Les infections génitales par les virus du papillome humains (HPV) sont les infections virales sexuellement transmises, les plus communes chez les femmes en âge de procréer. Il est désormais bien établi que l’infection persistante par les HPV classés «à haut risque» est l’un des facteurs indispensables au développement de lésions précancéreuses et cancéreuses du col de l’utérus. Ces HPV semblent aussi être impliqués dans le développement d’autres cancers de la région ano-génitale et pourraient être également impliqués dans les cancers de la tête et du cou. Durant cette dernière décennie, des études croissantes tendent à établir un rôle étiologique des HPV dans les dysfonctionnements gestationnels. La détection des ADN HPV dans les placentas issus d’avortements spontanés et leur capacité exceptionnelle à se répliquer in vitro dans les cellules trophoblastiques cultivées en monocouche, ont apporté de nouvelles perspectives quant à la possibilité que le placenta pourrait constituer aussi un tropisme naturel des infections par HPV. Six jours après la fécondation et suite à l’accolement du blastocyste à l’épithélium utérin, le trophoblaste s’engage dans des processus actifs de prolifération, d’invasion et de différenciation complexe pour la construction de l’interface physiologique indispensable aux échanges essentiels entre la mère et l’enfant ; le placenta. De façon intéressante, ses propriétés sont similaires à celles de la cellule tumorale maligne. Néanmoins, ses mécanismes sont étroitement régulés dans le trophoblaste, à la fois dans l’espace et le temps, assurant un développement normal à chaque étape de la grossesse. Devant toutes ces données, nous avions émis l’hypothèse que l’expression des protéines précoces E5, E6 et E7 d’HPV de type 16 (de haut risque), pourraient modifier le développement des trophoblastes infectés. Les résultats obtenus durant ce travail de doctorat démontrent que la protéine virale E5, hautement hydrophobe, est cytotoxique et affecte la viabilité du trophoblaste. Cette cytotoxicité est neutralisée, et la viabilité est améliorée, lorsque les oncoprotéines majeures E6 et E7 sont exprimées en présence de la protéine E5. Lorsque toutes les protéines précoces sont exprimées sous le contrôle de leur propre promoteur (LCR), la viabilité est favorisée. Ces observations ont été confirmées dans les cellules cervicales également. Il a été précédemment rapporté que les oncoprotéines E6 et E7 affectaient l’adhésion du trophoblaste aux cellules endométriales. Dans le présent travail, il a été retrouvé que la protéine E5 diminuait elle aussi l’adhésion, non seulement aux cellules endométriales, mais aussi au support de culture cellulaire. Les capacités de migration et d’invasion de la matrice extracellulaire sont augmentées par l’expression de E5 et dans une plus large proportion par l’expression de E6 et E7. Des résultats similaires ont été obtenus lorsque toutes les protéines de la région précoces sont exprimées sous le contrôle de leur propre promoteur (LCR). La diminution de l’expression de la E-cadhérine est considérée comme un marqueur de malignité et de mauvais pronostic pour les cancers. Nous avons démontré que l’expression de E5, E6 ou de E7, inhibait l’expression de la E-cadhérine, reflétant l’impact des oncoprotéines du virus HPV-16 sur la diminution de l’adhésion et l’augmentation du pouvoir invasif des cellules trophoblastiques. L’investigation d’autres marqueurs de malignité et de tolérance immunitaire, l’étude de l’impact du virus HPV-6 (de bas risque) sur la migration et l’invasion des cellules trophoblastiques, et l’étude de la capacité des protéines précoces d’HPV-16 à influencer l’entrée des particules virales, ont fait l’objet de résultats préliminaires, ouvrant de larges perspectives. Genital Human Papillomavirus (HPV) infections are the most common sexually transmitted infections amongst women on the age of reproduction. It is well established that persistent infection with high-risk HPVs is the necessary factor in the causation of precancerous and cancerous cervical lesions. High-risk HPVs have also been reported to be involved in the causation of head and neck cancers and other anogenital cancers. On this last decade, growing data are attempting to study the potential etiological association of HPV with gestational dysfunctions. The detection of HPV DNA in placentas resulting from spontaneous abortions and the unique ability of multiple HPV types to replicate in vitro in trophoblastic cells cultured in a monolayer system, rise new questions over the HPV tropism. Six days following fertilization and once the apposition of the blastocyst on the uterine wall takes place, the trophoblast, in a very active and complex process, starts to proliferate, invade and to differentiate in order to build a physiological interface; the placenta, from where multiple mother/foetus exchanges occur. Interestingly, the way that the trophoblast behaves is very similar to malignant tumoural cells. However, the trophoblast obeys to strict spatial-temporal regulatory confines, insuring a proper development all along the pregnancy. In regard to these data, we hypothesised that the expression of the high-risk HPV type 16 oncoproteins E5, E6 and E7, might modify the development of the infected trophoblast. During my Ph.D study, I demonstrated that the highly hydrophobic protein E5 is localized in many interne membranes compartments of the transfected trophoblast. E5 affects the viability of transiently and stably transfected trophoblastic cells. E6 and E7, favouring cell growth, neutralised the E5 cytotoxic effect. All HPV-16 early proteins, when expressed under the control of their endogenous promoter (LCR), favoured trophoblastic growth. These observations were also observed in cervical cell lines. In addition, E5 decreased the adhesiveness of trophoblastic cells to the tissue culture plastic and to endometrial cells similarly as previously described for E6 and E7. Cells expressing E6, E7 and in less extend E5 favoured chemotaxic migration and matrigel invasion compared to the cells expressing the LacZ control. These effects were also observed when early proteins were expressed under the control of their own viral promoter (LCR). Interestingly, the E-cadherin was down regulated in trophoblastic cells expressing E5, E6 and E7. In conclusion, HPV-16 early proteins enhanced trophoblastic growth and intensify the malignant phenotype by impairing cell adhesion leading to increased cellular motile and invasive properties. HPV-16 E5 participated, with E6 and E7, in these changes by impairing E-cadherin expression, a hallmark of malignant progression. Additional preliminary results consisting on the investigation of other markers of malignancy and immune tolerance, on studying the impact of the low-risk HPV type 6 early proteins on the migratory and invasive properties of trophoblastic cells and on the study of the ability of HPV-16 to influence the entry of virus particules, allowed to open wide perspectives.

Thèse d'exercice : Médecine. Gynécologie obstétrique : Nantes : 2007. / Bibliogr.

Reproduction de : Thèse d'exercice : Médecine. Médecine générale : Nantes : 2009. / Bibliogr.

Reproduction de : Thèse d'exercice : Médecine. Médecine générale : Nantes : 2009. / Bibliogr.

Reproduction de : Thèse d'exercice : Pharmacie : Nantes : 2008. / Bibliogr.

Human papillomavirus (HPV), a family of viruses with more than 40 genotypes is known to infect genital tract of males and females. High-risk HPV including genotypes 16, 18 can cause cervical cancer while low-risk HPV including genotypes 6, 11 can cause benign or low grade cervical lesions and genital warts. Considering HPV infection is the most common sexually transmitted infection worldwide, as well as in Macao, with prevalence up to 8.1%, and given that cervical cancer is the top ten most frequent female cancer which causes high burden in our health care system, it is important to have a comprehensive intervention for control HPV and cervical cancer. Since the HPV vaccine for preventing cervical cancer has been available in Macao, it is worth to know the willingness to be vaccinated among target population. Base on findings from previous studies, the parental attitudes and acceptance is the key factor of vaccination for young girls. Other potential factors, such as the HPV knowledge, vaccine safety and efficacy, cost, the age of daughter and the physician’s attitudes, may also affect parental acceptance. Given that no previous study on this topic has been conducted, this study is aimed to understand the knowledge, attitudes and acceptability of HPV vaccination, and to explore and identify the affecting factors for acceptance among school girls and their parents. A school-based simple cluster random sampling method was used. Data was collected by anonymous self-administrated questionnaires among 574 school girls aged at 12-22 and 702 parents aged at 30-65. About 47% of the school girls had heard of HPV and 88.3% had heard of HPV vaccine, while 57.1% of parents had heard of HPV and 83.2% had heard of HPV vaccine. Although the HPV-related knowledge was poor among young girls and their parents, 92% of girls indicated a positive intention to be vaccinated for herself and 88% parents would willing to consent daughter to be vaccinated if the HPV vaccine became in routine immunization. However, the parental vaccination acceptability for daughters decreased to 40% and only 30% of mothers would willing to accept for themselves, if they had to pay a full course for three doses of HPV vaccine. About 97% of school girls and 95% of parents supported that HPV vaccine should be included in government immunization programme. We also found that young girls and parents are more favor in later HPV vaccination rather than vaccination at recommended age. Cost is the dominant affecting factor in determining parental acceptability of HPV vaccination. In addition, daughter’s age, vaccine safety concern, Pap smear attendance and HPV knowledge are significantly associated with HPV vaccine acceptance. It may be worthwhile to further investigate the reasons for the delay vaccination among the young adolescent girls and among their parents, to examine if any underlying factors were unexpressed. / published_or_final_version / Public Health / Master / Master of Public Health

Cervical cancer is one of the common cancers among women and poses a great burden to the public health. Currently there are two human papillomavirus vaccines, CervarixTM and Gardasil®, against HPV type 16/18 and type 6/11/16/18 cervical cancer available in the market. Most clinical trials about immunogenicity and safety of the two vaccines were conducted among Caucasian females, rather than on Asian female populations. This systematic review aims to summarize and evaluate immunogenicity and safety of the two vaccines conducted mainly at the setting of randomized control trials on Asian female populations. This investigation would enhance understanding about whether ethnic difference impacts antibody responses, what were the severe adverse events in Asian populations, and whether the vaccines demonstrate satisfactory immunogenicity. Eleven relevant studies were identified from Pubmed and Medline with totally 4026 subjects involved. The quality and validity of these studies was critically appraised in terms of randomization, allocation ratio, blinding, analytical methods and other potential limitations. The two vaccines demonstrated high geometric mean antibody titer levels among Asian females. Injection-site pain was the mostly complained solicited local symptom, followed by redness and swelling. Few severe solicited local symptoms were reported. The unsolicited symptoms were not as common as solicited symptoms and quite a few of them were not related to the vaccination. One severe adverse event was confirmed in Japan’s study – a spontaneous abortion had taken place 15 days after vaccination. China lacks of systematic cancer registries, therefore it is difficult to estimate the disease burden. China’s Gross Domestic Product only reached $5445 per capita in 2011. HPV vaccination would not be cost-effective in the countries which had Gross Domestic Product lower than $8505 per capita, therefore piloting the HPV vaccination in major economic powerhouses like Shanghai and Beijing would be more realistic. To sum up, this systematic review demonstrated satisfactory immunogenicity on Asian females. The safety data were acceptable to some extent except one spontaneous abortion occurred in Japan’s study. / published_or_final_version / Public Health / Master / Master of Public Health

Background. Cervical cancer is a common female cancer in Hong Kong. Cervical screening has been used in detecting cervical lesions for several decades. Given that human papillomavirus (HPV) infection is the etiological cause of cervical cancer, highly efficacious HPV vaccines are recently developed for preventing against HPV infection. Hong Kong has a well-developed healthcare system but relatively high cervical cancer incidence compared to other developed countries partly due to its suboptimal cervical screening program. This highlights the significance to evaluate the potential of implementing organized HPV vaccination programs for further reducing cervical cancer burden on top of cervical screening in Hong Kong. Methods. Cross-sectional, population-based surveys were conducted to assess the acceptability of female adolescent HPV vaccination among girls from secondary schools in 2008 and among mothers of adolescent daughters in 2008 and 2012. Mathematical model with transmission dynamic and stochastic individual-based components was constructed to model the natural history of HPV infection and cervical cancer and thus to project the public health and economic impacts of organized female adolescent HPV vaccination programs in a societal perspective. The model used Markov Chain Monte Carlo algorithm to estimate natural history parameters of HPV infection and probabilistic sensitivity analysis to consider the uncertainty of costs and health utilities in the economic evaluation of organized HPV vaccination. Results. Reported vaccine uptake among11–18 year-old girls increased from 2.4% among schoolgirls in 2008 to 9.1% among daughters of interviewed mothers in 2012. Among interviewed mothers, 27.5% and 37.6% of them were willing to have their daughters vaccinated at market price in 2008 and 2012, respectively. The mathematical model projected that HPV prevalence decreased soon after mass HPV vaccination and vaccine-induced cervical cancer reduction became obvious after vaccination programs have been launched for 30 years. If HPV vaccinesprovided30-year protection, the median incremental cost-effectiveness ratio (ICER) of routine HPV vaccination programs for 12 year-old girls at 25–75% vaccination coverage was US$26,367–32,527 per quality-adjusted life-year (QALY). The median ICER was above US$48,000/QALY if adding 2-year catch-up program for13–18 year-old girls and above US$58,000/QALY if vaccines protect against HPV infection for only 15 years. Conclusions. This study presented the first evaluation of organized HPV vaccination programs in Hong Kong. If vaccine protection lasted for 30 years or longer, organized routine HPV vaccination for 12 year-old girls would potentially be a cost-effective add-on in substantially reducing cervical cancers and HPV-related diseases on top of cervical screening in Hong Kong at an ICER threshold of US$33,218/QALY. However, the current estimated vaccine uptake was unexpectedly low and vaccine acceptability was only moderate. The findings indicated the importance to devise efficient strategies in achieving high and universal coverage for maximizing the population-level benefits of HPV vaccination. Policymakers should consider integrating the organized HPV vaccination programs with existing infrastructures to promote higher acceptability, to translate willingness to vaccinate to actual uptake, to assess population effectiveness, and to monitor safety issue and potential replacement effect of non-vaccine targeted HPV types following mass vaccination. / published_or_final_version / Public Health / Doctoral / Doctor of Philosophy

No description available.

While most Human papillomavirus (HPV) infections are asymptomatic and self-resolved, high-risk types, such as HPV-16 and HPV-18 are responsible for 99% of cervical cancers worldwide, whereas low-risk types, such as HPV-6 and HPV-11, are responsible for 90% of genital warts. While the different types of HPV and their varying oncogenicities have been studied extensively, it is still not clear what features of a HPV type make it more oncogenic than another. Two aspects which could affect the oncogenicity of HPV were studied: HPV variants and the E6 protein’s interaction with membrane associated guanylate kinase (MAGUK) proteins. Previous studies have shown that some HPV-16 variants may be more oncogenic than others. The first goal of this work was to characterise the HPV-16 variants in a Manitoba cervical cancer sample population to possibly identify mutations which could be associated with an increased risk of developing cervical cancer. Seventy-five samples from different individuals were sequenced in three distinct regions: the long control region and the E6 and E7 open reading frames. The DNA sequences obtained from these genomic regions were then compared between HPV-16 cervical cancer samples and Manitoba HPV-16 non cancer samples to identify any mutations that were exclusive to the cervical cancer samples. No specific mutations in any of the regions could be associated with cervical cancer. It is also proposed that HPV16 E6 protein’s interaction with MAGUK proteins contributes to its oncogenicity since low-risk E6 proteins lack this ability. The second goal of this work was to investigate which regions of high-risk HPV E6 proteins are needed in order to achieve MAGUK protein degradation, more specifically MAGI-1 degradation. Wild-type high-risk HPV16E6, low-risk HPV6E6, as well as mutants, were synthesized and cloned into vectors. In vitro translated proteins were used in MAGI-1 degradation assays. The ability of both wild-type HPV6 and HPV16 E6 proteins to degrade MAGI-1 was confirmed. Based on the performance of the different mutants in these degradation assays, it was determined that the PDZ-binding domain is necessary but not sufficient to induce E6-induced MAGI-1 degradation. In conclusion, it was determined that the entire HPV16 E6 protein is needed for the induction of MAGI-1 degradation.