repeat amplification protocol, hTERT mRNA expression by reverse transcriptase polymerase chain reaction and presence of high risk HPV (HR-HPV) infection by polymerase chain reaction. Out of 154 cervical samples of different cytology, 90 (58.44%) were positive for HR-HPV types 16/18, while among 55 normal cervical scrapes, 10 (18.18%) were HPV DNA positive. All 59 invasive cancer samples showed a very high telomerase activity. Among dysplasia, seven (63.6%) mild dysplasia, 18 (100%) of moderate, 20 (100%) of severe dysplasia and 6 (100%) carcinoma in situ (CIS) samples were positive with mild to moderate to high to very high telomerase activity respectively. Seven (12.7%) samples of apparently normal cervical scrapes were weakly positive for telomerase activity. We observed a good correlation ( P <0.001) between telomerase activity and HR-HPV 16/18 positivity with a sensitivity of 88.1% for HPV and 100% for telomerase activity. It is suggested that telomerase activity may be used as an adjunct to cytology and HPV DNA testing in triaging women with cervical lesions.

Cervical cancer is the fourth most common cancer among women. Infection by high-risk human papillomavirus (HPV) is the main aetiology for the development of cervical cancer. Infection by high-risk human papillomavirus (HPV) and the integration of the HPV genome into the host chromosome of cervical epithelial cells are key early events in the neoplastic progression of cervical lesions. The viral oncoproteins, mainly E6 and E7, are responsible for the initial changes in epithelial cells. The viral proteins inactivate two main tumour suppressor proteins, p53, and retinoblastoma (pRb). Inactivation of these host proteins disrupts both the DNA repair mechanisms and apoptosis, leading to rapid cell proliferation. Multiple genes involved in DNA repair, cell proliferation, growth factor activity, angiogenesis, as well as mitogenesis genes become highly expressed in cervical intraepithelial neoplasia (CIN) and cancer. This genomic instability encourages HPV-infected cells to progress towards invasive carcinoma. The key molecular events involved in cervical carcinogenesis will be discussed in this review.

ObjectivesHuman papillomavirus infection (HPV) is the most common viral infection which is causes of cervical, penal, vulvar, anal and, oropharyngeal cancer. E7 protein of HPV is a suitable target for induction of T cell responses and controlling HPV-related cancer. The aim of the current study was to designed and evaluated a novel fusion protein containing the different E7 proteins of the HPV 16, 18, 6 and 11, linked to the cell-penetrating peptide HIV-1 Tat 49–57, in order to improve cytotoxic immune responses in in-vitro and in-vivo.ResultsIn this study whole sequence of HPV16,18,6,11 E7-Tat (47–57) and HPV16,18,6,11 E7 cloned into the vector and expressed in E. coli (BL21). The purified protein was confirmed by SDS page and western blotting and then injected into the C57BL/6 mice. The efficiency of the fusion protein vaccine was assessed by antibody response assay, cytokine assay (IL-4 and IFN-γ), CD + 8 cytotoxicity assay and tumor challenge experiment. Result showed that fusion proteins containing Adjuvant (IFA,CFA) could express higher titer of antibody. Also, we showed that vaccination with E7-Tat and, E7-Tat-ADJ induced high frequencies of E7-specific CD8 + T cells and CD107a expression as well as IFN-γ level and enhanced long-term survival in the therapeutic animal models.ConclusionOur finding suggested that this novel fusion protein vaccine was able to induce therapeutic efficacy and immunogenicity by improving CD8 + T cell in TC-1 tumor bearing mice; so this vaccine may be appreciated for research against HPV and tumor immunotherapies.

While the application of early screening and HPV vaccines has reduced the incidence and mortality rates of cervical cancer, it remains the third most common carcinoma and fourth leading cause of cancer-associated death among women worldwide. The precise mechanisms underlying progression of cervical cancer are not fully understood at present. Here, we detected significant down-regulation of 15-hydroxyprostaglandin dehydrogenase (HPGD) in cervical cancer tissues. Overexpression of HPGD inhibited cervical cancer cell proliferation, migration and anchorage-independent growth to a significant extent. To clarify the mechanisms underlying HPGD down-regulation in cervical cancer, miRNA microarray, bioinformatics and luciferase reporter analyses were performed. HPGD was identified as a direct target of miR-146b-3p displaying up-regulation in cervical cancer tissues. Similar to the effects of HPGD overexpression, down-regulation of miR-146b-3p strongly suppressed proliferation, migration and anchorage-independent growth of cervical cancer cells. Furthermore, HPGD negatively regulated activities of STAT3 and AKT that promote cervical cancer cell proliferation. Notably, HPV oncogenes E6 and E7 were determined as potential contributory factors to these alterations. Our results collectively suggest that the HPGD/miR-146b-3p axis plays a significant role in cervical cancer and may serve as a potentially effective therapeutic target.