5. Clifford, G.M.; Gallus, S.; Herrero, R.; Muñoz, N.; Snijders, P.J.; Vaccarella, S.; Anh, P.T.; Ferreccio, C.; Hieu, N.T.; Matos, E.; Molano, M.; Rajkumar, R.; Ronco, G.; de Sanjosé, S.; Shin, H.R.; Sukvirach, S.; Thomas, J.O.; Tunsakul, S.; Meijer, C.J.; Franceschi, S. (2005). Worldwide distribution of humanpapillomavirus types in cytologically normal women in the International Agency for Research on Cancer HPV prevalence surveys: a pooled analysis. Lancet, 366 (9490), 991-998. 6. de Sanjosé, S.; Díaz, M.; Castellsagué, X.; Clifford, G.; Bruni, L.;
Human immunodeficiency virus (HIV-1) has become an important risk factor for humanpapillomavirus (HPV) infection and the development of HPV associated lesions in the female genital tract. HIV-1 may also increase the oncogenicity of high risk HPV types and the activation of low risk types. The Center for Disease Control and Prevention declared invasive cervical cancer an acquired immunodeficience virus (AIDS) defining illness in HIV positive women. Furthermore, cervical cancer happens to be the second most common female cancer worldwide. The host’s local immune response plays a critical factor in controlling these conditions, as well as in changes in the number of professional antigen-presenting cells, cytokine, and MHC molecules expression. Also, the production of cytokines may determine which arm of the immune response will be stimulated and may influence the magnitude of immune protection. Although there are many studies describing the inflammatory response in HPV infection, few data are available to demonstrate the influence of the HIV infection and several questions regarding the cervical immune response are still unknown. In this review we present a brief account of the current understanding of HIV/ HPV co-infection, emphasizing cervical immune response.
There is considerable data to support a central role for humanpapillomavirus (HPV) in the etiology of cervical cancer. More than a 100 HPV types have been described, and 40 have been isolated from benign and malignant genital lesions. Consequently, there is strong motivation to evaluate HPV testing for cervical cancer screening. Few studies concerning the natural history of HPV infection have been conducted in the state of Rio de Janeiro. We determined the prevalence of HPV types in female genital lesions by using Hybrid Capture Assay (HCA) and we retrospectively analyzed the course of HPV infection. Our sample included 788 women attended at Laboratórios Sérgio Franco. The average age of the participants was 29.6 years. HPV prevalence and cytological diagnosis were determined. The overall prevalence of HPV DNA in the study group was 50.1% (395/788), ranging from 25% (NORMAL) to 100% in high-grade intraepithelial lesions (HSIL). High risk HPV was found in 12% inflammatory, 58.3% HPV, 63.2% LSIL and 100% HSIL. A retrospective analysis of 78 patients showed that 22 presented persistent lesions, 2 had progressive lesions, 4 had regressive lesions, 13 showed latent infections, 18 were transiently infected and 19 were submitted to curative treatment. No cases of cancer were registered in this population, which can afford private medical care and regular follow-up exams. We suggest that HCA be used in specific cases involving persistent and recurrent lesions.
Background: It is clinically important to detect and type humanpapillomavirus (HPV) in a sensitive and specific manner. Objectives: Development of a nested-polymerase chain reaction-restriction fragment length polymorphism (nested-PCR-RFLP) assay to detect and type HPV based on the analysis of L1 gene. Methods: Analysis of published DNA sequence of mucosal HPV types to se- lect sequences of new primers. Design of an original nested-PCR assay using the new primers pair selected and classical MY09/11 primers. HPV detection and typing in cervical samples using the nested-PCR-RFLP assay. Results: The nested-PCR-RFLP assay detected and typed HPV in cervical samples. Of the total of 128 clinical samples submitted to simple PCR and nested-PCR for detection of HPV, 37 (28.9%) were positive for the virus by both methods and 25 samples were positive only by nested-PCR (67.5% increase in detection rate compared with single PCR). All HPV positive samples were effectively typed by RFLP assay. Conclusion: The method of nested-PCR proved to be an effec- tive diagnostic tool for HPV detection and typing.
Humanpapillomavirus genomes are classified into molecular variants when they present more than 98% of similarity to the prototype sequence within the L1 gene. Comparative nucleotide sequence analy- ses of these viruses have elucidated some features of their phyloge- netic relationship. In addition, humanpapillomavirus intratype varia- bility has also been used as an important tool in epidemiological studies of viral transmission, persistence and progression to clinically relevant cervical lesions. Until the present, little has been published concerning the functional significance of molecular variants. It has been shown that nucleotide variability within the long control region leads to differences in the binding affinity of some cellular transcrip- tional factors and to the enhancement of the expression of E6 and E7 oncogenes. Furthermore, in vivo and in vitro studies revealed differ- ences in E6 and E7 biochemical and biological properties among molecular variants. Nevertheless, further correlation with additional functional information is needed to evaluate the significance of ge- nome intratypic variability. These results are also important for the development of vaccines and to determine the extent to which immu- nization with L1 virus-like particles of one variant could induce antibodies that cross-neutralize other variants.
Three young women who developed premature ovarian insufficiency following quadrivalent humanpapillomavirus (HPV) vaccination presented to a general practitioner in rural New South Wales, Australia. The unrelated girls were aged 16, 16, and 18 years at diagnosis. Each had received HPV vaccinations prior to the onset of ovarian decline. Vaccinations had been administered in different regions of the state of New South Wales and the 3 girls lived in different towns in that state. Each had been prescribed the oral contraceptive pill to treat menstrual cycle abnormalities prior to investigation and diagnosis. Vaccine research does not present an ovary histology report of tested rats but does present a testicular histology report. Enduring ovarian capacity and duration of function following vaccination is unresearched in preclinical studies, clinical and postlicensure studies. Postmarketing surveillance does not accurately represent diagnoses in adverse event notifications and can neither represent unnotified cases nor compare incident statistics with vaccine course administration rates. The potential significance of a case series of adolescents with idiopathic premature ovarian insufficiency following HPV vaccination presenting to a general practice warrants further research. Preservation of reproductive health is a primary concern in the recipient target group. Since this group includes all prepubertal and pubertal young women, demonstration of ongoing, uncompromised safety for the ovary is urgently required. This matter needs to be resolved for the purposes of population health and public vaccine confidence.
This summary aims to perform a bibliographic review of studies related to the HumanPapillomavirus (HPV) and the Human Immunodeficiency Virus (HIV) in order to promote and give visibility to the relationship between the viruses and the pathologies caused by them. To this end, eight scientific articles, both from national and international publications, taken from the Scientific Electronic Library Online (SciELO) platform were analyzed. The analysis of the studies allowed us to identify the prevalence of HPV infection in individuals with HIV-reactive serology, a fact mainly due to immunosuppression caused by the HIV virus. In addition, it was possible to find that both infections are related to low socioeconomic status, low schooling, multiple sexual partners, early first intercourse and unprotected sex. Thus, since they are closely linked diseases, the need arises to investigate the factors that propitiate co-infection and also to encourage the community habits of prevention of viral contagion.
There is increasing evidence supporting DNA virus regulation of the cell adhesion and tumour suppressor protein, E- cadherin. We previously reported that loss of E-cadherin in humanpapillomavirus (HPV) type 16-infected epidermis is contributed to by the major viral proto-oncogene E6 and is associated with reduced Langerhans cells density, potentially regulating the immune response. The focus of this study is determining how the HPV16 E6 protein mediates E-cadherin repression. We found that the E-cadherin promoter is repressed in cells expressing E6, resulting in fewer E-cadherin transcripts. On exploring the mechanism for this, repression by increased histone deacetylase activity or by increased binding of trans-repressors to the E-cadherin promoter Epal element was discounted. In contrast, DNA methyltransferase (DNMT) activity was increased in E6 expressing cells. Upon inhibiting DNMT activity using 5-Aza-29-deoxycytidine, E- cadherin transcription was restored in the presence of HPV16 E6. The E-cadherin promoter was not directly methylated, however a mutational analysis showed general promoter repression and reduced binding of the transactivators Sp1 and AML1 and the repressor Slug. Expression of E7 with E6 resulted in a further reduction in surface E-cadherin levels. This is the first report of HPV16 E6-mediated transcriptional repression of this adhesion molecule and tumour suppressor protein.
11. Carcopino X, Henry M, Benmoura D, Fallabregues AS, Richet H, Bou- bli L, et al. Determination of HPV type 16 and 18 viral load in cervical smears of women referred to colposcopy. J Med Virol. 2006;78:1131-40. 12. Ho GY, Burk RD, Klein S, Kadish AS, Chang CJ, Palan P, et al. Persis- tent genital humanpapillomavirus infection as a risk factor for persistent dysplasia. J Natl Cancer Inst. 1995;87:1365-71.
Humanpapillomavirus (HPV) is a DNA virus with oncogenic potential and is distrib- uted worldwide. HPV has a causal relationship with cervical cancer depending on the virus type and load, the characteristics of the infection, and the virus physical status - integrated or episomal (Schiffman and Burk, 1997; zur Hausen, 2009). Persistent HPV infection is an im- portant factor for the development of cervical neoplasia. The progression of cervical lesions is affected by additional co-factors such as multiple sex partners, early beginning of sexual activ- ity, contraceptives, smoking, and other sexually transmitted diseases (Herrero et al., 1990; Ho et al., 1998; Atalah et al., 2001; zur Hausen, 2009).
Two hundred and thirty paraffin-embedded biopsies obtained from female cervical lesions were tested for the presence of humanpapillomavirus (HPV) types 6/11,16/18 and 31/33/35 DNA using non- isotopic in situ hybridization. Specimens were classified according to the Bethesda System in low grade squamous intraepithelial lesion (LSIL), high grade SIL (HSIL) and squamous cell carcinoma (SCC). HPV prevalence ranged from 92.5% in LSIL to 68.5% in SCC. Benign types were prevalent in LSILs while oncogenic types infected predominantly HSILs and SCC. HPV infection showed to be age-depen- dent, but no significant relation to race has been detected. Patients were analyzed through a five-year period: 20.7% of the lesions spontaneously regressed while 48.9% persisted and 30.4% progressed to carcinoma. Patients submitted to treatment showed a 19.4% recurrence rate. High risk types were present in 78.6% (CrudeOR 13.8, P=0.0003) of the progressive lesions, and in 73.7% of the recurrent SILs (COR 19.3, P=0.0000001). Possible co-factors have also been evaluated: history of other sexually trans- mitted diseases showed to be positively related either to progression (Adjusted OR 13.0, P=0.0002) or to recurrence (AOR 17.2, P=0.0002) while oral contraceptive use and tobacco smoking were not sig- nificantly related to them (P>0.1). Association of two or more co-factors also proved to be related to both progression and recurrence, indicating that they may interact with HPV infection in order to in- crease the risk of developing malignant lesions.
HumanPapillomavirus (HPV) infection is the main cause of cervical cancers and cervical intraepithelial neoplasias (CIN) worldwide. Consequently, it would be useful to evaluate HPV testing to screen for cervical cancer. Recently developed, the second-generation Hybrid Capture (HCA II) test is a non-radioactive, relatively rapid, liquid hybridization assay designed to detect 18 HPV types, divided into high and low-risk groups. We evaluated 1055 women for HPV infection with the HCA II test. Five hundred and ten (48.3%) of these women had HPV infection; 60 (11.8%) had low cancer-risk HPV DNA; 269 (52.7%) had high-risk HPV types and 181 (35.5%) had both groups. Hence, 450 women (88.2%) in this HPV-infected group had at least one high risk HPV type, and were therefore considered to be at high risk for cancer. Among the group with Papanicolaou (Pap) test results, the overall prevalence of HPV DNA was 58.4%. Significant differences in HPV infection of the cervix were detected between Pap I (normal smears) and Pap IV (carcinomas) (p<0.0001). Values of HPV viral load obtained for Pap I and SILs were significantly different, with an upward trend (p<0.0001), suggesting a positive correlation between high viral load values and risk of SIL. Because of the high costs of the HCA II test, its use for routine cervical mass screening cannot be recommended in poor countries. Nevertheless, it is a useful tool when combined with cytology, diagnosing high-risk infections in apparently normal tissues. Use of this technique could help reduce the risk of cancer.
Women living in Latin American countries bear a disproportionate burden of cervical cancer, a condition caused by infection with the humanpapillomavirus (HPV). We performed a study in Santa Elena, Guayas (currently Santa Elena Province), Ecuador, to determine how often HPV could be detected in women attending a private cancer screening clinic. Participants underwent a Pap test, and vaginal and cervical swabs were performed for HPV testing by the polymerase chain reaction (PCR). Each participant completed a verbally administered survey. The mean age of 302 participants was 37.7 years (range 18 to 78 years). The majority of cervical and vaginal specimens contained sufficient DNA to perform PCR. Overall, 24.2% of the participants had either a cervical or vaginal swab that tested positive for HPV. In general, there was a good correlation between the HPV types detected in the cervical and vaginal swabs from the participants, but vaginal swabs were more likely to contain HPV DNA than were cervical swabs. The high-risk HPV types 16, 52, 58, and 59 and the low-risk HPV types 62, 71, 72, and 83 were the most frequently detected HPV types. The number of lifetime sexual partners was positively associated with detection of any HPV type, detection of oncogenic HPV, and abnormal Pap smears. Further studies are needed to determine if these results are representative of all Ecuadorian women and to determine if cervical cancers in Ecuadorian women are caused by the same HPV types found in the swab specimens obtained in this study.
The majority of humanpapillomavirus E2 proteins interact with Brd4, but Brd4 interacts with E2 protein during the regulation of transcription, hindering the study of viral replication and segregation [39–41]. E2 is localized at the chromatin-bound foci during different cell cycle phases. There are clear indications that other HPV proteins, such as E1 and E6, may have important roles in compartmentalization of E2 as well as in viral genome maintenance  . Three types of E2-containing foci have been identified in human keratinocytes in inter- phase. The first type are authentic replication foci that form during S and G2 phases in human keratinocytes  and U2OS cells , which exhibit active ongoing viral genome replication and contain cellular and viral replication factors. These factors replicate the viral genome, while other factors are involved in DNA repair and recombination. Brd4 is localized adjacent to these foci . The second type of foci are formed upon expression of the E1 and E2 proteins and transfection of an origin-containing replicon and do not require Brd4 for their formation. These foci are formed in the presence of E2 that is deficient for binding Brd4 . The third type of foci contain E1, E2 and Brd4 but not replicon DNA. These data suggest that E1 can modulate the interaction of E2 with cellular factors, including Brd4 . In C-33A cells , Brd4 is recruited to E1/E2 replication foci. Most of these studies have been performed using epitope-tagged E1 and E2 expression vectors that maintain efficient support of the viral origin of replication but do not necessarily reflect the actual expression levels of these proteins during normal viral infection. Overexpression of E1 induces a DNA damage response and growth arrest in these cells   . Thus, it has been difficult to study E2 mitotic chromatin bind- ing in the presence of E1 protein in these experiments. Alpha-papillomavirus E2 proteins are not easily detected on mitotic chromosomes  and do not bind tightly to host chromatin with Brd4 . Biomolecular fluorescence complementation has enabled the observation of the interaction of Brd4 with HPV16 E2 during all phases of mitosis . This interaction is dependent on the phosphorylation of serine 243 in the hinge region of HPV16 E2 . How- ever, most of these data have been obtained in cell lines that do not support transient or stable replication of the viral genome or HPV-18 gene expression, and the relevance of these observa- tions to HPV genome segregation remains unclear.
The association between humanpapillomavirus infection and the development of epithelial lesions is complex. Close to 200 HPV types have been characterized, and particularly the alpha HPV types are classified into high risk or low risk types according to their association with anogenital malignancies . An individual can be infected with multiple HPV types, which may also increase the risk of developing a cervical lesion . Moreover, many HPVs have been identified from healthy individuals without any clinical symptoms. The rare path from initial infection to severe epithelial lesion is still not understood in detail. We have previously shown that the viral E5 oncogene regulates the expression of a number of cellular mRNAs and microRNAs with key functions in cell adhesion and motility, epithelial differentiation, and immune response [6,39], and we were able to confirm some of these regulations in cervical disease . Our recent results suggest that microRNAs play a key role in the manifestation of HPV infections in epithelial target cells . Many dsDNA viruses, such as polyomaviruses, encode miRNAs [9,16,20]. Papillomaviruses have initially been suspected to encode
Paavonen J, Jenkins D, Bosch FX, Naud P, Salmeron J, Wheeler CM, Chow SN, Alter DL, Kitchener HC, Castellsague X, de Carvalho NS, Skinner RS, Harper DM, Hedrick JA, Jaisamrarn U, Limson GAM, Dionea M, Quint W, Spiessens B, Peeters P, Struyf F, Wiet- ing SL, Lehtinen MO, Dubien G, for the PATRICIA study group 2007. Efficacy of a prophylactic adjuvanted bivalent L1 virus- like-particle vaccine against infection with humanpapillomavirus types 16 and 18 in young women: an interim analysis of a phase III double-blind, randomised controlled trial. Lancet 369: 2161-2170. Piña P, Hernandez D, López R, Vazquez G 2006. Human papillomavi- rus-specific viral types are common in Mexican women affected by cervical lesions. Int J Gynecol Cancer 16: 1041-1047. Qu W, Jiang G, Cruz Y, Chang CJ, Ho GY, Klein RS, Burk RD 1997.
21. Ferlay J, Shin HR, Bray F, et al. Estimates of worldwide burden of cancer in 2008: GLOBOCAN 2008. Int J Cancer. 2010; 127(12): 2893-917. 22. Mak R, Renterghem LV, Cuvelier C. Cervical smears and humanpapillomavirus typing in sex workers. Sex Transm Infect. 2004; 80(2): 118-20. 23. Su S, Chow EPF, Muessig KR, et al. Sustained high prevalence of viral hepatitis and sexually transmissible infections among female sex workers in China: a systematic review and meta-analysis. BMC Infect Dis. 2016; 16: 2. 24. Lowy DR, Solomon D, Hildesheim A, et al. Humanpapillomavirus infection and the primary and secondary prevention of cervical cancer. Cancer. 2008; 113(S7): 1980-93.
The influence of different infectious agents and their association with humanpapillomavirus (HPV) in cervi- cal carcinogenesis have not been completely elucidated. This study describes the association between cytological changes in cervical epithelium and the detection of the most relevant aetiological agents of sexually transmitted diseases. Samples collected from 169 patients were evaluated by conventional cytology followed by molecular analy- sis to detect HPV DNA, Chlamydia trachomatis, herpes simplex virus 1 and 2, Neisseria gonorrhoeae, Mycoplasma genitalium, Trichomonas vaginalis, and Treponema pallidum, besides genotyping for most common high-risk HPV. An association between cytological lesions and different behavioural habits such as smoking and sedentariness was observed. Intraepithelial lesions were also associated with HPV and C. trachomatis detection. An association was also found between both simple and multiple genotype infection and cytological changes. The investigation of HPV and C. trachomatis proved its importance and may be considered in the future for including in screening programs, since these factors are linked to the early diagnosis of patients with precursor lesions of cervical cancer.
Human papillo mavirus (HPV) is a DNA virus fro m the Papo vaviridae family that has been identi- fied in a variety o f epithelial lesio ns o f the skin and muco sa. Up to the present day, mo re than 70 types o f HPV have been iso lated, so me with kno wn o nco genic po tential infecting the genital tract, urinary bladder, larynx, o ral cavity and co njunctiva. 1 The po tential fo r
of reaction mixture (1 X polymerase chain reaction [PCR] buffer, 200 mM dNTPs, 1.5 mM MgCl2, 50 pmol of each primer, 0.25 U unit of Taq polymerase, and 5 µL of sample) with 35 cycles of amplification. Each cycle included a denaturation step at 94 °C for one minute, an annealing step at 55 °C for two minutes, and a chain elongation step at 72 °C for two minutes using DNA Thermal Cycler (Perkin Elmer, CETUS). The beta-actin primers (0.1 pmol each), which amplify a 330-bp region of the human DNA, were used as an internal control. Polymerase chain reaction products were analyzed on 1.3% agarose gel with ethidium bromide staining for visualization of DNA under ultraviolet light and their molecular weight was determined by comparison with a 100-bp DNA ladder.