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Sample records for human papillomavirus oncogene

  1. Oncogenic Activities of Human Papillomaviruses

    PubMed Central

    McLaughlin-Drubin, Margaret E.; Münger, Karl

    2009-01-01

    Infectious etiologies for certain human cancers have long been suggested by epidemiological studies and studies with animals. Important support for this concept came from the discovery by Harald zur Hausen’s group that human cervical carcinoma almost universally contains certain “high-risk” human papillomavirus (HPV) types. Over the years, much has been learned about the carcinogenic activities of high-risk HPVs. These studies have revealed that two viral proteins, E6 and E7, that are consistently expressed in HPV-associated carcinomas, are necessary for induction and maintenance of the transformed phenotype. Hence, HPV-associated tumors are unique amongst human solid tumors in that they are universally caused by exposure to the same, molecularly defined oncogenic agents, and the molecular signal transduction pathways subverted by these viral transforming agents are frequently disrupted in other, non-virus associated human cancers. PMID:19540281

  2. Role of papillomavirus oncogenes in human cervical cancer: Transgenic animal studies

    SciTech Connect

    Griep, A.E.; Lambert, P.F.

    1994-05-01

    Human papillomaviruses are believed to be etiologic agents for the majority of human cervical carcinoma, a common cancer that is a leading cause of death by cancer among women worldwide. In cervical carcinoma, a subset of papillomaviral genes, namely E6 and E7, are expressed. In vitro tissue culture studies indicate that HPV E6 and E7 are oncogenes, and that their oncogenicity is due in part to their capacity to inactivate cellular tumor suppressor genes. The behavior of E6 and E7 in vitro and the genetic evidence from analysis of human cancers suggest that the E6 and E7 genes play a significant role in the development of cervical cancer. This hypothesis is now being tested using animal models. In this review, we summarize our current knowledge of the oncogenicity of papillomavirus genes that has been generated through their study in transgenic mice. 82 refs., 4 figs., 1 tab.

  3. Oncogenic potential diverge among human papillomavirus type 16 natural variants

    SciTech Connect

    Sichero, Laura; Simao Sobrinho, Joao; Lina Villa, Luisa

    2012-10-10

    We compared E6/E7 protein properties of three different HPV-16 variants: AA, E-P and E-350G. Primary human foreskin keratinocytes (PHFK) were transduced with HPV-16 E6 and E7 and evaluated for proliferation and ability to grow in soft agar. E-P infected keratinocytes presented the lowest efficiency in colony formation. AA and E-350G keratinocytes attained higher capacity for in vitro transformation. We observed similar degradation of TP53 among HPV-16 variants. Furthermore, we accessed the expression profile in early (p5) and late passage (p30) transduced cells of 84 genes commonly involved in carcinogenesis. Most differences could be attributed to HPV-16 E6/E7 expression. In particular, we detected different expression of ITGA2 and CHEK2 in keratinocytes infected with AA and AA/E-350G late passage cells, respectively, and higher expression of MAP2K1 in E-350G transduced keratinocytes. Our results indicate differences among HPV-16 variants that could explain, at least in part, differences in oncogenic potential attributed to these variants.

  4. Individual and Complementary Effects of Human Papillomavirus Oncogenes on Epithelial Cell Proliferation and Differentiation.

    PubMed

    Bergner, Sven; Halec, Gordana; Schmitt, Markus; Aubin, François; Alonso, Angel; Auvinen, Eeva

    2016-01-01

    Previous studies on human papillomavirus (HPV) type 16 protein functions have established the oncogenic nature of three viral proteins: E5, E6 and E7. Here we have studied the functions of these proteins by functional deletion of the individual E5, E6 or E7, or both E6 and E7 oncogenes in the context of the whole viral genome. These mutants, or the intact wild-type genome, were expressed from the natural viral promoters along with differentiation of epithelial HaCaT cells in three-dimensional collagen raft cultures. High episomal viral copy numbers were obtained using a transfection-based loxp-HPV16-eGFP-N1 vector system. All epithelial equivalents carrying the different HPV type 16 genomes showed pronounced hyperplastic and dysplastic morphology. Particularly the E7 oncogene, with contribution of E6, was shown to enhance cell proliferation. Specifically, the crucial role of E7 in HPV-associated hyperproliferation was clearly manifested. Based on morphological characteristics, immunohistochemical staining for differentiation and proliferation markers, and low expression of E1^E4, we propose that our raft culture models produce cervical intraepithelial neoplasia (CIN)1 and CIN2-like tissue. Our experimental setting provides an alternative tool to study concerted functions of HPV proteins in the development of epithelial dysplasia. PMID:26636751

  5. Development of neutralizing monoclonal antibodies for oncogenic human papillomavirus types 31, 33, 45, 52, and 58.

    PubMed

    Brown, Martha J; Seitz, Hanna; Towne, Victoria; Müller, Martin; Finnefrock, Adam C

    2014-04-01

    Human papillomavirus (HPV) is the etiological agent for all cervical cancers, a significant number of other anogenital cancers, and a growing number of head and neck cancers. Two licensed vaccines offer protection against the most prevalent oncogenic types, 16 and 18, responsible for approximately 70% of cervical cancer cases worldwide and one of these also offers protection against types 6 and 11, responsible for 90% of genital warts. The vaccines are comprised of recombinantly expressed major capsid proteins that self-assemble into virus-like particles (VLPs) and prevent infection by eliciting neutralizing antibodies. Adding the other frequently identified oncogenic types 31, 33, 45, 52, and 58 to a vaccine would increase the coverage against HPV-induced cancers to approximately 90%. We describe the generation and characterization of panels of monoclonal antibodies to these five additional oncogenic HPV types, and the selection of antibody pairs that were high affinity and type specific and recognized conformation-dependent neutralizing epitopes. Such characteristics make these antibodies useful tools for monitoring the production and potency of a prototype vaccine as well as monitoring vaccine-induced immune responses in the clinic. PMID:24574536

  6. Oncogenic potential of Human Papillomavirus (HPV) and its relation with cervical cancer

    PubMed Central

    2011-01-01

    Human Papillomavirus (HPV) is the most common cause of cervical cancer. Cervical cancer being the second most common cancer after lung cancer, affecting women of different age groups; has a prevalence of about 20% in young sexually active women. Among different types of HPV, HPV16 the major strain causing this cancer and is sexually transmitted had been unnoticed for decades. Keeping in mind the multiple risk factors related with cervical cancer such as early age sexual activities, teenage pregnancies, smoking, use of oral contraceptives, having multiple sex partners, hormone replacement therapies and various other unknown factors lead to the onset of the disease. Awareness for various diagnostic procedures such as Pap smears screening prove to be an effective way in eradicating the oncogenic potential of HPV. PMID:21635792

  7. Determination of Oncogenic Human Papillomavirus (HPV) Genotypes in Anogenital Cancers in Myanmar.

    PubMed

    Mu Mu Shwe; Hlaing Myat Thu; Khin Saw Aye; Aye Aye Myint; Mya Thida; Khin Shwe Mar; Khin Khin Oo; Khin Sandar Aye; Okada, Shigeru; Kyaw Zin Thant

    2016-04-01

    Molecular and epidemiologic investigations suggest a causal role for human papillomavirus (HPV) in anogenital cancers. This study identified oncogenic HPV genotypes in anogenital cancers among men and women in a 2013 cross-sectional descriptive study in Myanmar. In total, 100 biopsy tissues of histologically confirmed anogenital cancers collected in 2008-2012 were studied, including 30 penile and 9 anal cancers from Yangon General Hospital and 61 vulvar cancers from Central Women's Hospital, Yangon. HPV-DNA testing and genotyping were performed by polymerase chain reaction-restriction fragment length polymorphism. Overall, 34% of anogenital cancers were HPV-positive. HPV was found in 44.4% of anal (4/9), 36.1% of vulvar (22/61), and 26.7% of penile (8/30) cancers. The most frequent genotypes in anal cancers were HPV 16 (75% ) and 18 (25% ). In vulvar cancers, HPV 33 was most common (40.9% ), followed by 16 (31.8% ), 31 (22.7% ), and 18 (4.6% ). In penile cancers, HPV 16 (62.5% ) was most common, followed by 33 (25% ) and 18 (12.5% ). This is the first report of evidencebased oncogenic HPV genotypes in anogenital cancers among men and women in Myanmar. This research provides valuable information for understanding the burden of HPV-associated cancers of the anus, penis, and vulva and considering the effectiveness of prophylactic HPV vaccination. PMID:27094835

  8. Arsenic trioxide inhibits cell proliferation and human papillomavirus oncogene expression in cervical cancer cells

    SciTech Connect

    Wang, Hongtao; Gao, Peng; Zheng, Jie

    2014-09-05

    Highlights: • As{sub 2}O{sub 3} inhibits growth of cervical cancer cells and expression of HPV oncogenes in these cells. • HPV-negative cervical cancer cells are more sensitive to As{sub 2}O{sub 3} than HPV-positive cervical cancer cells. • HPV-18 positive cervical cancer cells are more sensitive to As{sub 2}O{sub 3} than HPV-16 positive cancer cells. • Down-regulation of HPV oncogenes by As{sub 2}O{sub 3} is partially due to the diminished AP-1 binding. - Abstract: Arsenic trioxide (As{sub 2}O{sub 3}) has shown therapeutic effects in some leukemias and solid cancers. However, the molecular mechanisms of its anticancer efficacy have not been clearly elucidated, particularly in solid cancers. Our previous data showed that As{sub 2}O{sub 3} induced apoptosis of human papillomavirus (HPV) 16 DNA-immortalized human cervical epithelial cells and cervical cancer cells and inhibited the expression of HPV oncogenes in these cells. In the present study, we systemically examined the effects of As{sub 2}O{sub 3} on five human cervical cancer cell lines and explored the possible molecular mechanisms. MTT assay showed that HPV-negative C33A cells were more sensitive to growth inhibition induced by As{sub 2}O{sub 3} than HPV-positive cervical cancer cells, and HPV 18-positive HeLa and C4-I cells were more sensitive to As{sub 2}O{sub 3} than HPV 16-positive CaSki and SiHa cells. After As{sub 2}O{sub 3} treatment, both mRNA and protein levels of HPV E6 and E7 obviously decreased in all HPV positive cell lines. In contrast, p53 and Rb protein levels increased in all tested cell lines. Transcription factor AP-1 protein expression decreased significantly in HeLa, CaSki and C33A cells with ELISA method. These results suggest that As{sub 2}O{sub 3} is a potential anticancer drug for cervical cancer.

  9. Role of Cdc6 in re-replication in cells expressing human papillomavirus E7 oncogene.

    PubMed

    Fan, Xueli; Zhou, Yunying; Chen, Jason J

    2016-08-01

    The E7 oncoprotein of high-risk human papillomavirus (HPV) types induces DNA re-replication that contributes to carcinogenesis; however, the mechanism is not fully understood. To better understand the mechanism by which E7 induces re-replication, we investigated the expression and function of cell division cycle 6 (Cdc6) in E7-expressing cells. Cdc6 is a DNA replication initiation factor and exhibits oncogenic activities when overexpressed. We found that in E7-expressing cells, the steady-state level of Cdc6 protein was upregulated and its half-life was increased. Cdc6 was localized to the nucleus and associated with chromatin, especially upon DNA damage. Importantly, downregulation of Cdc6 reduced E7-induced re-replication. Interestingly, the level of Cdc6 phosphorylation at serine 54 (S54P) was increased in E7-expressing cells. S54P was associated with an increase in the total amount of Cdc6 and chromatin-bound Cdc6. DNA damage-enhanced upregulation and chromatin binding of Cdc6 appeared to be due to downregulation of cyclin-dependent kinase 1 (Cdk1) as Cdk1 knockdown increased Cdc6 levels. Furthermore, Cdk1 knockdown or inhibition led to re-replication. These findings shed light on the mechanism by which HPV induces genomic instability and may help identify potential targets for drug development. PMID:27207654

  10. Enhanced human papillomavirus type 8 oncogene expression levels are crucial for skin tumorigenesis in transgenic mice

    SciTech Connect

    Hufbauer, M.; Lazic, D.; Akguel, B.; Brandsma, J.L.; Pfister, H.; Weissenborn, S.J.

    2010-08-01

    Human papillomavirus 8 (HPV8) is involved in skin cancer development in epidermodysplasia verruciformis patients. Transgenic mice expressing HPV8 early genes (HPV8-CER) developed papillomas, dysplasias and squamous cell carcinomas. UVA/B-irradiation and mechanical wounding of HPV8-CER mouse skin led to prompt papilloma induction in about 3 weeks. The aim of this study was to analyze the kinetics and level of transgene expression in response to skin irritations. Transgene expression was already enhanced 1 to 2 days after UVA/B-irradiation or tape-stripping and maintained during papilloma development. The enhanced transgene expression could be assigned to UVB and not to UVA. Papilloma development was thus always paralleled by an increased transgene expression irrespective of the type of skin irritation. A knock-down of E6 mRNA by tattooing HPV8-E6-specific siRNA led to a delay and a lower incidence of papilloma development. This indicates that the early increase of viral oncogene expression is crucial for induction of papillomatosis.

  11. Direct benefit of vaccinating boys along with girls against oncogenic human papillomavirus: bayesian evidence synthesis

    PubMed Central

    Wallinga, Jacco; Brakenhoff, Ruud H; Meijer, Chris J L M; Berkhof, Johannes

    2015-01-01

    Objective To assess the reduction in the vaccine preventable burden of cancer in men if boys are vaccinated along with girls against oncogenic human papillomavirus (HPV). Design Bayesian evidence synthesis approach used to evaluate the impact of vaccination against HPV types 16 and 18 on the burden of anal, penile, and oropharyngeal carcinomas among heterosexual men and men who have sex with men. The reduced transmission of vaccine-type HPV from vaccination of girls was assumed to lower the risk of HPV associated cancer in all men but not to affect the excess risk of HPV associated cancers among men who have sex with men. Setting General population in the Netherlands. Intervention Inclusion of boys aged 12 into HPV vaccination programmes. Main outcome measures Quality adjusted life years (QALYs) and numbers needed to vaccinate. Results Before HPV vaccination, 14.9 (95% credible interval 12.2 to 18.1) QALYs per thousand men were lost to vaccine preventable cancers associated with HPV in the Netherlands. This burden would be reduced by 37% (28% to 48%) if the vaccine uptake among girls remains at the current level of 60%. To prevent one additional case of cancer among men, 795 boys (660 to 987) would need to be vaccinated; with tumour specific numbers for anal, penile, and oropharyngeal cancer of 2162, 3486, and 1975, respectively. The burden of HPV related cancer in men would be reduced by 66% (53% to 805) if vaccine uptake among girls increases to 90%. In that case, 1735 boys (1240 to 2900) would need to be vaccinated to prevent an additional case; with tumour specific numbers for anal, penile, and oropharyngeal cancer of 2593, 29107, and 6484, respectively. Conclusions Men will benefit indirectly from vaccination of girls but remain at risk of cancers associated with HPV. The incremental benefit of vaccinating boys when vaccine uptake among girls is high is driven by the prevention of anal carcinomas, which underscores the relevance of HPV prevention efforts for

  12. The human oncogenic viruses

    SciTech Connect

    Luderer, A.A.; Weetall, H.H

    1986-01-01

    This book contains eight selections. The titles are: Cytogenetics of the Leukemias and Lymphomas; Cytogenetics of Solid Tumors: Renal Cell Carcinoma, Malignant Melanoma, Retinoblastoma, and Wilms' Tumor; Elucidation of a Normal Function for a Human Proto-Oncogene; Detection of HSV-2 Genes and Gene Products in Cervical Neoplasia; Papillomaviruses in Anogennital Neoplasms; Human Epstein-Barr Virus and Cancer; Hepatitis B Virus and Hepatocellular Carcinoma; and Kaposi's Sarcoma: Acquired Immunodeficiency Syndrome (AIDS) and Associated Viruses.

  13. The CD63-Syntenin-1 Complex Controls Post-Endocytic Trafficking of Oncogenic Human Papillomaviruses.

    PubMed

    Gräßel, Linda; Fast, Laura Aline; Scheffer, Konstanze D; Boukhallouk, Fatima; Spoden, Gilles A; Tenzer, Stefan; Boller, Klaus; Bago, Ruzica; Rajesh, Sundaresan; Overduin, Michael; Berditchevski, Fedor; Florin, Luise

    2016-01-01

    Human papillomaviruses enter host cells via a clathrin-independent endocytic pathway involving tetraspanin proteins. However, post-endocytic trafficking required for virus capsid disassembly remains unclear. Here we demonstrate that the early trafficking pathway of internalised HPV particles involves tetraspanin CD63, syntenin-1 and ESCRT-associated adaptor protein ALIX. Following internalisation, viral particles are found in CD63-positive endosomes recruiting syntenin-1, a CD63-interacting adaptor protein. Electron microscopy and immunofluorescence experiments indicate that the CD63-syntenin-1 complex controls delivery of internalised viral particles to multivesicular endosomes. Accordingly, infectivity of high-risk HPV types 16, 18 and 31 as well as disassembly and post-uncoating processing of viral particles was markedly suppressed in CD63 or syntenin-1 depleted cells. Our analyses also present the syntenin-1 interacting protein ALIX as critical for HPV infection and CD63-syntenin-1-ALIX complex formation as a prerequisite for intracellular transport enabling viral capsid disassembly. Thus, our results identify the CD63-syntenin-1-ALIX complex as a key regulatory component in post-endocytic HPV trafficking. PMID:27578500

  14. The CD63-Syntenin-1 Complex Controls Post-Endocytic Trafficking of Oncogenic Human Papillomaviruses

    PubMed Central

    Gräßel, Linda; Fast, Laura Aline; Scheffer, Konstanze D.; Boukhallouk, Fatima; Spoden, Gilles A.; Tenzer, Stefan; Boller, Klaus; Bago, Ruzica; Rajesh, Sundaresan; Overduin, Michael; Berditchevski, Fedor; Florin, Luise

    2016-01-01

    Human papillomaviruses enter host cells via a clathrin-independent endocytic pathway involving tetraspanin proteins. However, post-endocytic trafficking required for virus capsid disassembly remains unclear. Here we demonstrate that the early trafficking pathway of internalised HPV particles involves tetraspanin CD63, syntenin-1 and ESCRT-associated adaptor protein ALIX. Following internalisation, viral particles are found in CD63-positive endosomes recruiting syntenin-1, a CD63-interacting adaptor protein. Electron microscopy and immunofluorescence experiments indicate that the CD63-syntenin-1 complex controls delivery of internalised viral particles to multivesicular endosomes. Accordingly, infectivity of high-risk HPV types 16, 18 and 31 as well as disassembly and post-uncoating processing of viral particles was markedly suppressed in CD63 or syntenin-1 depleted cells. Our analyses also present the syntenin-1 interacting protein ALIX as critical for HPV infection and CD63-syntenin-1-ALIX complex formation as a prerequisite for intracellular transport enabling viral capsid disassembly. Thus, our results identify the CD63-syntenin-1-ALIX complex as a key regulatory component in post-endocytic HPV trafficking. PMID:27578500

  15. Different mechanisms contribute to the E2-mediated transcriptional repression of human papillomavirus type 18 viral oncogenes.

    PubMed

    Demeret, C; Desaintes, C; Yaniv, M; Thierry, F

    1997-12-01

    Transcription of the human papillomavirus type 18 (HPV18) E6 and E7 oncogenes is repressed by the viral E2 protein. In C33 cells, we have previously shown that of the four E2 binding sites (E2 BS) present in the HPV18 long control region (LCR), only the binding site adjacent to the TATA box (E2 BS 1) was involved in E2-mediated repression. In the present study, we sought to determine whether this phenomenon was conserved in other cell lines. We first showed that all three E2 BS proximal to the P105 promoter were required for full repression of its activity in HeLa and HaCaT cells. Repression by E2 at E2 BS 2 occurred through the displacement of Sp1. Second, a truncated E2 product, lacking the N-terminal transactivation domain, repressed transcription more efficiently than the full-length protein. Repression was abolished when the N-terminal domain of E2 was replaced by the activation domain of VP16. The VP16-E2 chimeric protein could activate transcription from an LCR mutated in its TATA box. DNA-protein binding studies showed that E2 associates with its four binding sites in the LCR with similar affinities. However, challenge of such complexes with excess binding sites demonstrated that interaction with E2 BS 4 was the most stable while interaction with E2 BS 1 was the least stable. Furthermore, complexes with the full-length E2 were less stable than those formed with the N-terminally truncated protein. PMID:9371593

  16. Loss of Dependence on Continued Expression of the Human Papillomavirus 16 E7 Oncogene in Cervical Cancers and Precancerous Lesions Arising in Fanconi Anemia Pathway-Deficient Mice

    PubMed Central

    Park, Soyeong; Park, Jung Wook; Pitot, Henry C.

    2016-01-01

    ABSTRACT   Fanconi anemia (FA) is a rare genetic disorder caused by defects in DNA damage repair. FA patients often develop squamous cell carcinoma (SCC) at sites where high-risk human papillomaviruses (HPVs) are known to cause cancer, including the cervix. However, SCCs found in human FA patients are often HPV negative, even though the majority of female FA patients with anogenital cancers had preexisting HPV-positive dysplasia. We hypothesize that HPVs contribute to the development of SCCs in FA patients but that the continued expression of HPV oncogenes is not required for the maintenance of the cancer state because FA deficiency leads to an accumulation of mutations in cellular genes that render the cancer no longer dependent upon viral oncogenes. We tested this hypothesis, making use of Bi-L E7 transgenic mice in which we temporally controlled expression of HPV16 E7, the dominant viral oncogene in HPV-associated cancers. As seen before, the persistence of cervical neoplastic disease was highly dependent upon the continued expression of HPV16 E7 in FA-sufficient mice. However, in mice with FA deficiency, cervical cancers persisted in a large fraction of the mice after HPV16 E7 expression was turned off, indicating that these cancers had escaped from their dependency on E7. Furthermore, the severity of precancerous lesions also failed to be reduced significantly in the mice with FA deficiency upon turning off expression of E7. These findings confirm our hypothesis and may explain the fact that, while FA patients have a high frequency of infections by HPVs and HPV-induced precancerous lesions, the cancers are frequently HPV negative. Importance   Fanconi anemia (FA) patients are at high risk for developing squamous cell carcinoma (SCC) at sites where high-risk human papillomaviruses (HPVs) frequently cause cancer. Yet these SCCs are often HPV negative. FA patients have a genetic defect in their capacity to repair damaged DNA. HPV oncogenes cause an

  17. Loss of Dependence on Continued Expression of the Human Papillomavirus 16 E7 Oncogene in Cervical Cancers and Precancerous Lesions Arising in Fanconi Anemia Pathway-Deficient Mice.

    PubMed

    Park, Soyeong; Park, Jung Wook; Pitot, Henry C; Lambert, Paul F

    2016-01-01

    Fanconi anemia (FA) is a rare genetic disorder caused by defects in DNA damage repair. FA patients often develop squamous cell carcinoma (SCC) at sites where high-risk human papillomaviruses (HPVs) are known to cause cancer, including the cervix. However, SCCs found in human FA patients are often HPV negative, even though the majority of female FA patients with anogenital cancers had preexisting HPV-positive dysplasia. We hypothesize that HPVs contribute to the development of SCCs in FA patients but that the continued expression of HPV oncogenes is not required for the maintenance of the cancer state because FA deficiency leads to an accumulation of mutations in cellular genes that render the cancer no longer dependent upon viral oncogenes. We tested this hypothesis, making use of Bi-L E7 transgenic mice in which we temporally controlled expression of HPV16 E7, the dominant viral oncogene in HPV-associated cancers. As seen before, the persistence of cervical neoplastic disease was highly dependent upon the continued expression of HPV16 E7 in FA-sufficient mice. However, in mice with FA deficiency, cervical cancers persisted in a large fraction of the mice after HPV16 E7 expression was turned off, indicating that these cancers had escaped from their dependency on E7. Furthermore, the severity of precancerous lesions also failed to be reduced significantly in the mice with FA deficiency upon turning off expression of E7. These findings confirm our hypothesis and may explain the fact that, while FA patients have a high frequency of infections by HPVs and HPV-induced precancerous lesions, the cancers are frequently HPV negative. IMPORTANCE  : Fanconi anemia (FA) patients are at high risk for developing squamous cell carcinoma (SCC) at sites where high-risk human papillomaviruses (HPVs) frequently cause cancer. Yet these SCCs are often HPV negative. FA patients have a genetic defect in their capacity to repair damaged DNA. HPV oncogenes cause an accumulation of DNA

  18. Induction of promyelocytic leukemia (PML) oncogenic domains (PODs) by papillomavirus

    SciTech Connect

    Nakahara, Tomomi; Lambert, Paul F.

    2007-09-30

    Promyelocytic leukemia oncogenic domains (PODs), also called nuclear domain 10 (ND10), are subnuclear structures that have been implicated in a variety of cellular processes as well as the life cycle of DNA viruses including papillomaviruses. In order to investigate the interplay between papillomaviruses and PODs, we analyzed the status of PODs in organotypic raft cultures of human keratinocytes harboring HPV genome that support the differentiation-dependent HPV life cycle. The number of PODs per nucleus was increased in the presence of HPV genomes selectively within the poorly differentiated layers but was absent in the terminally differentiated layers of the stratified epithelium. This increase in PODs was correlated with an increase in abundance of post-translationally modified PML protein. Neither the E2-dependent transcription nor viral DNA replication was reliant upon the presence of PML. Implications of these findings in terms of HPV's interaction with its host are discussed.

  19. Characterization of Intra-Type Variants of Oncogenic Human Papillomaviruses by Next-Generation Deep Sequencing of the E6/E7 Region.

    PubMed

    Lavezzo, Enrico; Masi, Giulia; Toppo, Stefano; Franchin, Elisa; Gazzola, Valentina; Sinigaglia, Alessandro; Masiero, Serena; Trevisan, Marta; Pagni, Silvana; Palù, Giorgio; Barzon, Luisa

    2016-03-01

    Different human papillomavirus (HPV) types are characterized by differences in tissue tropism and ability to promote cell proliferation and transformation. In addition, clinical and experimental studies have shown that some genetic variants/lineages of high-risk HPV (HR-HPV) types are characterized by increased oncogenic activity and probability to induce cancer. In this study, we designed and validated a new method based on multiplex PCR-deep sequencing of the E6/E7 region of HR-HPV types to characterize HPV intra-type variants in clinical specimens. Validation experiments demonstrated that this method allowed reliable identification of the different lineages of oncogenic HPV types. Advantages of this method over other published methods were represented by its ability to detect variants of all HR-HPV types in a single reaction, to detect variants of HR-HPV types in clinical specimens with multiple infections, and, being based on sequencing of the full E6/E7 region, to detect amino acid changes in these oncogenes potentially associated with increased transforming activity. PMID:26985902

  20. Characterization of Intra-Type Variants of Oncogenic Human Papillomaviruses by Next-Generation Deep Sequencing of the E6/E7 Region

    PubMed Central

    Lavezzo, Enrico; Masi, Giulia; Toppo, Stefano; Franchin, Elisa; Gazzola, Valentina; Sinigaglia, Alessandro; Masiero, Serena; Trevisan, Marta; Pagni, Silvana; Palù, Giorgio; Barzon, Luisa

    2016-01-01

    Different human papillomavirus (HPV) types are characterized by differences in tissue tropism and ability to promote cell proliferation and transformation. In addition, clinical and experimental studies have shown that some genetic variants/lineages of high-risk HPV (HR-HPV) types are characterized by increased oncogenic activity and probability to induce cancer. In this study, we designed and validated a new method based on multiplex PCR-deep sequencing of the E6/E7 region of HR-HPV types to characterize HPV intra-type variants in clinical specimens. Validation experiments demonstrated that this method allowed reliable identification of the different lineages of oncogenic HPV types. Advantages of this method over other published methods were represented by its ability to detect variants of all HR-HPV types in a single reaction, to detect variants of HR-HPV types in clinical specimens with multiple infections, and, being based on sequencing of the full E6/E7 region, to detect amino acid changes in these oncogenes potentially associated with increased transforming activity. PMID:26985902

  1. [Human papillomaviruses].

    PubMed

    Gross, G

    2003-10-01

    Human papillomaviruses (HPV) infect exclusively the basal cells of the skin and of mucosal epithelia adjacent to the skin such as the mouth, the upper respiratory tract, the lower genital tract and the anal canal. HPV does not lead to a viremia. Basically there are three different types of HPV infection: Clinically visible lesions, subclinical HPV infections and latent HPV infections. Distinct HPV types induce morphologically and prognostically different clinical pictures. The most common HPV associated benign tumor of the skin is the common wart. Infections of the urogenitoanal tract with specific HPV-types are recognised as the most frequent sexually transmitted viral infections. So-called "high-risk" HPV-types (HPV16, 18 and others) are regarded by the world health organisation as important risk-factors for the development of genital cancer (mainly cervical cancer), anal cancer and upper respiratory tract cancer in both genders. Antiviral substances with a specific anti-HPV effect are so far unknown. Conventional therapies of benign skin warts and of mucosal warts are mainly nonspecific. They comprise tissue-destroying therapies such as electrocautery, cryotherapy and laser. In addition cytotoxic substances such as podophyllotoxin and systemic therapy with retinoids are in use. Systemically and topically administered immunotherapies represent a new approach for treatment. Both interferons and particularly the recently developed imiquimod, an interferon-alpha and cytokine-inductor lead to better results and are better tolerated then conventional therapies. HPV-specific vaccines have been developed in the last 5 years and will be used in future for prevention and treatment of benign and malignant HPV-associated tumors of the genitoanal tract in both sexes. PMID:14610898

  2. Reactive Carbon Nano-Onion Modified Glassy Carbon Surfaces as DNA Sensors for Human Papillomavirus Oncogene Detection with Enhanced Sensitivity.

    PubMed

    Bartolome, Joanne P; Echegoyen, Luis; Fragoso, Alex

    2015-07-01

    Glassy carbon electrodes were modified with small carbon nano-onions (CNOs) and activated by electrografting of diazonium salts bearing terminal carboxylic acid and maleimide groups. The CNO-modified surfaces were characterized by ESEM and AFM microscopy as well as by electrochemical techniques. The modified electrodes were used for the amperometric detection of a model DNA target sequence associated with the human papillomavirus by immobilizing short recognition sequences by amidation or thiol-maleimide reactions. The analytical parameters of the developed biosensors were compared with glassy carbon electrodes without CNOs. In both cases, the incorporation of CNOs resulted in an enhancement in sensitivity and a decrease in detection limits ascribed to a combination of large surface areas and enhanced electron transfer properties of the CNO-modified electrodes. These results offer promise for the construction of other CNO-based biomolecule detection platforms with enhanced sensitivities. PMID:26067834

  3. Tobacco exposure results in increased E6 and E7 oncogene expression, DNA damage and mutation rates in cells maintaining episomal human papillomavirus 16 genomes

    PubMed Central

    Wei, Lanlan; Griego, Anastacia M.; Chu, Ming; Ozbun, Michelle A.

    2014-01-01

    High-risk human papillomavirus (HR-HPV) infections are necessary but insufficient agents of cervical and other epithelial cancers. Epidemiological studies support a causal, but ill-defined, relationship between tobacco smoking and cervical malignancies. In this study, we used mainstream tobacco smoke condensate (MSTS-C) treatments of cervical cell lines that maintain either episomal or integrated HPV16 or HPV31 genomes to model tobacco smoke exposure to the cervical epithelium of the smoker. MSTS-C exposure caused a dose-dependent increase in viral genome replication and correspondingly higher early gene transcription in cells with episomal HPV genomes. However, MSTS-C exposure in cells with integrated HR-HPV genomes had no effect on genome copy number or early gene transcription. In cells with episomal HPV genomes, the MSTS-C-induced increases in E6 oncogene transcription led to decreased p53 protein levels and activity. As expected from loss of p53 activity in tobacco-exposed cells, DNA strand breaks were significantly higher but apoptosis was minimal compared with cells containing integrated viral genomes. Furthermore, DNA mutation frequencies were higher in surviving cells with HPV episomes. These findings provide increased understanding of tobacco smoke exposure risk in HPV infection and indicate tobacco smoking acts more directly to alter HR-HPV oncogene expression in cells that maintain episomal viral genomes. This suggests a more prominent role for tobacco smoke in earlier stages of HPV-related cancer progression. PMID:25064354

  4. Papillomavirus sequences integrate near cellular oncogenes in some cervical carcinomas

    SciTech Connect

    Duerst, M.; Croce, C.M.; Gissmann, L.; Schwarz, E.; Huebner, K.

    1987-02-01

    The chromosomal locations of cellular sequences flanking integrated papillomavirus DNA in four cervical cell lines and a primary cervical carcinoma have been determined. The two human papillomavirus (HPV) 16 flanking sequences derived from the tumor were localized to chromosomes regions 20pter..-->..20q13 and 3p25..-->..3qter, regions that also contain the protooncogenes c-src-1 and c-raf-1, respectively. The HPV 16 integration site in the SiHa cervical carcinoma-derived cell line is in chromosome region 13q14..-->..13q32. The HPV 18 integration site in SW756 cervical carcinoma cells is in chromosome 12 but is not closely linked to the Ki-ras2 gene. Finally, in two cervical carcinoma cell lines, HeLa and C4-I, HPV 18 DNA is integrated in chromosome 8, 5' of the c-myc gene. The HeLaHPV 18 integration site is within 40 kilobases 5' of the c-myc gene, inside the HL60 amplification unit surrounding and including the c-myc gene. Additionally, steady-state levels of c-myc mRNA are elevated in HeLa and C4-I cells relative to other cervical carcinoma cell lines. Thus, in at least some genital tumors, cis-activation of cellular oncogenes by HPV may be involved in malignant transformation of cervical cells.

  5. Systemic delivery of siRNA by actively targeted polyion complex micelles for silencing the E6 and E7 human papillomavirus oncogenes.

    PubMed

    Nishida, Haruka; Matsumoto, Yoko; Kawana, Kei; Christie, R James; Naito, Mitsuru; Kim, Beob Soo; Toh, Kazuko; Min, Hyun Su; Yi, Yu; Matsumoto, Yu; Kim, Hyun Jin; Miyata, Kanjiro; Taguchi, Ayumi; Tomio, Kensuke; Yamashita, Aki; Inoue, Tomoko; Nakamura, Hiroe; Fujimoto, Asaha; Sato, Masakazu; Yoshida, Mitsuyo; Adachi, Katsuyuki; Arimoto, Takahide; Wada-Hiraike, Osamu; Oda, Katsutoshi; Nagamatsu, Takeshi; Nishiyama, Nobuhiro; Kataoka, Kazunori; Osuga, Yutaka; Fujii, Tomoyuki

    2016-06-10

    Human papillomavirus (HPV) E6 and E7 oncogenes are essential for the immortalization and maintenance of HPV-associated cancer and are ubiquitously expressed in cervical cancer lesions. Small interfering RNA (siRNA) coding for E6 and E7 oncogenes is a promising approach for precise treatment of cervical cancer, yet a delivery system is required for systemic delivery to solid tumors. Here, an actively targeted polyion complex (PIC) micelle was applied to deliver siRNAs coding for HPV E6/E7 to HPV cervical cancer cell tumors in immune-incompetent tumor-bearing mice. A cell viability assay revealed that both HPV type 16 and 18 E6/E7 siRNAs (si16E6/E7 and si18E6/E7, respectively) interfered with proliferation of cervical cancer cell lines in an HPV type-specific manner. A fluorescence imaging biodistribution analysis further revealed that fluorescence dye-labeled siRNA-loaded PIC micelles efficiently accumulated within the tumor mass after systemic administration. Ultimately, intravenous injection of si16E6/E7 and si18E6/E7-loaded PIC micelles was found to significantly suppress the growth of subcutaneous SiHa and HeLa tumors, respectively. The specific activity of siRNA treatment was confirmed by the observation that p53 protein expression was restored in the tumors excised from the mice treated with si16E6/E7- and si18E6/E7-loaded PIC micelles for SiHa and HeLa tumors, respectively. Therefore, the actively targeted PIC micelle incorporating HPV E6/E7-coding siRNAs demonstrated its therapeutic potential against HPV-associated cancer. PMID:26979870

  6. Codon optimization of the human papillomavirus E7 oncogene induces a CD8+ T cell response to a cryptic epitope not harbored by wild-type E7.

    PubMed

    Lorenz, Felix K M; Wilde, Susanne; Voigt, Katrin; Kieback, Elisa; Mosetter, Barbara; Schendel, Dolores J; Uckert, Wolfgang

    2015-01-01

    Codon optimization of nucleotide sequences is a widely used method to achieve high levels of transgene expression for basic and clinical research. Until now, immunological side effects have not been described. To trigger T cell responses against human papillomavirus, we incubated T cells with dendritic cells that were pulsed with RNA encoding the codon-optimized E7 oncogene. All T cell receptors isolated from responding T cell clones recognized target cells expressing the codon-optimized E7 gene but not the wild type E7 sequence. Epitope mapping revealed recognition of a cryptic epitope from the +3 alternative reading frame of codon-optimized E7, which is not encoded by the wild type E7 sequence. The introduction of a stop codon into the +3 alternative reading frame protected the transgene product from recognition by T cell receptor gene-modified T cells. This is the first experimental study demonstrating that codon optimization can render a transgene artificially immunogenic through generation of a dominant cryptic epitope. This finding may be of great importance for the clinical field of gene therapy to avoid rejection of gene-corrected cells and for the design of DNA- and RNA-based vaccines, where codon optimization may artificially add a strong immunogenic component to the vaccine. PMID:25799237

  7. HPV (Human Papillomavirus)

    MedlinePlus

    ... Health Topics Mammography Women and Diabetes HPV, HIV, Birth Control Heart Health for Women Pregnancy Menopause More Women's Health Topics Resources for You Human Papillomavirus Vaccine HPV Information in Other Languages Women ...

  8. E2F-Rb Complexes Assemble and Inhibit cdc25A Transcription in Cervical Carcinoma Cells following Repression of Human Papillomavirus Oncogene Expression

    PubMed Central

    Wu, Lingling; Goodwin, Edward C.; Naeger, Lisa Kay; Vigo, Elena; Galaktionov, Konstantin; Helin, Kristian; DiMaio, Daniel

    2000-01-01

    Expression of the bovine papillomavirus E2 protein in cervical carcinoma cells represses expression of integrated human papillomavirus (HPV) E6/E7 oncogenes, followed by repression of the cdc25A gene and other cellular genes required for cell cycle progression, resulting in dramatic growth arrest. To explore the mechanism of repression of cell cycle genes in cervical carcinoma cells following E6/E7 repression, we analyzed regulation of the cdc25A promoter, which contains two consensus E2F binding sites and a consensus E2 binding site. The wild-type E2 protein inhibited expression of a luciferase gene linked to the cdc25A promoter in HT-3 cervical carcinoma cells. Mutation of the distal E2F binding site in the cdc25A promoter abolished E2-induced repression, whereas mutation of the proximal E2F site or the E2 site had no effect. None of these mutations affected the activity of the promoter in the absence of E2 expression. Expression of the E2 protein also led to posttranscriptional increase in the level of E2F4, p105Rb, and p130 and induced the formation of nuclear E2F4-p130 and E2F4-p105Rb complexes. This resulted in marked rearrangement of the protein complexes that formed at the distal E2F site in the cdc25A promoter, including the replacement of free E2F complexes with E2F4-p105Rb complexes. These experiments indicated that repression of E2F-responsive promoters following HPV E6/E7 repression was mediated by activation of the Rb tumor suppressor pathway and the assembly of repressing E2F4-Rb DNA binding complexes. Importantly, these experiments revealed that HPV-induced alterations in E2F transcription complexes that occur during cervical carcinogenesis are reversed by repression of HPV E6/E7 expression. PMID:10982822

  9. A Chimeric 18L1-45RG1 Virus-Like Particle Vaccine Cross-Protects against Oncogenic Alpha-7 Human Papillomavirus Types

    PubMed Central

    Huber, Bettina; Schellenbacher, Christina; Jindra, Christoph; Fink, Dieter; Shafti-Keramat, Saeed; Kirnbauer, Reinhard

    2015-01-01

    Persistent infection with oncogenic human papillomaviruses (HPV) types causes all cervical and a subset of other anogenital and oropharyngeal carcinomas. Four high-risk (hr) mucosal types HPV16, 18, 45, or 59 cause almost all cervical adenocarcinomas (AC), a subset of cervical cancer (CxC). Although the incidence of cervical squamous cell carcinoma (SCC) has dramatically decreased following introduction of Papanicolaou (PAP) screening, the proportion of AC has relatively increased. Cervical SCC arise mainly from the ectocervix, whereas AC originate primarily from the endocervical canal, which is less accessible to obtain viable PAP smears. Licensed (bivalent and quadrivalent) HPV vaccines comprise virus-like particles (VLP) of the most important hr HPV16 and 18, self-assembled from the major capsid protein L1. Due to mainly type-restricted efficacy, both vaccines do not target 13 additional hr mucosal types causing 30% of CxC. The papillomavirus genus alpha species 7 (α7) includes a group of hr types of which HPV18, 45, 59 are proportionally overrepresented in cervical AC and only partially (HPV18) targeted by current vaccines. To target these types, we generated a chimeric vaccine antigen that consists of a cross-neutralizing epitope (homologue of HPV16 RG1) of the L2 minor capsid protein of HPV45 genetically inserted into a surface loop of HPV18 L1 VLP (18L1-45RG1). Vaccination of NZW rabbits with 18L1-45RG1 VLP plus alum-MPL adjuvant induced high-titer neutralizing antibodies against homologous HPV18, that cross-neutralized non-cognate hr α7 types HPV39, 45, 68, but not HPV59, and low risk HPV70 in vitro, and induced a robust L1-specific cellular immune response. Passive immunization protected mice against experimental vaginal challenge with pseudovirions of HPV18, 39, 45 and 68, but not HPV59 or the distantly related α9 type HPV16. 18L1-45RG1 VLP might be combined with our previously described 16L1-16RG1 VLP to develop a second generation bivalent vaccine

  10. Complementation of human papillomavirus type 16 E6 and E7 by Jagged1-specific Notch1-phosphatidylinositol 3-kinase signaling involves pleiotropic oncogenic functions independent of CBF1;Su(H);Lag-1 activation.

    PubMed

    Veeraraghavalu, Karthikeyan; Subbaiah, Vanitha K; Srivastava, Sweta; Chakrabarti, Oishee; Syal, Ruchi; Krishna, Sudhir

    2005-06-01

    We have analyzed the induction and role of phosphatidylinositol 3-kinase (PI3K) by Notch signaling in human papillomavirus (HPV)-derived cancers. Jagged1, in contrast to Delta1, is preferentially upregulated in human cervical tumors. Jagged1 and not Delta1 expression sustained in vivo tumors by HPV16 oncogenes in HaCaT cells. Further, Jagged1 expression correlates with the rapid induction of PI3K-mediated epithelial-mesenchymal transition in both HaCaT cells and a human cervical tumor-derived cell line, suggestive of Delta1;Serrate/Jagged;Lag2 ligand-specific roles. Microarray analysis and dominant-negatives reveal that Notch-PI3K oncogenic functions can be independent of CBF1;Su(H);Lag-1 activation and instead relies on Deltex1, an alternative Notch effector. PMID:15919944

  11. Complementation of Human Papillomavirus Type 16 E6 and E7 by Jagged1-Specific Notch1-Phosphatidylinositol 3-Kinase Signaling Involves Pleiotropic Oncogenic Functions Independent of CBF1;Su(H);Lag-1 Activation†

    PubMed Central

    Veeraraghavalu, Karthikeyan; Subbaiah, Vanitha K.; Srivastava, Sweta; Chakrabarti, Oishee; Syal, Ruchi; Krishna, Sudhir

    2005-01-01

    We have analyzed the induction and role of phosphatidylinositol 3-kinase (PI3K) by Notch signaling in human papillomavirus (HPV)-derived cancers. Jagged1, in contrast to Delta1, is preferentially upregulated in human cervical tumors. Jagged1 and not Delta1 expression sustained in vivo tumors by HPV16 oncogenes in HaCaT cells. Further, Jagged1 expression correlates with the rapid induction of PI3K-mediated epithelial-mesenchymal transition in both HaCaT cells and a human cervical tumor-derived cell line, suggestive of Delta1;Serrate/Jagged;Lag2 ligand-specific roles. Microarray analysis and dominant-negatives reveal that Notch-PI3K oncogenic functions can be independent of CBF1;Su(H);Lag-1 activation and instead relies on Deltex1, an alternative Notch effector. PMID:15919944

  12. Two less common human microRNAs miR-875 and miR-3144 target a conserved site of E6 oncogene in most high-risk human papillomavirus subtypes.

    PubMed

    Lin, Lin; Cai, Qingqing; Zhang, Xiaoyan; Zhang, Hongwei; Zhong, Yang; Xu, Congjian; Li, Yanyun

    2015-08-01

    Human papillomaviruses (HPVs) including high-risk (HR) and low-risk (LR) subtypes have distinguishable variation on both genotypes and phenotypes. The co-infection of multiple HR-HPVs, headed by HPV16, is common in cervical cancer in female. Recently accumulating reports have focused on the interaction between virus and host, particularly the role of human microRNAs (miRNAs) in anti-viral defense by targeting viral genome. Here, we found a well-conserved target site of miRNAs in the genomes of most HR-HPVs, not LR-HPVs, by scanning all potential target sites of human miRNAs on 24 HPVs of unambiguous subtypes of risk. The site is targeted by two less common human miRNAs, miR-875 and miR-3144, and is located in E6 oncogene open reading frame (ORF) and overlap with the first alternative splice exon of viral early transcripts. In validation tests, miR-875 and miR-3144 were identified to suppress the target reporter activity markedly and inhibit the expression of both synthetically exogenous E6 and endogenous E6 oncogene. High level of two miRNAs can inhibit cell growth and promote apoptosis in HPV16-positive cervical cancer cells. This study provides a promising common target of miRNAs for most HR-HPVs and highlights the effects of two low expressed human miRNAs on tumour suppression. PMID:25913515

  13. Papillomaviruses and human disease

    SciTech Connect

    Syrjanen, K.; Gissman, L.; Koss, L.G.

    1987-01-01

    This book contains 17 selections. Some of the titles are: Papillomaviruses: particles, genome organization and proteins; Physical state of papillomavirus DNA in tumors; Transforming and regulatory functions of bovine papillomavirus Type 1; and Transcription of papillomavirus genomes.

  14. [Network Research on Human Papillomavirus].

    PubMed

    Almeida-Gutiérrez, Eduardo; Paniagua, Ramón; Furuya, María ElenaYuriko

    2015-01-01

    In order to increase the research in important health questions at a national and institutional levels, the Human Papillomavirus Research Network of the Health Research Coordination of the Instituto Mexicano del Seguro Social offers this supplement with the purpose of assisting patients that daily look for attention due to the human papillomavirus or to cervical cancer. PMID:26462505

  15. Nongenital human papillomavirus disease.

    PubMed

    Mayeaux, E J; Khan, Michelle J

    2013-06-01

    Human papillomavirus (HPV) is the most common viral cause of cancer, and is responsible for 5% of cancers worldwide. Following demonstration of the causative link between HPV and cervical cancer, HPV has been shown to be associated with several anogenital malignancies and with oral pharyngeal cancers. HPV-related anal and oral pharyngeal disease is rising in incidence and includes anal warts and neoplasia, recurrent respiratory papillomatosis, and oral pharyngeal neoplasia. This article presents an overview of the epidemiology, clinical manifestations, diagnosis, and treatment of nongenital HPV-related disease. PMID:23732034

  16. Targeted expression of the E6 and E7 oncogenes of human papillomavirus type 16 in the epidermis of transgenic mice elicits generalized epidermal hyperplasia involving autocrine factors.

    PubMed Central

    Auewarakul, P; Gissmann, L; Cid-Arregui, A

    1994-01-01

    The E6 and E7 early genes of human papillomavirus type 16 have been shown in vitro to play a central role in the transforming capability of this virus. To explore their effects on differentiating epithelial cells in vivo, we used a bovine cytokeratin 10 (K10) promoter to target the expression of E6 and E7 to the suprabasal layers of the epidermis of transgenic mice. In two different lines of mice efficiently expressing the transgene, animals displayed generalized epidermal hyperplasia, hyperkeratosis and parakeratosis in the skin and the forestomach, both known to be sites of K10 expression. Northern (RNA) blot analysis revealed high levels of E6 and E7 transcripts, and in situ hybridizations localized these transcripts to the suprabasal strata of epidermis. In vivo labeling of proliferating cells showed two distinct effects of E6 and E7 expression in the epidermis: (i) an increase in the number of growing cells in the undifferentiated basal layer and (ii) abnormal proliferation of differentiated cells in the suprabasal strata. The expression of c-myc in the skin of transgenics was higher than that in control animals. The induction of c-myc transcription by topical application of tetradecanoyl phorbol acetate was prevented by simultaneous treatment with transforming growth factor beta 1 in nontransgenic skin but not in transgenic skin. In addition, transforming growth factor alpha was found to be overexpressed in the suprabasal layers of the transgenic epidermis. These findings suggest that autocrine mechanisms are involved in the development and maintenance of epidermal hyperplasia. Animals of both lines developed papillomas in skin sites exposed to mechanical irritation and wounding, suggesting that secondary events are necessary for progression to neoplasia. Collectively, these results provide new insights into the tumor promoter activities of human papillomavirus type 16 in epithelial cells in vivo. Images PMID:7969162

  17. Durable immunity to oncogenic human papillomaviruses elicited by adjuvanted recombinant Adeno-associated virus-like particle immunogen displaying L2 17-36 epitopes.

    PubMed

    Jagu, Subhashini; Karanam, Balusubramanyam; Wang, Joshua W; Zayed, Hatem; Weghofer, Margit; Brendle, Sarah A; Balogh, Karla K; Tossi, Kerstin Pino; Roden, Richard B S; Christensen, Neil D

    2015-10-13

    Vaccination with the minor capsid protein L2, notably the 17-36 neutralizing epitope, induces broadly protective antibodies, although the neutralizing titers attained in serum are substantially lower than for the licensed L1 VLP vaccines. Here we examine the impact of other less reactogenic adjuvants upon the induction of durable neutralizing serum antibody responses and protective immunity after vaccination with HPV16 and HPV31 L2 amino acids 17-36 inserted at positions 587 and 453 of VP3, respectively, for surface display on Adeno-Associated Virus 2-like particles [AAVLP (HPV16/31L2)]. Mice were vaccinated three times subcutaneously with AAVLP (HPV16/31L2) at two week intervals at several doses either alone or formulated with alum, alum and MPL, RIBI adjuvant or Cervarix. The use of adjuvant with AAVLP (HPV16/31L2) was necessary in mice for the induction of L2-specific neutralizing antibody and protection against vaginal challenge with HPV16. While use of alum was sufficient to elicit durable protection (>3 months after the final immunization), antibody titers were increased by addition of MPL and RIBI adjuvants. To determine the breadth of immunity, rabbits were immunized three times with AAVLP (HPV16/31L2) either alone, formulated with alum±MPL, or RIBI adjuvants, and after serum collection, the animals were concurrently challenged with HPV16/31/35/39/45/58/59 quasivirions or cottontail rabbit papillomavirus (CRPV) at 6 or 12 months post-immunization. Strong protection against all HPV types was observed at both 6 and 12 months post-immunization, including robust protection in rabbits receiving the vaccine without adjuvant. In summary, vaccination with AAVLP presenting HPV L2 17-36 epitopes at two sites on their surface induced cross-neutralizing serum antibody, immunity against HPV16 in the genital tract, and long-term protection against skin challenge with the 7 most common oncogenic HPV types when using a clinically relevant adjuvant. PMID:26382603

  18. Durable immunity to oncogenic human papillomaviruses elicited by adjuvanted recombinant Adeno-associated virus-like particle immunogen displaying L2 17–36 epitopes

    PubMed Central

    Jagu, Subhashini; Karanam, Balusubramanyam; Wang, Joshua W.; Zayed, Hatem; Weghofer, Margit; Brendle, Sarah A.; Balogh, Karla K.; Tossi, Kerstin Pino; Roden, Richard B.S.; Christensen, Neil D.

    2016-01-01

    Vaccination with the minor capsid protein L2, notably the 17–36 neutralizing epitope, induces broadly protective antibodies, although the neutralizing titers attained in serum are substantially lower than for the licensed L1 VLP vaccines. Here we examine the impact of other less reactogenic adjuvants upon the induction of durable neutralizing serum antibody responses and protective immunity after vaccination with HPV16 and HPV31 L2 amino acids 17–36 inserted at positions 587 and 453 of VP3, respectively, for surface display on Adeno-Associated Virus 2-like particles [AAVLP (HPV16/31L2)]. Mice were vaccinated three times subcutaneously with AAVLP (HPV16/31L2) at two week intervals at several doses either alone or formulated with alum, alum and MPL, RIBI adjuvant or Cervarix. The use of adjuvant with AAVLP (HPV16/31L2) was necessary in mice for the induction of L2-specific neutralizing antibody and protection against vaginal challenge with HPV16. While use of alum was sufficient to elicit durable protection (>3 months after the final immunization), antibody titers were increased by addition of MPL and RIBI adjuvants. To determine the breadth of immunity, rabbits were immunized three times with AAVLP (HPV16/31L2) either alone, formulated with alum ± MPL, or RIBI adjuvants, and after serum collection, the animals were concurrently challenged with HPV16/31/35/39/45/58/59 quasivirions or cottontail rabbit papillomavirus (CRPV) at 6 or 12 months post-immunization. Strong protection against all HPV types was observed at both 6 and 12 months post-immunization, including robust protection in rabbits receiving the vaccine without adjuvant. In summary, vaccination with AAVLP presenting HPV L2 17–36 epitopes at two sites on their surface induced cross-neutralizing serum antibody, immunity against HPV16 in the genital tract, and long-term protection against skin challenge with the 7 most common oncogenic HPV types when using a clinically relevant adjuvant. PMID:26382603

  19. Human Papillomavirus and Cervical Cancer

    PubMed Central

    Burd, Eileen M.

    2003-01-01

    Of the many types of human papillomavirus (HPV), more than 30 infect the genital tract. The association between certain oncogenic (high-risk) strains of HPV and cervical cancer is well established. Although HPV is essential to the transformation of cervical epithelial cells, it is not sufficient, and a variety of cofactors and molecular events influence whether cervical cancer will develop. Early detection and treatment of precancerous lesions can prevent progression to cervical cancer. Identification of precancerous lesions has been primarily by cytologic screening of cervical cells. Cellular abnormalities, however, may be missed or may not be sufficiently distinct, and a portion of patients with borderline or mildly dyskaryotic cytomorphology will have higher-grade disease identified by subsequent colposcopy and biopsy. Sensitive and specific molecular techniques that detect HPV DNA and distinguish high-risk HPV types from low-risk HPV types have been introduced as an adjunct to cytology. Earlier detection of high-risk HPV types may improve triage, treatment, and follow-up in infected patients. Currently, the clearest role for HPV DNA testing is to improve diagnostic accuracy and limit unnecessary colposcopy in patients with borderline or mildly abnormal cytologic test results. PMID:12525422

  20. Modulation of therapeutic sensitivity by human papillomavirus.

    PubMed

    Swick, Adam D; Chatterjee, Anirban; De Costa, Anna-Maria A; Kimple, Randall J

    2015-09-01

    Human papillomaviruses (HPVs) are small double-stranded DNA viruses that pose significant public health concerns as the causative agent of approximately 5% of worldwide cancers. The HPV oncogenes E6 and E7 play key roles in carcinogenesis. In the last 15years there has been a significant increase in the incidence of HPV-related head and neck cancers arising primarily in the oropharynx. Patients with HPV-positive head and neck cancers (HNCs) have a significantly improved prognosis compared to those with HPV-negative disease. In this review we will discuss data suggesting how HPV oncogenes modulate both the intrinsic radiation sensitivity of HNCs and also have important effects upon the tumor microenvironment. Together, these findings contribute to the improved outcomes seen in patients with HPV-positive HNC. PMID:26364887

  1. Comparison of the immunogenicity of Cervarix® and Gardasil® human papillomavirus vaccines for oncogenic non-vaccine serotypes HPV-31, HPV-33, and HPV-45 in HIV-infected adults

    PubMed Central

    Toft, Lars; Tolstrup, Martin; Müller, Martin; Sehr, Peter; Bonde, Jesper; Storgaard, Merete; Østergaard, Lars; Søgaard, Ole S

    2014-01-01

    Individuals infected with human immunodeficiency virus (HIV) have excess risk of developing human papillomavirus (HPV)-related disease. A substantial fraction of HPV-associated cancers is caused by HPV serotypes not included in the currently available vaccines. Among healthy women, both Cervarix® (HPV-16/18, GlaxoSmithKline Biologicals, GSK) and Gardasil® (HPV-6/11/16/18, Merck) have demonstrated partial cross-protection against certain oncogenic non-vaccine HPV-types. Currently, there are no available data on vaccine-induced cross-protection in men and little is known about cross-reactive immunity after HPV-vaccination of HIV-infected individuals. In an investigator-initiated trial, we randomized 91 HIV-positive men and women to receive vaccination with Cervarix® or Gardasil®. The HPV-DNA status of the participants was determined with pcr before and after immunization. Cross-reactive antibody responses against HPV-31, HPV-33, and HPV-45 were evaluated for up to 12 months using a pseudovirion-based neutralization assay (PBNA). Geometric mean antibody titers (GMTs) were compared among vaccine groups and genders at 7 and 12 months. Both vaccines induced anti-HPV-31, -33, and -45 neutralizing antibodies in participants who were seronegative and HPV-DNA negative for those types at study entry. Geometric mean antibody titers were comparable between vaccine groups. Interestingly, anti-HPV-31 and -33 antibody titers were higher among women compared with men at 7 and 12 months. In conclusion, both licensed HPV-vaccines induced cross-neutralizing antibodies against frequent oncogenic non-vaccine serotypes HPV-31, HPV-33, and HPV-45 in HIV-infected adults, and women had greater serological responses against HPV-31 and -33 compared with men. PMID:24553190

  2. Emerging human papillomavirus vaccines

    PubMed Central

    Ma, Barbara; Maraj, Bharat; Tran, Nam Phuong; Knoff, Jayne; Chen, Alexander; Alvarez, Ronald D; Hung, Chien-Fu; Wu, T.-C.

    2013-01-01

    Introduction Identification of human papillomavirus (HPV) as the etiologic factor of cervical, anogenital, and a subset of head and neck cancers has stimulated the development of preventive and therapeutic HPV vaccines to control HPV-associated malignancies. Excitement has been generated by the commercialization of two preventive L1-based vaccines, which use HPV virus-like particles (VLPs) to generate capsid-specific neutralizing antibodies. However, factors such as high cost and requirement for cold chain have prevented widespread implementation where they are needed most. Areas covered Next generation preventive HPV vaccine candidates have focused on cost-effective stable alternatives and generating broader protection via targeting multivalent L1 VLPs, L2 capsid protein, and chimeric L1/L2 VLPs. Therapeutic HPV vaccine candidates have focused on enhancing T cell-mediated killing of HPV-transformed tumor cells, which constitutively express HPV-encoded proteins, E6 and E7. Several therapeutic HPV vaccines are in clinical trials. Expert opinion Although progress is being made, cost remains an issue inhibiting the use of preventive HPV vaccines in countries that carry the majority of the cervical cancer burden. In addition, progression of therapeutic HPV vaccines through clinical trials may require combination strategies employing different therapeutic modalities. As research in the development of HPV vaccines continues, we may generate effective strategies to control HPV-associated malignancies. PMID:23163511

  3. Pathogenesis of infection by human papillomavirus.

    PubMed

    Brendle, Sarah A; Bywaters, Stephanie M; Christensen, Neil D

    2014-01-01

    Human papillomaviruses (HPVs) are associated with benign lesions known as warts and several cancer types including cancer of the cervix, penis, anus and oral cavity. HPVs are classified by their oncogenic potential and are divided into high-risk oncogenic HPVs and low-risk HPVs. Tissue tropism is used as another means of classifying the virus, and HPVs are divided into types that infect mucosal or cutaneous tissues. Several risk factors have been identified that elevate an individual's likelihood of becoming infected with HPV including cigarette smoking, a large number of lifetime sexual partners and immunosuppression. Most HPV infections are cleared naturally, although persistent infection with oncogenic HPV types can lead to the cancers mentioned above. HPV has employed several mechanisms to avoid detection by the host immune system. Virus is released along with shedding skin cells in a nonlytic manner, and the virus has an altered codon usage leading to reduced expression of viral proteins. Infections from high-risk oncogenic HPV types that progress cause neoplasias that are defined as CIN1-CIN3 depending on the amount of abnormal cell growth and the level of cellular differentiation. PMID:24643177

  4. Human papillomavirus vaccination in adolescence.

    PubMed

    Russell, Michelle; Raheja, Vinita; Jaiyesimi, Rotimi

    2013-11-01

    Cervical cancer is the third most common female cancer worldwide. It remains the highest ranking preventable cancer affecting women in developing countries. Cervical cancer is caused by sexual transmission of human papillomavirus (HPV). It is estimated that more than 80% of sexually active women will be infected with HPV in their lifetime, usually in their mid to late teens, 20s and early 30s. Persistence of high-risk oncogenic subtypes can lead to the development of precancerous change (cervical intraepithelial neoplasia (CIN)), which can ultimately lead to cervical cancer. Progression from CIN to cancer is slow in most cases, and it is believed that progression from CIN 3 to cancer at 10, 20 and 30 years is 16%, 25% and 31.3%, respectively. The cervical screening programme has been successful in reducing the incidence of cervical cancer by recognising early precancerous changes and treating them. A promising advance in women's health has been the development of a vaccine targeting high-risk oncogenic subtypes 16 and 18, which are responsible for 70% of all cervical cancers. Two HPV vaccines are available: Merck & Co.'s Gardasil(®) and GlaxoSmithKline's Cervarix(®). The aim of this programme is to provide three doses prior to sexual debut with the hope that it will reduce the rates of cervical cancer in the future. Women who are already sexually active can still be vaccinated, but, the vaccine has been shown to be less effective in them. Uptake remains a challenge for public health, and efforts should focus on educating parents about the association between HPV and cervical cancer. Routine vaccination of young men is a debatable issue and has been found to be less cost-effective, as the burden of disease such as anal and penile cancers in males is less than cervical cancers in women. Current evidence suggests that the HPV vaccination programme should focus on increasing and maintaining high coverage of vaccination in girls. There may, however, be some benefit in

  5. [The first vaccine against cancer: the human papillomavirus vaccine].

    PubMed

    Bősze, Péter

    2013-04-21

    The last 20 years is one of the most remarkable periods in the fight against cancer, with the realization that some human papillomaviruses are causally related to cancer and with the development of the vaccine against human papillomavirus infections. This is a historical event in medicine and the prophylactic human papillomavirus vaccines have provided powerful tools for primary prevention of cervical cancer and other human papillomavirus-associated diseases. This is very important as human papillomavirus infection is probably the most common sexually transmitted infection worldwide, and over one million women develop associated cancer yearly, which is about 5% of all female cancers, and half of them die of their disease. Cancers associated with oncogenic human papillomaviruses, mostly HPV16 and 18, include cervical cancer (100%), anal cancer (95%), vulvar cancer (40%), vaginal cancer (60%), penile cancer (40%), and oro-pharingeal cancers (65%). In addition, pre-cancers such as genital warts and the rare recurrent respiratory papillomatosis are also preventable by vaccination. Currently, the human papillomavirus vaccines have the potential to significantly reduce the burden of human papillomavirus associated conditions, including prevention of up to 70% of cervical cancers. Two prophylactic human papillomavirus vaccines are currently available worldwide: a bivalent vaccine (types 16 and 18), and a quadrivalent vaccine (types 6, 11, 16, and 18). Randomized controlled trials conducted on several continents during the last 10 years have demonstrated that these vaccines are safe without serious side effects; they are highly immunogenic and efficacious in preventing incident and persistent vaccine-type human papillomavirus infections, high grade cervical, vulvar and vaginal intraepithelial neoplasia and so on. In addition, the quadrivalent vaccine has been shown to prevent genital warts in women and men. The vaccine is most effective when given to human papillomavirus

  6. [General aspects of structure, classification and replication of human papillomavirus].

    PubMed

    Santos-López, Gerardo; Márquez-Domínguez, Luis; Reyes-Leyva, Julio; Vallejo-Ruiz, Verónica

    2015-01-01

    Human papillomavirus (HPV) refers to a group of viruses which belongs to a larger group, commonly referred to as papillomaviruses. These viruses are taxonomically located in the Papillomaviridae family. Papillomaviruses are small, non-enveloped with a genome of double-stranded DNA and they have affinity for epithelial tissue. Many of them are associated with human infection; they induce benign lesions of the skin (warts) and mucous membranes (condylomas), but they are also associated with some epithelial malignancies, such as cervical cancer and other tumors of the urogenital tract. Papillomaviridae contains 16 genera, which are named with a Greek letter prefix and the termination papillomavirus, e.g., Alphapapillomavirus, Betapapillomavirus, etcetera. From the clinical point of view, human papillomaviruses infecting the genital tract (which are located in the genus Alphapapilomavirus) have been divided into two groups: those of low risk, associated with benign genital warts, and those of high risk, with oncogenic potential, which are the etiological agents of cervical cancer. In this paper we review some relevant aspects of the structure, replication cycle and classification of human papillomaviruses. PMID:26462512

  7. Epigenetics of human papillomaviruses

    SciTech Connect

    Johannsen, Eric; Lambert, Paul F.

    2013-10-15

    Human papilllomaviruses (HPVs) are common human pathogens that infect cutaneous or mucosal epithelia in which they cause warts, self-contained benign lesions that commonly regress. The HPV life cycle is intricately tied to the differentiation of the host epithelium it infects. Mucosotropic HPVs are the most common sexually transmitted pathogen known to mankind. A subset of the mucosotropic HPVs, so-called high risk HPVs, is etiologically associated with numerous cancers of the anogenital tract, most notably the cervix, as well as a growing fraction of head and neck cancers. In these cancers, the HPV genome, which normally exists an a double stranded, circular, nuclear plasmid, is commonly found integrated into the host genome and expresses two viral oncogenes, E6 and E7, that are implicated in the development and maintainance of the cancers caused by these high risk HPVs. Numerous studies, primarily on the high risk HPV16, have documented that the methylation status of the viral genome changes not only in the context of the viral life cycle but also in the context of the progressive neoplastic disease that culminates in cancer. In this article, we summarize the knowledge gained from those studies. We also provide the first analysis of available ChIP-seq data on the occupancy of both epigentically modified histones as well as transcription factors on the high risk HPV18 genome in the context of HeLa cells, a cervical cancer-derived cell line that has been the subject of extensive analyses using this technique. - Highlights: • Methylation status of HPV genomes is dynamic. • Changes are seen in both the viral life cycle and neoplasia. • Histone modification status at LCR is predictive of transcription factor occupancy. • Novel transcription factor binding noted by ChIP-seq.

  8. Oncogenic Papillomavirus and Polyomavirus in Water Environments: Is There a Potential for Waterborne Transmission?

    PubMed

    Fratini, M; Di Bonito, P; La Rosa, G

    2014-03-01

    Waterborne exposure to human viruses through contact with sewage-contaminated water environments can result in infections associated with a wide range of illnesses. Gastrointestinal symptoms are the most commonly encountered manifestations of waterborne viral illness. Respiratory diseases, neurological diseases and paralysis can also occur. Whether viral infections resulting in health outcomes like cancer might also be transmitted by the waterborne route is unknown. Recently, viruses belonging to two oncogenic groups-Human Papillomaviruses (HPVs) and Human Polyomaviruses (HPyVs)-have been detected in urban sewages worldwide. The latter have also been identified in other water environments. HPVs are epitheliotropic viruses responsible for several diseases of skin and mucosae, from common warts to squamous intraepithelial lesions that can either heal or progress to invasive carcinoma of the cervix, vulva, vagina, penis, anus or oropharynx. Human PyVs infect different tissues and organs, causing infections that are usually subclinical in immunocompetent individuals but can be serious in immunocompromised hosts. These pathogens belong to a family of DNA tumour viruses. Merkel cell polyomavirus, a HPyV identified in recent years, has attracted much attention due to its link with a rare and aggressive form of human cancer. Merkel cell carcinoma, the incidence of which has tripled over the past two decades. JC polyomavirus and BK polyomavirus are also potentially oncogenic. The observed abundance and wide dissemination of HPVs and HPyVs in water environments strongly suggest the need to shed light on the fate of these viruses in water environments and to elucidate their potential for waterborne transmission. Such information is essential for the improvement of wastewater management programs in terms of both sewage treatment and water quality surveillance. PMID:24293168

  9. Oncogenes and RNA splicing of human tumor viruses.

    PubMed

    Ajiro, Masahiko; Zheng, Zhi-Ming

    2014-09-01

    Approximately 10.8% of human cancers are associated with infection by an oncogenic virus. These viruses include human papillomavirus (HPV), Epstein-Barr virus (EBV), Merkel cell polyomavirus (MCV), human T-cell leukemia virus 1 (HTLV-1), Kaposi's sarcoma-associated herpesvirus (KSHV), hepatitis C virus (HCV) and hepatitis B virus (HBV). These oncogenic viruses, with the exception of HCV, require the host RNA splicing machinery in order to exercise their oncogenic activities, a strategy that allows the viruses to efficiently export and stabilize viral RNA and to produce spliced RNA isoforms from a bicistronic or polycistronic RNA transcript for efficient protein translation. Infection with a tumor virus affects the expression of host genes, including host RNA splicing factors, which play a key role in regulating viral RNA splicing of oncogene transcripts. A current prospective focus is to explore how alternative RNA splicing and the expression of viral oncogenes take place in a cell- or tissue-specific manner in virus-induced human carcinogenesis. PMID:26038756

  10. [Human papillomavirus infection and adolescence].

    PubMed

    Sam Soto, Selene; de la Peña y Carranza, Alejandro Ortiz; Plascencia, Josefina Lira

    2011-04-01

    Infection with human papillomavirus has increased dramatically in recent years. The highest prevalence rates are among adolescents and young women, reflecting changes in sexual behavior associated with biological factors in adolescent development. Adolescents who begin sexual activity early are at greater risk of precursor lesions and cervical cancer. There are adolescents with special circumstances, where no early decision should be delayed cervical cytology and in whom it is important to initiate consultations and periodic reviews with a preventive approach. Cervical cancer can be avoided when the diagnosis and treatment of precursor lesions is early. Despite efforts at sex education based on "safe sex" with the correct use of condoms has not been able to reduce the incidence of infections with human papillomavirus in adolescents. While better than nothing, condom use is not 100% reliable. Studies show that consistent and correct use provides protection against the human papillomavirus only 70%. In Mexico, reported an overall ratio of actual use of condoms from 24.6%. It is clear that the physician who provides care for adolescents plays a fundamental role in sex education. The key to future prevention of cervical cancer and its precursor lesions could be the vaccination. PMID:21966809

  11. Human papillomavirus DNA and mRNA prevalence and association with cervical cytological abnormalities in the Irish HIV population.

    PubMed

    Loy, Aisling; McInerney, Jamie; Pilkington, Loretto; Keegan, Helen; Delamere, Sandra; Martin, Cara M; Sheils, Orla; O'Leary, John J; Mulcahy, Fiona

    2015-10-01

    The complex interplay between HIV and human papillomavirus and its link to cervical dysplasia is poorly understood. This is the first study to assess the prevalence of oncogenic human papillomavirus mRNA in HIV-positive women, its relationship to HIV and its potential use in the triage of cervical cancer screening in HIV-positive women. In this cross-sectional study, we included 321 HIV-positive women. In all, 28.7% had abnormal cervical cytology, 51.1% were human papillomavirus DNA-positive and 21.8% tested positive for human papillomavirus mRNA. Women with a CD4 count of <200 × 10(6)/L were more likely to test positive for human papillomavirus DNA and mRNA. Virally suppressed women were less likely to be human papillomavirus DNA-positive; however, the same did not hold true for human papillomavirus mRNA. We found the human papillomavirus mRNA screening to be more specific when screening for low-grade squamous intraepithelial lesion and high-grade squamous intraepithelial lesion than human papillomavirus DNA at 84.53% compared to 57.36%. However, the sensitivity was less at 51.59% versus 91.07% for human papillomavirus DNA. It may be possible in the future to use human papillomavirus mRNA/DNA testing within a triage algorithm for the screening and management of cervical cancer in the HIV-positive patient. PMID:25258395

  12. Oral Human Papillomavirus Infection in Children.

    PubMed

    Ilea, Aranka; Boşca, Bianca; Miclăuş, Viorel; Rus, Vasile; Băbţan, Anida Maria; Mesaros, Anca; Crişan, Bogdan; Câmpian, Radu Septimiu

    2016-02-01

    Oral human papillomavirus infection is rare in children, but the presence of a villous lesion with slow but continuous growth concerns parents, who need information and therapeutic solutions from the physician. All these aspects are discussed based on a case report of a 9-year-old child with an oral human papillomavirus infection. PMID:26588443

  13. Activated Notch1 signaling cooperates with papillomavirus oncogenes in transformation and generates resistance to apoptosis on matrix withdrawal through PKB/Akt.

    PubMed

    Rangarajan, A; Syal, R; Selvarajah, S; Chakrabarti, O; Sarin, A; Krishna, S

    2001-07-20

    Invasive cervical tumors, a major subset of human epithelial neoplasms, are characterized by the consistent presence of papillomavirus oncogenes 16 or 18 E6 and E7 products. Cervical tumors also consistently exhibit cytosolic and nuclear forms of Notch1, suggesting the possible persistent activation of the Notch pathway. Here we show that activated Notch1 synergizes with papillomavirus oncogenes in transformation of immortalized epithelial cells and leads to the generation of resistance to anoikis, an apoptotic response induced on matrix withdrawal. This resistance to anoikis by activated Notch1 is mediated through the activation of PKB/Akt, a key effector of activated Ras in transformation. We suggest that activated Notch signaling may serve to substitute for the lack of activated Ras mutations in the majority of human cervical neoplasms. PMID:11448155

  14. Human Papillomavirus (HPV) Vaccine (Gardasil-9)

    MedlinePlus

    ... vaccinated?Gardasil-9 prevents many cancers caused by human papillomavirus (HPV) infections, including:cervical cancer in females ... 9) Information Statement. U.S. Department of Health and Human Services/Centers for Disease Control and Prevention National ...

  15. Papillomaviruses

    PubMed Central

    Félez-Sánchez, Marta

    2015-01-01

    Papillomaviruses (PVs) are a numerous family of small dsDNA viruses infecting virtually all mammals. PVs cause infections without triggering a strong immune response, and natural infection provides only limited protection against reinfection. Most PVs are part and parcel of the skin microbiota. In some cases, infections by certain PVs take diverse clinical presentations from highly productive self-limited warts to invasive cancers. We propose PVs as an excellent model system to study the evolutionary interactions between the immune system and pathogens causing chronic infections: genotypically, PVs are very diverse, with hundreds of different genotypes infecting skin and mucosa; phenotypically, they display extremely broad gradients and trade-offs between key phenotypic traits, namely productivity, immunogenicity, prevalence, oncogenicity and clinical presentation. Public health interventions have been launched to decrease the burden of PV-associated cancers, including massive vaccination against the most oncogenic human PVs, as well as systematic screening for PV chronic anogenital infections. Anti-PVs vaccines elicit protection against infection, induce cross-protection against closely related viruses and result in herd immunity. However, our knowledge on the ecological and intrapatient dynamics of PV infections remains fragmentary. We still need to understand how the novel anthropogenic selection pressures posed by vaccination and screening will affect viral circulation and epidemiology. We present here an overview of PV evolution and the connection between PV genotypes and the phenotypic, clinical manifestations of the diseases they cause. This differential link between viral evolution and the gradient cancer-warts-asymptomatic infections makes PVs a privileged playground for evolutionary medicine research. PMID:25634317

  16. Anorectal Human Papillomavirus: Current Concepts

    PubMed Central

    Assi, Roland; Reddy, Vikram; Einarsdottir, Hulda; Longo, Walter E.

    2014-01-01

    Increased anorectal human papillomavirus (HPV) infection is related to the recent trends in sexual behavior in both homosexual and heterosexual groups and prevalence of infection with human immunodeficiency virus (HIV). Clinical presentation and natural history depend on the serotype involved. HPV 6 and 11 are found in the benign wart. Local control can be achieved with a wide selection of surgical and topical techniques. HPV 16, 18, and 31 are found in dysplastic lesions and have the potential to progress to invasive anal squamous cell carcinoma. Recognition and early management of dysplastic lesions is crucial to prevent the morbidity and mortality associated with anal cancer. While low-grade lesions can be closely observed, high-grade lesions should be eradicated. Different strategies can be used to eradicate the disease while preserving anorectal function. Studies on the efficacy of vaccination on anorectal HPV showed promising results in select population groups and led to the recent expansion of current vaccination recommendations. PMID:25506286

  17. [Melanoma and Human Papillomaviruses: Is There an Outlook for Study?].

    PubMed

    Volgareva, G M; Mikhaylova, I N; Golovina, D A

    2016-01-01

    Melanoma is one of the most aggressive human malignant tumors. Its incidence and mortality are growing steadily. Ultraviolet irradiation is the main risk factor for melanoma involved in melanomagenesis. The probability of viral etiology of melanoma has been discussed. Human papillomaviruses (HPV) have been mentioned among candidates for its etiologic agents because some HPV types are the powerful carcinogens causing cervical cancer and other cancers. The review analyses the literature data on the association of melanoma with HPV Several groupsfound HPVin skin melanomas as well as in mucosa; viruses of high oncogenic risk were detected in some cases. For some organs the etiological role of high-risk HPV as inducers of invasive carcinomas is confirmed. These organs require special mention: cervix uteri, vulva, vagina, penis, anal region, and oral cavity. However in the majority of the studies in which viral DNA-positive melanomas were found, testing for viral genome expression was not done while this is the fact of primary importance. HPVare found in normal skin and mucous membranes thus creating justifiable threat of tumor specimen contamination with viral DNA in vivo. There are limited data on aggravation of the disease prognosis in papillomavirus-positive melanomas. However, any systematic observation of a sizeable patient group distinguished by that tumor type has not been performed yet. Viral E6 and E7 oncogenes of high-risk papillomaviruses were shown to be able to transform normal human melanocytes in vitro experiments. Thus, we can assume the presence of the association of melanoma with oncogenic HPV. The clinical significance of this problem is indisputable under the conditions of the steady increase in melanoma incidence and mortality rates in Russia and abroad. The problem requires further study. PMID:27522713

  18. Human Papillomavirus (HPV) Vaccine (Gardasil-9)

    MedlinePlus

    ... 9 prevents many cancers caused by human papillomavirus (HPV) infections, including:cervical cancer in females vaginal and ... Gardasil-9 can prevent most of these cancers. HPV infection usually comes from sexual contact, and most ...

  19. Recombinant Human Papillomavirus (HPV) Nonavalent Vaccine

    Cancer.gov

    This page contains brief information about recombinant human papillomavirus (HPV) nonavalent vaccine and a collection of links to more information about the use of this vaccine, research results, and ongoing clinical trials.

  20. Recombinant Human Papillomavirus (HPV) Bivalent Vaccine

    Cancer.gov

    This page contains brief information about recombinant human papillomavirus (HPV) bivalent vaccine and a collection of links to more information about the use of this vaccine, research results, and ongoing clinical trials.

  1. Recombinant Human Papillomavirus (HPV) Quadrivalent Vaccine

    Cancer.gov

    This page contains brief information about recombinant human papillomavirus (HPV) quadrivalent vaccine and a collection of links to more information about the use of this vaccine, research results, and ongoing clinical trials.

  2. Adolescent Male Human Papillomavirus Vaccination

    PubMed Central

    Nanagas, Vivian C.; Stolfi, Adrienne; Nanagas, Maria T.; Eberhart, Gregory M.; Alter, Sherman J.

    2016-01-01

    Objective. To determine male vaccination rates with quadrivalent human papillomavirus vaccine (HPV4) before and after the October 2011 national recommendation to routinely immunize adolescent males. Methods. We reviewed HPV4 dose 1 (HPV4-1) uptake in 292 adolescent males in our urban clinic prior to national recommendations and followed-up for HPV4 series completion rates. After national recommendation, 248 urban clinic and 247 suburban clinic males were reviewed for HPV4-1 uptake. Factors associated with HPV4-1 refusal were determined with multiple logistic regression. Results. Of the initial 292 males, 78% received HPV4-1 and 38% received the 3-dose series. After recommendation, HPV4-1 uptake was 59% and 7% in urban and suburban clinics, respectively. Variables associated with HPV4-1 uptake/refusal included time period, race, type of insurance, and receipt of concurrent vaccines. Conclusions. HPV4-1 vaccination rates in our urban clinic were high before and after routine HPV vaccine recommendations for adolescent males. Our vaccination rates were much higher than in a suburban practice. PMID:27336012

  3. Biology and pathological associations of the human papillomaviruses: a review.

    PubMed

    Cheah, P L; Looi, L M

    1998-06-01

    Historical cottontail rabbit papillomavirus studies raised early indications of a mammalian DNA oncogenic virus. Today, molecular cloning recognises numerous animal and human papillomaviruses (HPVs) and the development of in vitro transformation assays has escalated oncological research in HPVs. Currently, their detection and typing in tissues is usually by Southern blotting, in-situ hybridization and polymerase chain reaction methods. The complete papillomavirus virion constitutes a protein coat (capsid) surrounding a circular, double-stranded DNA organised into coding and non-coding regions. 8 early (E1-E8) open reading frames (ORFs) and 2 late (L1, L2) ORFs have been identified in the coding region of all papillomaviruses. The early ORFs encode proteins which interact with the host genome to produce new viral DNA while late ORFs are activated only after viral DNA replication and encode for viral capsid proteins. All papillomaviruses are obligatory intranuclear organisms with specific tropism for keratinocytes. Three possible courses of events can follow papillomaviruses entry into cells: (1) viral DNA are maintained as intranuclear, extrachromosomal, circular DNA episomes, which replicates synchronously with the host cell, establishing a latent infection; (2) conversion from latent into productive infection with assembly of complete infective virions; (3) integration of viral DNA into host cellular genome, a phenomenon seen in HPV infections associated with malignant transformation. Human papillomaviruses (HPVs) essentially induce skin and mucosal epithelial lesions. Various skin warts are well known to be HPV-associated (HPVs 1, 2, 3, 7 and 10). Besides HPVs 3 and 10, HPVs 5, 8, 17 and 20 have been recovered from Epidermodysplasia verruciformis lesions. Anogenital condyloma acuminatum, strongly linked with HPVs 6 and 11 are probably sexually transmitted. The same HPVs, demonstrable in recurrent juvenile laryngeal papillomas, are probably transmitted by passage

  4. Cellular transformation by human papillomaviruses: Lessons learned by comparing high- and low-risk viruses

    PubMed Central

    Klingelhutz, Aloysius J.; Roman, Ann

    2013-01-01

    The oncogenic potential of papillomaviruses (PVs) has been appreciated since the 1930s yet the mechanisms of virally-mediated cellular transformation are still being revealed. Reasons for this include: a) the oncoproteins are multifunctional, b) there is an ever-growing list of cellular interacting proteins, c) more than one cellular protein may bind to a given region of the oncoprotein, and d) there is only limited information on the proteins encoded by the corresponding non-oncogenic PVs. The perspective of this review will be to contrast the activities of the viral E6 and E7 proteins encoded by the oncogenic human PVs (termed high-risk HPVs) to those encoded by their non-oncogenic counterparts (termed low-risk HPVs) in an attempt to sort out viral life cycle-related functions from oncogenic functions. The review will emphasize lessons learned from the cell culture studies of the HPVs causing mucosal/genital tract cancers. PMID:22284986

  5. Global challenges of implementing human papillomavirus vaccines

    PubMed Central

    2011-01-01

    Human Papillomavirus vaccines are widely hailed as a sweeping pharmaceutical innovation for the universal benefit of all women. The implementation of the vaccines, however, is far from universal or equitable. Socio-economically marginalized women in emerging and developing, and many advanced economies alike, suffer a disproportionately large burden of cervical cancer. Despite the marketing of Human Papillomavirus vaccines as the solution to cervical cancer, the market authorization (licensing) of the vaccines has not translated into universal equitable access. Vaccine implementation for vulnerable girls and women faces multiple barriers that include high vaccine costs, inadequate delivery infrastructure, and lack of community engagement to generate awareness about cervical cancer and early screening tools. For Human Papillomavirus vaccines to work as a public health solution, the quality-assured delivery of cheaper vaccines must be integrated with strengthened capacity for community-based health education and screening. PMID:21718495

  6. The biology of human papillomaviruses.

    PubMed

    Nguyen, Harrison P; Ramírez-Fort, Marigdalia K; Rady, Peter L

    2014-01-01

    Human papillomaviruses (HPVs) are small, double-stranded DNA viruses that cause lesions in cutaneous and mucosal tissue and are responsible for carcinomas of the cervix, vagina, vulva and penis. HPVs sort into 5 genera with a total of approximately 150 species that have been sequenced. Its genome is comprised of an early (E) region encoding the viral regulatory proteins, a late (L) region encoding the viral structural proteins and a noncoding region that is essential to the viral life cycle. For infection to occur, the virus must access the basal epidermal layer where, following endocytosis and viral capsid disassembly, the L2 protein mediates viral genome transfer to the nuclei of mitotic keratinocytes. The viral genome is maintained in episomal form during the normal life cycle and replicates in synchrony with the host cell DNA under the mediation of E1, E2, E4 and E5 viral proteins. In most high-grade cervical neoplasms, however, the viral DNA is integrated into the host genome through the disruption of the E2 open reading frame. The oncoproteins E6 and E7, which were previously suppressed by E2, are then free to inhibit the Rb and p53 tumor suppressor pathways. The viral life cycle concludes with the packaging of the viral genome and virus release, which entails the E2-mediated recruitment of L2 to regions of replication, the expression of L1 and the assembly of the icosahedral capsid in the nucleus. Overall, the complex biology of HPV continues to be an important area of research with substantial implications for public health. PMID:24643175

  7. Human Papillomavirus: A Catalyst to a Killer

    ERIC Educational Resources Information Center

    Richman, Alice

    2005-01-01

    Genital human papillomavirus (HPV) is the most prevalent and widespread sexually transmitted disease and is responsible for almost all cases of cervical cancer worldwide. However, HPV has received little public health attention, is not a reportable STD, and often is absent from the repertoire of STDs. In addition, there is pervasive misinformation…

  8. Oncogenicity of human N-ras oncogene and proto-oncogene introduced into retroviral vectors

    SciTech Connect

    Souyri, M.; Vigon, I.; Charon, M.; Tambourin, P. )

    1989-09-01

    The N-ras gene is the only member of the ras family which has never been naturally transduced into a retrovirus. In order to study the in vitro and in vivo oncogenicity of N-ras and to compare its pathogenicity to that of H-ras, the authors have inserted an activated or a normal form of human N-ras cDNA into a slightly modified Harvey murine sarcoma virus-derived vector in which the H-ras p21 coding region had been deleted. The resulting constructions were transfected into NIH 3T3 cells. The activated N-ras-containing construct (HSN) induced 10{sup 4} foci per {mu}g of DNA and was found to be as transforming as H-ras was. After infection of the transfected cells by either the ecotropic Moloney murine leukemia virus or the amphotropic 4070A helper viruses, rescued transforming viruses were injected into newborn mice. Both pseudotypes of HSN virus containing activated N-ras induced the typical Harvey disease with similar latency. However, they found that the virus which contained normal N-ras p21 (HSn) was also pathogenic and induced splenomegaly, lymphadenopathies, and sarcoma in mice after a latency of 3 to 7 weeks. In addition, Moloney murine leukemia virus pseudotypes of N-ras caused neurological disorders in 30% of the infected animals. These results differed markedly from those of previous experiments in which the authors had inserted the activated form of N-ras in the pSV(X) vector: the resulting SVN-ras virus was transforming on NIH 3T3 cells but was poorly oncogenic in vivo. Altogether, these data demonstrated unequivocally that N-ras is potentially as oncogenic as H-ras and that such oncogenic effect could depend on the vector environment.

  9. Post Hoc Analysis of the PATRICIA Randomized Trial of the Efficacy of Human Papillomavirus Type 16 (HPV-16)/HPV-18 AS04-Adjuvanted Vaccine against Incident and Persistent Infection with Nonvaccine Oncogenic HPV Types Using an Alternative Multiplex Type-Specific PCR Assay for HPV DNA

    PubMed Central

    Colau, Brigitte; Wheeler, Cosette M.; Naud, Paulo; Garland, Suzanne; Quint, Wim; Chow, Song-Nan; Salmerón, Jorge; Lehtinen, Matti; Del Rosario-Raymundo, M. Rowena; Paavonen, Jorma; Teixeira, Júlio C.; Germar, Maria Julieta; Peters, Klaus; Skinner, S. Rachel; Limson, Genara; Castellsagué, Xavier; Poppe, Willy A. J.; Ramjattan, Brian; Klein, Terry D.; Schwarz, Tino F.; Chatterjee, Archana; Tjalma, Wiebren A. A.; Diaz-Mitoma, Francisco; Lewis, David J. M.; Harper, Diane M.; Molijn, Anco; van Doorn, Leen-Jan; David, Marie-Pierre; Dubin, Gary

    2014-01-01

    The efficacy of the human papillomavirus type 16 (HPV-16)/HPV-18 AS04-adjuvanted vaccine against cervical infections with HPV in the Papilloma Trial against Cancer in Young Adults (PATRICIA) was evaluated using a combination of the broad-spectrum L1-based SPF10 PCR-DNA enzyme immunoassay (DEIA)/line probe assay (LiPA25) system with type-specific PCRs for HPV-16 and -18. Broad-spectrum PCR assays may underestimate the presence of HPV genotypes present at relatively low concentrations in multiple infections, due to competition between genotypes. Therefore, samples were retrospectively reanalyzed using a testing algorithm incorporating the SPF10 PCR-DEIA/LiPA25 plus a novel E6-based multiplex type-specific PCR and reverse hybridization assay (MPTS12 RHA), which permits detection of a panel of nine oncogenic HPV genotypes (types 16, 18, 31, 33, 35, 45, 52, 58, and 59). For the vaccine against HPV types 16 and 18, there was no major impact on estimates of vaccine efficacy (VE) for incident or 6-month or 12-month persistent infections when the MPTS12 RHA was included in the testing algorithm versus estimates with the protocol-specified algorithm. However, the alternative testing algorithm showed greater sensitivity than the protocol-specified algorithm for detection of some nonvaccine oncogenic HPV types. More cases were gained in the control group than in the vaccine group, leading to higher point estimates of VE for 6-month and 12-month persistent infections for the nonvaccine oncogenic types included in the MPTS12 RHA assay (types 31, 33, 35, 45, 52, 58, and 59). This post hoc analysis indicates that the per-protocol testing algorithm used in PATRICIA underestimated the VE against some nonvaccine oncogenic HPV types and that the choice of the HPV DNA testing methodology is important for the evaluation of VE in clinical trials. (This study has been registered at ClinicalTrials.gov under registration no. NCT00122681.) PMID:25540273

  10. Post hoc analysis of the PATRICIA randomized trial of the efficacy of human papillomavirus type 16 (HPV-16)/HPV-18 AS04-adjuvanted vaccine against incident and persistent infection with nonvaccine oncogenic HPV types using an alternative multiplex type-specific PCR assay for HPV DNA.

    PubMed

    Struyf, Frank; Colau, Brigitte; Wheeler, Cosette M; Naud, Paulo; Garland, Suzanne; Quint, Wim; Chow, Song-Nan; Salmerón, Jorge; Lehtinen, Matti; Del Rosario-Raymundo, M Rowena; Paavonen, Jorma; Teixeira, Júlio C; Germar, Maria Julieta; Peters, Klaus; Skinner, S Rachel; Limson, Genara; Castellsagué, Xavier; Poppe, Willy A J; Ramjattan, Brian; Klein, Terry D; Schwarz, Tino F; Chatterjee, Archana; Tjalma, Wiebren A A; Diaz-Mitoma, Francisco; Lewis, David J M; Harper, Diane M; Molijn, Anco; van Doorn, Leen-Jan; David, Marie-Pierre; Dubin, Gary

    2015-02-01

    The efficacy of the human papillomavirus type 16 (HPV-16)/HPV-18 AS04-adjuvanted vaccine against cervical infections with HPV in the Papilloma Trial against Cancer in Young Adults (PATRICIA) was evaluated using a combination of the broad-spectrum L1-based SPF10 PCR-DNA enzyme immunoassay (DEIA)/line probe assay (LiPA25) system with type-specific PCRs for HPV-16 and -18. Broad-spectrum PCR assays may underestimate the presence of HPV genotypes present at relatively low concentrations in multiple infections, due to competition between genotypes. Therefore, samples were retrospectively reanalyzed using a testing algorithm incorporating the SPF10 PCR-DEIA/LiPA25 plus a novel E6-based multiplex type-specific PCR and reverse hybridization assay (MPTS12 RHA), which permits detection of a panel of nine oncogenic HPV genotypes (types 16, 18, 31, 33, 35, 45, 52, 58, and 59). For the vaccine against HPV types 16 and 18, there was no major impact on estimates of vaccine efficacy (VE) for incident or 6-month or 12-month persistent infections when the MPTS12 RHA was included in the testing algorithm versus estimates with the protocol-specified algorithm. However, the alternative testing algorithm showed greater sensitivity than the protocol-specified algorithm for detection of some nonvaccine oncogenic HPV types. More cases were gained in the control group than in the vaccine group, leading to higher point estimates of VE for 6-month and 12-month persistent infections for the nonvaccine oncogenic types included in the MPTS12 RHA assay (types 31, 33, 35, 45, 52, 58, and 59). This post hoc analysis indicates that the per-protocol testing algorithm used in PATRICIA underestimated the VE against some nonvaccine oncogenic HPV types and that the choice of the HPV DNA testing methodology is important for the evaluation of VE in clinical trials. (This study has been registered at ClinicalTrials.gov under registration no. NCT00122681.). PMID:25540273

  11. Human papillomavirus vaccine trials and tribulations: Clinical perspectives.

    PubMed

    Handler, Marc Z; Handler, Nancy S; Majewski, Slawomir; Schwartz, Robert A

    2015-11-01

    Human papillomavirus (HPV) affects hundreds of millions of people worldwide and is associated with both benign and malignant neoplasms in men and women. It is a double-stranded DNA virus with an icosahedral capsid. Forty HPV types are known to infect mucosal keratinocytes. If not cured by the immune system, the infection can lead to genital warts, mucosal dysplasia, or cancer. The most common oncogenic types are 16 and 18. The vaccine to prevent HPV and its associated morbidity and mortality has existed since 2006. Several variations protect against an increasing number of HPV types. The recommended vaccination age is before sexual exposure; administration of the vaccine to children has been controversial. This continuing medical education review evaluates the current HPV vaccines available to clinicians. Part I focuses on the debate over who should be vaccinated, at what age, and in which populations. PMID:26475534

  12. Human Papillomaviruses As Therapeutic Targets in Human Cancer

    PubMed Central

    Hellner, Karin; Münger, Karl

    2011-01-01

    Cervical carcinomas are almost universally associated with high-risk human papillomavirus (HPV) infections, and are a leading cause of cancer death in women worldwide. HPV oncoproteins contribute to cancer initiation and progression and their expression is necessary for the maintenance of the transformed state. The fact that the initiating oncogenic insult, infection with a high-risk HPV and viral oncoprotein expression, is common to almost all cervical cancers offers unique opportunities for prevention, early detection, and therapy. The potential for prevention has been realized by introduction of prophylactic vaccines that are to prevent transmission of specific high-risk HPVs. Given, however, that these vaccines have no therapeutic efficacy and HPV-associated cervical cancers arise years if not decades after the initial infection, it has been estimated that there will be no measurable decline of HPV-associated tumors before 2040. Cervical cancer alone will be diagnosed in more than 375,000 US women between now and 2040. Other HPV-associated anogenital and head and neck cancers are predicted to afflict another 700,000 men and women over this time period. Hence, therapeutic efforts to combat high-risk HPV-associated disease remain of critical importance. PMID:21220591

  13. Genitoanal human papillomavirus infection and associated neoplasias.

    PubMed

    Gross, Gerd

    2014-01-01

    Human papillomavirus (HPV) infection is the most common sexually transmitted virus infection; about 40 out of 150 known HPV genotypes have been associated with genitoanal lesions in the female and male. They have been divided into low-risk (LR) and high-risk (HR) HPV types according to the association of each HPV genotype with genitoanal benign warts, genitoanal cancer and precursor lesions. For the most part, genitoanal HPV infection is equally common in men and in women. Genitoanal HPVs are predominantly transmitted by sexual intercourse. In a minor number of individuals where HR HPV infection has persisted, malignant squamous-cell tumors may develop. There are 15 mucosal oncogenic HPV types which are the etiological factor of cervical cancer and other genitoanal cancers. DNAs of HR HPV types are present in 100% of all cervical carcinomas and in 100% of the precursor lesions, the cervical intraepithelial neoplasias 2 and 3. HPV-16 and -18 alone account for 70% of the oncogenic mucosal HPV types identified. HR HPV types, mostly HPV-16 and -18, are the causes of vaginal and vulvar cancers in females, anal cancers in both genders and cancer of the penis in men. While anal cancers are linked to HR HPVs in more than 80% of cases, only 40% of vulvar cancers and 50% of penile cancers are HPV positive. Genitoanal cancers have a similar anatomy, histology and similar risk factors as well as natural histories. About 60% of vulvar and 50% of penile cancers are HPV negative, but associated with chronic inflammatory disorders, mainly lichen sclerosus. Clinical manifestations of LR HPVs in both sexes are genitoanal warts (condylomata acuminata), which are benign highly infectious tumors. The highest rate of warts is observed in females 16-24 years of age. In males the peak is at the age of 20-24 years. Diagnosis of genitoanal warts should exclude other sexually transmitted infections and diseases. A high number of genitoanal dermatoses, benign tumors, malignant squamous

  14. TARGETING ONCOGENIC BRAF IN HUMAN CANCER

    PubMed Central

    Pratilas, Christine; Xing, Feng; Solit, David

    2012-01-01

    MAPK pathway activation is a frequent event in human cancer and is often the result of activating mutations in the BRAF and RAS oncogenes. BRAF missense kinase domain mutations, the vast majority of which are V600E, occur in approximately 8% of human tumors. These mutations, which are non-overlapping in distribution with RAS mutations, are observed most frequently in melanoma but also in tumors arising in the colon, thyroid, lung and other sites. Supporting its classification as an oncogene, V600EBRAF stimulates ERK signaling, induces proliferation and is capable of promoting transformation. Given the frequent occurrence of BRAF mutations in human cancer and the continued requirement for BRAF activity in the tumors in which it is mutated, efforts are underway to develop targeted inhibitors of BRAF and its downstream effectors. These agents offer the possibility of greater efficacy and less toxicity than the systemic therapies currently available for tumors driven by activating mutations in the MAPK pathway. Early clinical results with the BRAF-selective inhibitors PLX4032 and GSK2118436 suggest that this strategy will prove successful in a select group of patients whose tumors are driven by oncogenic BRAF. PMID:21818706

  15. Epidemiology of oral human papillomavirus infection

    PubMed Central

    Chung, Christine H.; Bagheri, Ashley; D'Souza, Gypsyamber

    2013-01-01

    Human papillomavirus (HPV) infection is known to cause a subset of oropharyngeal cancers. Data regarding oral HPV infection is limited but emerging. HPV infection of the genital tract has been more thoroughly researched and helps inform our understanding of oral HPV infection. In this article we review current data on HPV prevalence, natural history, mode of acquisition, and risk factors for oral HPV infection. PMID:24080455

  16. Oncogenes

    SciTech Connect

    Compans, R.W.; Cooper, M.; Koprowski, H.; McConell, I.; Melchers, F.; Nussenzweig, V.; Oldstone, M.; Olsnes, S.; Saedler, H.; Vogt, P.K.

    1989-01-01

    This book covers the following topics: Roles of drosophila proto-oncogenes and growth factor homologs during development of the fly; Interaction of oncogenes with differentiation programs; Genetics of src: structure and functional organization of a protein tyrosine kinase; Structures and activities of activated abl oncogenes; Eukaryotic RAS proteins and yeast proteins with which they interact. This book presents up-to-data review articles on oncogenes. The editor includes five contributions which critically evaluate recent research in the field.

  17. Structure of mutant human oncogene protein determined

    SciTech Connect

    Baum, R.

    1989-01-16

    The protein encoded by a mutant human oncogene differs only slightly in structure from the native protein that initiates normal cell division, a finding that may complicate efforts to develop inhibitors of the mutant protein. Previously, the x-ray structure of the protein encoded by the normal c-Ha-ras gene, a protein believed to signal cells to start or stop dividing through its interaction with guanosine triphosphate (GTP), was reported. The structure of the protein encoded by a transforming c-Ha-ras oncogene, in which a valine codon replaces the normal glycine codon at position 12 in the gene, has now been determined. The differences in the structures of the mutant and normal proteins are located primarily in a loop that interacts with the /beta/-phosphate of a bound guanosine diphosphate (GDP) molecule.

  18. Comparison of the immunogenicity of the human papillomavirus (HPV)-16/18 vaccine and the HPV-6/11/16/18 vaccine for oncogenic non-vaccine types HPV-31 and HPV-45 in healthy women aged 18–45 years

    PubMed Central

    Baron, Mira; Levin, Myron J; Chatterjee, Archana; Fox, Bradley; Scholar, Sofia; Rosen, Jeffrey; Chakhtoura, Nahida; Lebacq, Marie; van der Most, Robbert; Moris, Philippe; Giannini, Sandra L; Schuind, Anne; Datta, Sanjoy K; Descamps, Dominique

    2011-01-01

    Protection against oncogenic non-vaccine types (cross-protection) offered by human papillomavirus (HPV) vaccines may provide a significant medical benefit. Available clinical efficacy data suggest the two licensed vaccines [HPV-16/18 vaccine, GlaxoSmithKline Biologicals (GSK), and HPV-6/11/16/18 vaccine, Merck and Co., Inc.,] differ in terms of protection against oncogenic non-vaccine HPV types -31/45. The immune responses induced by the two vaccines against these two non-vaccine HPV types (cross-reactivity) was compared in an observer-blind study up to Month 24 (18 mo postvaccination), in women HPV DNA-negative and seronegative prior to vaccination for the HPV type analyzed [HPV-010 (NCT00423046)]. Geometric mean antibody titers (GMTs) measured by pseudovirion-based neutralization assay (PBNA) and enzyme-linked immunosorbent assay (ELISA ) were similar between vaccines for HPV-31/45. Seropositivity rates for HPV-31 were also similar between vaccines; however, there was a trend for higher seropositivity with the HPV-16/18 vaccine (13.0–16.7%) vs. the HPV-6/11/16/18 vaccine (0.0–5.0%) for HPV-45 with PBNA, but not ELISA . HPV-31/45 cross-reactive memory B-cell responses were comparable between vaccines. Circulating antigen-specific CD4+ T-cell frequencies were higher for the HPV-16/18 vaccine than the HPV-6/11/16/18 vaccine {HPV-31 [geometric mean ratio (GMR) = 2.0; p = 0.0002] and HPV-45 [GMR = 2.6; p = 0.0092]}, as were the proportion of T-cell responders (HPV-31, p = 0.0009; HPV-45, p = 0.0793). In conclusion, immune response to oncogenic non-vaccine HPV types -31/45 was generally similar for both vaccines with the exception of T-cell response which was higher with the HPV-16/18 vaccine. Considering the differences in cross-protective efficacy between the two vaccines, the results might provide insights into the underlying mechanism(s) of protection. PMID:22048172

  19. Sensitivity of APTIMA HPV E6/E7 mRNA test in comparison with hybrid capture 2 HPV DNA test for detection of high risk oncogenic human papillomavirus in 396 biopsy confirmed cervical cancers.

    PubMed

    Basu, Partha; Banerjee, Dipanwita; Mittal, Srabani; Dutta, Sankhadeep; Ghosh, Ishita; Chowdhury, Nilarun; Abraham, Priya; Chandna, Puneet; Ratnam, Sam

    2016-07-01

    The sensitivity of E6/E7 mRNA-based Aptima HPV test (AHPV; Hologic, Inc.) for detection of cervical cancer has been reported based on only a small number of cases. We determined the sensitivity of AHPV in comparison with the DNA-based Hybrid Capture 2 HPV test (HC2; Qiagen) for the detection of oncogenic HPV in a large number of cervical cancers at the time of diagnosis using cervical samples obtained in ThinPrep (Hologic). Samples yielding discordant results were genotyped using Linear Array assay (LA; Roche). Of 396 cases tested, AHPV detected 377 (sensitivity, 95.2%; 95%CI: 93.1-97.3), and HC2 376 (sensitivity, 94.9%; 95%CI: 92.7-97.1) with an agreement of 97.2% (kappa 0.7; 95%CI: 0.54-0.87). Among six AHPV+/HC2- cases, LA identified oncogenic HPV types in four including a type 73 and was negative in two. Among five AHPV-/HC2+ cases, LA detected oncogenic HPV types in two including a type 73 and was negative in three. Of 14 AHPV-/HC2- cases, 13 were genotyped. LA detected oncogenic HPV types in six, non-oncogenic types in three, and was negative in four. This is the largest study to demonstrate the sensitivity of AHPV for the detection of invasive cervical cancer and this assay showed equal sensitivity to HC2. J. Med. Virol. 88:1271-1278, 2016. © 2015 Wiley Periodicals, Inc. PMID:26693677

  20. Risk Factors for Anogenital Human Papillomavirus Infection in Men

    PubMed Central

    Nielson, Carrie M.; Harris, Robin B.; Dunne, Eileen F.; Abrahamsen, Martha; Papenfuss, Mary R.; Flores, Roberto; Markowitz, Lauri E.; Giuliano, Anna R.

    2013-01-01

    Background Human papillomavirus (HPV) is strongly associated with cervical and other anogenital cancers. Identification of risk factors for HPV infection in men may improve our understanding of HPV transmission and prevention. Methods HPV testing for 37 types was conducted in 463 men 18–40 years old recruited from 2 US cities. The entire anogenital region and semen were sampled. A self-administered questionnaire was completed. Multivariate logistic regression aided the identification of independent risk factors for any HPV type, oncogenic HPV types, and nononcogenic HPV types. Results Prevalence was 65.4% for any HPV, 29.2% for oncogenic HPV, and 36.3% for nononcogenic HPV. Factors significantly associated with any HPV were smoking ≥10 cigarettes per day (odds ratio [OR], 2.3 [95% confidence interval {CI}, 1.0–5.3]) and lifetime number of female sex partners (FSPs) (OR for ≥21, 2.5 [95% CI, 1.3–4.6]), and factors significantly associated with oncogenic HPV were lifetime number of FSPs (OR for ≥21, 7.4 [95% CI, 3.4–16.3]) and condom use during the past 3 months (OR for more than half the time, 0.5 [95% CI, 0.3–0.8]). For nononcogenic HPV, a significant association was found for number of FSPs during the past 3 months (OR for ≥2, 2.9 [95% CI, 1.4–6.3]). Conclusions Lifetime and recent number of FSPs, condom use, and smoking were modifiable risk factors associated with HPV infection in men. PMID:17955431

  1. HPV (Human Papillomavirus) Gardasil Vaccine - What You Need to Know

    MedlinePlus

    ... taken in its entirety from the CDC HPV (Human Papillomavirus) Vaccine - Gardasil® Vaccine Information Statement (VIS): www. ... WHAT IS HPV? Genital human papillomavirus (HPV) is the most common ... in the United States. More than half of sexually active men ...

  2. HPV vaccine (human papillomavirus) Cervarix - what you need to know

    MedlinePlus

    ... taken in its entirety from the CDC HPV (Human Papillomavirus) Cervarix® Vaccine Information Statement: www.cdc.gov/ ... What is HPV? Genital human papillomavirus (HPV) is the most common ... in the United States. More than half of sexually active men ...

  3. Identification of Human Papillomavirus Infection in Cancer Tissue by Targeted Next-generation Sequencing.

    PubMed

    Montgomery, Nathan D; Parker, Joel S; Eberhard, David A; Patel, Nirali M; Weck, Karen E; Sharpless, Norman E; Hu, Zhiyuan; Hayes, David Neil; Gulley, Margaret L

    2016-08-01

    Human papillomaviruses (HPV) are oncogenic DNA viruses implicated in squamous cell carcinomas of several anatomic sites, as well as endocervical adenocarcinomas. Identification of HPV is an actionable finding in some carcinomas, potentially influencing tumor classification, prognosis, and management. We incorporated capture probes for oncogenic HPV strains 16 and 18 into a broader next-generation sequencing (NGS) panel designed to identify actionable mutations in solid malignancies. A total of 21 head and neck, genitourinary, and gynecologic squamous cell carcinomas and endocervical adenocarcinomas were sequenced as part of the UNCSeq project. Using p16 immunohistochemical results as the gold standard, we set a cutoff for proportion of aligned HPV reads that maximized performance of our NGS assay (92% sensitive, 100% specific for HPV). These results suggest that sequencing of oncogenic pathogens can be incorporated into targeted NGS panels, extending the clinical utility of genomic assays. PMID:26371432

  4. Human papillomavirus testing in cervical cancer screening.

    PubMed

    Castle, Philip E; Cremer, Miriam

    2013-06-01

    Human papillomavirus (HPV) testing is more reliable and sensitive but less specific than Papanicolaou (Pap) testing/cervical cytology for the detection of cervical precancer and cancer. HPV-negative women are at lower risk of cervical cancer than Pap-negative women. In high-resource settings, HPV testing can be used to make cervical cancer prevention programs more efficient by focusing clinical attention on women who have HPV. In lower-resource settings, where Pap testing has not been sustained or widespread, new, lower-cost HPV tests may make cervical cancer screening feasible. PMID:23732037

  5. Global Delivery of Human Papillomavirus Vaccines.

    PubMed

    Wigle, Jannah; Fontenot, Holly B; Zimet, Gregory D

    2016-02-01

    Worldwide, cervical cancer is the fourth most common cancer among women. Human papillomavirus (HPV) vaccination, if broadly implemented, has the potential to significantly reduce global rates of morbidity and mortality associated with cervical and other HPV-related cancers. More than 100 countries around the world have licensed HPV vaccines. As of February, 2015, there were an estimated 80 national HPV immunization programs and 37 pilot programs. This article discusses global implementation of HPV vaccination programs and issues such as vaccine financing and different approaches to HPV vaccine delivery. PMID:26613690

  6. [Infection therapeutic modalities in human papillomavirus].

    PubMed

    Carrillo Pacheco, Adia; Hernández Valencia, Marcelino; Hernández Quijano, Tomás; Zárate, Arturo

    2012-11-01

    Human papillomavirus (HPV) genital it can infect any mucous of the body and to cause cancer of the uterine cervix. Until recently specific treatments did not exist on this infection, for what had to destroy or to remove the injured tissue by diverse procedures, what could have obstetric repercussions in young women. Recently some surgical modalities and topical drugs have arisen, as well as of systemic employment that allow to arrive to the lesions difficult to approach, and have demonstrated good effectiveness to cure the infection for HPV, for what an analysis of the medical treatment of this infection type is made. PMID:23427640

  7. The human papillomavirus E7 oncoprotein

    SciTech Connect

    McLaughlin-Drubin, Margaret E. Muenger, Karl

    2009-02-20

    The human papillomavirus (HPV) E7 oncoprotein shares functional similarities with such proteins as adenovirus E1A and SV40 large tumor antigen. As one of only two viral proteins always expressed in HPV-associated cancers, E7 plays a central role in both the viral life cycle and carcinogenic transformation. In the HPV viral life cycle, E7 disrupts the intimate association between cellular differentiation and proliferation in normal epithelium, allowing for viral replication in cells that would no longer be in the dividing population. This function is directly reflected in the transforming activities of E7, including tumor initiation and induction of genomic instability.

  8. Human Papillomavirus (HPV) Vaccine (Cervarix)

    MedlinePlus

    ... std/hpv and http://www.cdc.gov/vaccines HPV Vaccine (Cervarix) Information Statement. U.S. Department of Health and Human Services/Centers for Disease Control and Prevention National Immunization Program. 5/3/2011.

  9. Vaccines and immunization against human papillomavirus.

    PubMed

    Christensen, Neil D; Budgeon, Lynn R

    2014-01-01

    Prophylactic and therapeutic immunization strategies are an effective method to control human papillomavirus (HPV)-associated diseases and cancers. Current protective virus-like particle and capsid-based vaccines are highly protective against vaccine-matched HPV types, and continued improvements in second-generation vaccines will lead to broader protection and cross-protection against the cancer-associated types. Increasing the effectiveness of broadly cross-protective L2-based immunogens will require adjuvants that activate innate immunity to thus enhance adaptive immunity. Therapeutic immunization strategies are needed to control and cure clinical disease and HPV-associated cancers. Significant advances in strategies to improve induction of cell-mediated immunity to HPV early (and capsid) proteins have been pretested in preclinical animal papillomavirus models. Several of these effective protocols have translated into successful therapeutic immune-mediated clearance of clinical lesions. Nevertheless, there are significant challenges in activating immunity to cancer-associated lesions due to various immune downregulatory events that are triggered by persistent HPV infections. A better understanding of immune responses to HPV lesions in situ is needed to optimize immune effector T cells that efficiently locate to sites of infection and which should lead to an effective immunotherapeutic management of this important human viral pathogen. The most effective immunization strategy may well require combination antiviral and immunotherapeutic treatments to achieve complete clearance of HPV infections and associated cancers. PMID:24643192

  10. Human papillomaviruses and cervical cancer in Bangkok. III. The role of husbands and commercial sex workers.

    PubMed

    Thomas, D B; Ray, R M; Kuypers, J; Kiviat, N; Koetsawang, A; Ashley, R L; Qin, Q; Koetsawang, S

    2001-04-15

    Between September 1991 and September 1993, husbands of women with and without cervical neoplasia and commercial sex workers in one brothel and one massage parlor in Bangkok, Thailand, were interviewed; serologic tests for sexually transmitted infections were performed; and cervical and penile scrapings were tested for human papillomavirus (HPV) DNA. The risks of cervical carcinoma in monogamous women and of oncogenic HPV in their husbands were associated with the men's having unprotected intercourse with prostitutes. The prevalence of oncogenic HPV was higher in commercial sex workers than in women attending gynecologic and family planning clinics. Oncogenic HPV prevalence declined with age in human immunodeficiency virus (HIV)-negative, but not in healthy HIV-positive, commercial sex workers and was weakly associated with hepatitis B antigenemia, suggesting that persistence of HPV infection is due to subtle changes in immunity. Associations of HPV with recent pregnancy and oral contraceptive use suggest that hormonal factors may increase the risk of cervical neoplasia by enhancing persistence of HPV infection. The prevalence of high-grade squamous intraepithelial lesions was strongly related to oncogenic HPV types and weakly to HIV infection only in their presence. Commercial sex workers in Bangkok are reservoirs of oncogenic HPV, and cervical cancer in monogamous Thai women develops in part as a result of transmission of these viruses to them by their husbands from prostitutes. PMID:11296145

  11. Transplacental transmission of Human Papillomavirus

    PubMed Central

    Rombaldi, Renato L; Serafini, Eduardo P; Mandelli, Jovana; Zimmermann, Edineia; Losquiavo, Kamille P

    2008-01-01

    This paper aimed at studying the transplacental transmission of HPV and looking at the epidemiological factors involved in maternal viral infection. The following sampling methods were used: (1) in the pregnant woman, (a) genital; (b) peripheral blood; (2) in the newborn, (a) oral cavity, axillary and inguinal regions; (b) nasopharyngeal aspirate, and (c) cord blood; (3) in the placenta. The HPV DNA was identified using two methods: multiplex PCR of human β-globin and of HPV using the PGMY09 and PGMY11 primers; and nested-PCR, which combines degenerated primers of the E6/E7 regions of the HPV virus, that allowed the identification of genotypes 6/11, 16, 18, 31, 33, 42, 52 and 58. Transplacental transmission was considered when type-specific HPV concordance was found between the mother, the placenta and the newborn or the mother and cord blood. The study included 49 HPV DNA-positive pregnant women at delivery. Twelve placentas (24.5%, n = 12/49) had a positive result for HPV DNA. Eleven newborn were HPV DNA positive in samples from the nasopharyngeal or buccal and body or cord blood. In 5 cases (10.2%, n = 5/49) there was HPV type-specific agreement between genital/placenta/newborn samples. In one case (2%, n = 1/49) there was type specific HPV concordance between genital/cord blood and also suggested transplacental transmission. A positive and significant correlation was observed between transplacental transmission of HPV infection and the maternal variables of immunodepression history (HIV, p = 0.011). In conclusion the study suggests placental infection in 23.3% of the cases studied and transplacental transmission in 12.2%. It is suggested that in future HPV DNA be researched in the normal endometrium of women of reproductive age. The possible consequence of fetal exposure to HPV should be observed. PMID:18817577

  12. Human Papillomavirus-Associated Cancers - United States, 2008-2012.

    PubMed

    Viens, Laura J; Henley, S Jane; Watson, Meg; Markowitz, Lauri E; Thomas, Cheryll C; Thompson, Trevor D; Razzaghi, Hilda; Saraiya, Mona

    2016-01-01

    Human papillomavirus (HPV) is a known cause of cervical cancers, as well as some vulvar, vaginal, penile, oropharyngeal, anal, and rectal cancers (1,2). Although most HPV infections are asymptomatic and clear spontaneously, persistent infections with one of 13 oncogenic HPV types can progress to precancer or cancer. To assess the incidence of HPV-associated cancers, CDC analyzed 2008-2012 high-quality data from the CDC's National Program of Cancer Registries and the National Cancer Institute's Surveillance, Epidemiology, and End Results program. During 2008-2012, an average of 38,793 HPV-associated cancers were diagnosed annually, including 23,000 (59%) among females and 15,793 (41%) among males. By multiplying these counts by the percentages attributable to HPV (3), CDC estimated that approximately 30,700 new cancers were attributable to HPV, including 19,200 among females and 11,600 among males. Cervical precancers can be detected through screening, and treatment can prevent progression to cancer; HPV vaccination can prevent infection with HPV types that cause cancer at cervical and other sites (3). Vaccines are available for HPV types 16 and 18, which cause 63% of all HPV-associated cancers in the United States, and for HPV types 31, 33, 45, 52, and 58, which cause an additional 10% (3). Among the oncogenic HPV types, HPV 16 is the most likely to both persist and to progress to cancer (3). The impact of these primary and secondary prevention interventions can be monitored using surveillance data from population-based cancer registries. PMID:27387669

  13. New treatments for human papillomavirus infection.

    PubMed

    Muñoz-Santos, C; Pigem, R; Alsina, M

    2013-12-01

    Human papillomavirus infection is very common. In this article, we review the latest developments in the treatment of lesions caused by this virus, with a particular focus on anogenital warts. Sinecatechins and new imiquimod formulations are among the most significant new developments. Others include photodynamic therapy and intralesional immunotherapy, but there is insufficient evidence to recommend their routine use. Finally, while therapeutic vaccines and inhibitory molecules appear to hold great promise, they are still in the early phases of investigation. More studies are needed, and these should have similar designs, larger samples, and sufficiently long follow-up periods to enable the direct comparison of the short-term and long-term effectiveness of different treatment options. PMID:23706272

  14. Human papillomavirus vaccines--immune responses.

    PubMed

    Stanley, Margaret; Pinto, Ligia A; Trimble, Connie

    2012-11-20

    Prophylactic human papillomavirus (HPV) virus-like particle (VLP) vaccines are highly effective. The available evidence suggests that neutralising antibody is the mechanism of protection. However, despite the robust humoral response elicited by VLP vaccines, there is no immune correlate, no minimum level of antibody, or any other immune parameter, that predicts protection against infection or disease. The durability of the antibody response and the importance of antibody isotype, affinity and avidity for vaccine effectiveness are discussed. Once infection and disease are established, then cellular immune responses are essential to kill infected cells. These are complex processes and understanding the local mucosal immune response is a prerequisite for the rational design of therapeutic HPV vaccines. This article forms part of a special supplement entitled "Comprehensive Control of HPV Infections and Related Diseases" Vaccine Volume 30, Supplement 5, 2012. PMID:23199968

  15. Clinical significance of human papillomavirus genotyping

    PubMed Central

    Choi, Youn Jin

    2016-01-01

    Cervical cancer is the fourth most common cancer in women worldwide, and the human papillomavirus (HPV) is the main causative agent for its development. HPV is a heterogeneous virus, and a persistent infection with a high-risk HPV contributes to the development of cancer. In recent decades, great advances have been made in understanding the molecular biology of HPV, and HPV’s significance in cervical cancer prevention and management has received increased attention. In this review, we discuss the role of HPV genotyping in cervical cancer by addressing: clinically important issues in HPV virology; the current application of HPV genotyping in clinical medicine; and potential future uses for HPV genotyping. PMID:26768784

  16. Human Papillomaviruses and the Interferon Response

    PubMed Central

    Beglin, Melanie; Melar-New, Marta

    2009-01-01

    Human papillomaviruses (HPV) are small DNA viruses that target stratified keratinocytes for infection. A subset of HPV types infect epithelia in the genital tract and are the causative agents of cervical as well as other anogenital cancers. Interferon treatment of existing genital HPV lesions has had mixed results. While HPV proteins down-regulate the expression of interferon-inducible genes, interferon treatment ultimately induces their high-level transcription after a delay. Cells containing complete HPV genomes that are able to undergo productive replication upon differentiation are sensitive to interferon-induced growth arrest, while cells from high-grade cancers that only express E6 and E7 are resistant. Recent studies indicate this sensitivity is dependent upon the binding of the interferon-inducible factor, p56, to the E1 replication protein. The response to interferon by HPV proteins is complex and results from the action of multiple viral proteins. PMID:19715460

  17. Early Defensive Mechanisms against Human Papillomavirus Infection.

    PubMed

    Moerman-Herzog, Andrea; Nakagawa, Mayumi

    2015-08-01

    Cervical cancer is the fourth most common cancer in women and is almost exclusively caused by human papillomavirus (HPV) infection. HPV is also frequently associated with other cancers arising from mucosal epithelium, including anal and oropharyngeal cancers, which are becoming more common in both men and women. Viral persistence and progression through precancerous lesion stages are prerequisites for HPV-associated cancer and reflect the inability of cell-mediated immune mechanisms to clear infections and eliminate abnormal cells in some individuals. Cell-mediated immune responses are initiated by innate pathogen sensing and subsequent secretion of soluble immune mediators and amplified by the recruitment and activation of effector T lymphocytes. This review discusses early defensive mechanisms of innate responders to natural HPV infection, their influence on response polarization, and the underappreciated role of keratinocytes in this process. PMID:26063238

  18. Human papillomavirus (HPV) infection: a Mozambique overview.

    PubMed

    Pizzol, Damiano; Putoto, Giovanni; Chhaganlal, Kajal D

    2016-06-01

    Human Papillomavirus is agent of the most common sexually transmitted disease which is able to infect mucosal and cutaneous membranes of the anogenital region, upper aerodigestive tract, and other head and neck mucosal regions. Although mainly HPV infection can be asymptomatic and transient, it may persist and give rise to various lesions such as warts, condyloma dysplasia and cancers depending on low or high risk type of HPV infection. Moreover, growing recent evidence suggests a role of this virus in male and female fertility. To date no effective prevention, test, treatment and control strategies are provided for people in developing countries despite the reported high incidence of HPV both in women and men. This paper reviews the more recent literature about HPV infection highlighting epidemiology, related pathologies and possible fertility effects of HPV in male and female with particular attention to the Mozambique context. PMID:27366761

  19. Early Defensive Mechanisms against Human Papillomavirus Infection

    PubMed Central

    Moerman-Herzog, Andrea

    2015-01-01

    Cervical cancer is the fourth most common cancer in women and is almost exclusively caused by human papillomavirus (HPV) infection. HPV is also frequently associated with other cancers arising from mucosal epithelium, including anal and oropharyngeal cancers, which are becoming more common in both men and women. Viral persistence and progression through precancerous lesion stages are prerequisites for HPV-associated cancer and reflect the inability of cell-mediated immune mechanisms to clear infections and eliminate abnormal cells in some individuals. Cell-mediated immune responses are initiated by innate pathogen sensing and subsequent secretion of soluble immune mediators and amplified by the recruitment and activation of effector T lymphocytes. This review discusses early defensive mechanisms of innate responders to natural HPV infection, their influence on response polarization, and the underappreciated role of keratinocytes in this process. PMID:26063238

  20. Human papillomavirus types and recurrent cervical warts

    SciTech Connect

    Nuovo, G.J. ); Pedemonte, B.M. )

    1990-03-02

    The authors analyzed cervical intraepithelial neoplasias (CINs) detected after cryotherapy to determine if recurrence is associated with the same human papillomavirus (HPV) type found in the original lesion. Eight women had detectable HPV DNA in CINs that occurred after ablation of another CIN, and for each patient the HPV type in the pretreatment lesion was different from that in the CIN that appeared after cryotherapy. This compares with 12 women who had HPV detected in two or more CINs present at the same time, 11 of whom had the same HPv type noted. they concluded that although multiple, simultaneous CINs in a woman often contain the same HPV type, recurrent CINs that occur after cryotherapy contain an HPV type different from that present in the pretreatment lesion.

  1. HPV (Human Papillomavirus) Gardasil Vaccine - What You Need to Know

    MedlinePlus

    ... is taken in its entirety from the CDC HPV (Human Papillomavirus) Vaccine - Gardasil® Vaccine Information Statement (VIS): www.cdc.gov/vaccines/hcp/vis/vis-statements/hpv-gardasil.html . CDC review information for HPV Gardasil® ...

  2. HPV vaccine (human papillomavirus) Cervarix - what you need to know

    MedlinePlus

    ... is taken in its entirety from the CDC HPV (Human Papillomavirus) Cervarix® Vaccine Information Statement: www.cdc.gov/vaccines/hcp/vis/vis-statements/hpv-cervarix.html . CDC review information for HPV Cervarix® ...

  3. Differential effects of human papillomavirus type 6, 16, and 18 DNAs on immortalization and transformation of human cervical epithelial cells

    SciTech Connect

    Pecoraro, G.; Morgan, D.; Defendi, V. )

    1989-01-01

    The human papillomaviruses (HPVs) are associated with specific benign and malignant lesions of the skin and mucosal epithelia. Cloned viral DNAs from HPV types 6b, 16, and 18 associated with different pathological manifestations of genital neoplasia in vivo were introduced into primary human cervical epithelial cells by electroporation. Cells transfected with HPV16 or HPV18 DNA acquired indefinite lifespans, distinct morphological alterations, and anchorage-independent growth (HPV18), and contain integrated transcriptionally active viral genomes. HPV6b or plasmid electroporated cells senesced at low passage. The alterations in growth and differentiation of the cells appear to reflect the progressive oncogenic processes that result in cervical carcinoma in vivo.

  4. Next generation prophylactic human papillomavirus vaccines.

    PubMed

    Schiller, John T; Müller, Martin

    2015-05-01

    The two licensed bivalent and quadrivalent human papillomavirus (HPV) L1 (the major papillomavirus virion protein) virus-like particle (VLP) vaccines are regarded as safe, effective, and well established prophylactic vaccines. However, they have some inherent limitations, including a fairly high production and delivery cost, virus-type restricted protection, and no reported therapeutic activity, which might be addressed with the development of alternative dosing schedules and vaccine products. A change from a three-dose to a two-dose protocol for the licensed HPV vaccines, especially in younger adolescents (aged 9-13 years), is underway in several countries and is likely to become the future norm. Preliminary evidence suggests that recipients of HPV vaccines might derive prophylactic benefits from one dose of the bivalent vaccine. Substantial interest exists in both the academic and industrial sectors in the development of second-generation L1 VLP vaccines in terms of cost reduction-eg, by production in Escherichia coli or alternative types of yeast. However, Merck's nonavalent vaccine, produced via the Saccharomyces cerevisiae production system that is also used for their quadrivalent vaccine, is the first second-generation HPV VLP vaccine to be available on the market. By contrast, other pharmaceutical companies are developing microbial vectors that deliver L1 genes. These two approaches would add an HPV component to existing live attenuated vaccines for measles and typhoid fever. Prophylactic vaccines that are based on induction of broadly cross-neutralising antibodies to L2, the minor HPV capsid protein, are also being developed both as simple monomeric fusion proteins and as virus-like display vaccines. The strong interest in developing the next generation of vaccines, particularly by manufacturers in middle-to-high income countries, increases the likelihood that vaccine production will become decentralised with the hope that effective HPV vaccines will be

  5. Using organotypic (raft) epithelial tissue cultures for the biosynthesis and isolation of infectious human papillomaviruses

    PubMed Central

    Ozbun, Michelle A.; Patterson, Nicole A.

    2014-01-01

    Papillomaviruses have a strict tropism for epithelial cells and they are fully reliant on cellular differentiation for completion of their life cycles, resulting in the production of progeny virions. Thus, a permissive environment for full viral replication in vitro wherein virion morphogenesis occurs under cooperative viral and cellular cues requires the cultivation of epithelium. Presented in the first section of this unit is a protocol for growing differentiating epithelial tissues, whose structure and function mimics many important morphological and biochemical aspects of normal skin. The technique, pioneered by Asslineau and Pruniéras (Asselineau and Prunieras 1984) and modified by Kopan et al. (Kopan et al. 1987), involves growing epidermal cells atop a dermal equivalent consisting of live fibroblasts and a collagen lattice. Epithelial stratification and differentiation ensues when the keratinocyte-dermal equivalent is placed at the air-liquid interface. The apparent floating nature of the cell-matrix in this method led to the nickname “raft” cultures. The general technique can be applied to normal low passage keratinocytes, to cells stably transfected with papillomavirus genes or genomes, as well as keratinocytes established from neoplastic lesions. However, infectious papillomavirus particles have only been isolated from organotypic epithelial cultures initiated with cells that maintain oncogenic human papillomavirus genomes in an extrachomosomal replicative form. The second section of this unit is dedicated to a virion isolation method that minimizes aerosol and skin exposure to these human carcinogens. Although the focus of the protocols is on the growth of tissues that yields infectious papillomavirus progeny, this culture system facilitates the investigation of these fastidious viruses during their complex replicative cycles, and raft tissues can be manipulated and harvested at any point during the process. Importantly, a single step virus growth

  6. Immunoprevention of human papillomavirus-associated malignancies

    PubMed Central

    Wang1, Joshua W.; Hung, Chein-fu; Huh, Warner K.; Trimble, Cornelia L.; Roden, Richard B.S.

    2014-01-01

    Persistent infection by one of fifteen high risk human papillomavirus (hrHPV) types is a necessary but not sufficient cause of 5% of all human cancers. This provides a remarkable opportunity for cancer prevention via immunization. Since Harald zur Hausen’s pioneering identification of hrHPV types 16 and 18, found in ~50% and ~20% of cervical cancers respectively, two prophylactic HPV vaccines containing virus-like particles (VLP) of each genotype have been widely licensed. These vaccines are beginning to impact infection and HPV-associated neoplasia rates after immunization campaigns in adolescents. Here we review recent progress and opportunities to better prevent HPV-associated cancers, including: broadening immune-protection to cover all hrHPV types, reducing the cost of HPV vaccines especially for developing countries that have the highest rates of cervical cancer, and immune-based treatment of established HPV infections. Screening based upon George Papanicolaou’s cervical cytology testing, and more recently detection of hrHPV DNA/RNA, followed by ablative treatment of high grade cervical intraepithelial neoplasia (CIN2/3) have substantially reduced cervical cancer rates, and we examine their interplay with immune-based modalities for the prevention and eventual elimination of cervical cancer and other HPV-related malignancies. PMID:25488410

  7. Immunoprevention of human papillomavirus-associated malignancies.

    PubMed

    Wang, Joshua W; Hung, Chein-Fu; Huh, Warner K; Trimble, Cornelia L; Roden, Richard B S

    2015-02-01

    Persistent infection by one of 15 high-risk human papillomavirus (hrHPV) types is a necessary but not sufficient cause of 5% of all human cancers. This provides a remarkable opportunity for cancer prevention via immunization. Since Harald zur Hausen's pioneering identification of hrHPV types 16 and 18, found in approximately 50% and 20% of cervical cancers, respectively, two prophylactic HPV vaccines containing virus-like particles (VLP) of each genotype have been widely licensed. These vaccines are beginning to affect infection and HPV-associated neoplasia rates after immunization campaigns in adolescents. Here, we review recent progress and opportunities to better prevent HPV-associated cancers, including broadening immune protection to cover all hrHPV types, reducing the cost of HPV vaccines especially for developing countries that have the highest rates of cervical cancer, and immune-based treatment of established HPV infections. Screening based upon George Papanicolaou's cervical cytology testing, and more recently detection of hrHPV DNA/RNA, followed by ablative treatment of high-grade cervical intraepithelial neoplasia (CIN2/3) have substantially reduced cervical cancer rates, and we examine their interplay with immune-based modalities for the prevention and eventual elimination of cervical cancer and other HPV-related malignancies. PMID:25488410

  8. Searching for antiviral drugs for human papillomaviruses.

    PubMed

    Underwood, M R; Shewchuk, L M; Hassell, A M; Phelps, W C

    2000-12-01

    The human papillomaviruses (HPVs) are ubiquitous human pathogens that cause a wide variety of benign and pre-malignant epithelial tumours. Of the almost 100 different types of HPV that have been characterized to date, approximately two dozen specifically infect genital and oral mucosa. Mucosal HPVs are most frequently sexually transmitted and, with an incidence roughly twice that of herpes simplex virus infection, are considered one of the most common sexually transmitted diseases throughout the world. A subset of genital HPVs, termed 'high-risk' HPVs, is highly associated with the development of genital cancers including cervical carcinoma. The absence of a simple monolayer cell culture system for analysis and propagation of the virus has substantially retarded progress in the development of diagnostic and therapeutic strategies for HPV infection. In spite of these difficulties, great progress has been made in the elucidation of the molecular controls of virus gene expression, replication and pathogenesis. With this knowledge and some important new tools, there is great potential for the development of improved diagnostic and prognostic tests, prophylactic and therapeutic vaccines, and traditional antiviral medicines. PMID:11142617

  9. A novel dithiocarbamate derivative induces cell apoptosis through p53-dependent intrinsic pathway and suppresses the expression of the E6 oncogene of human papillomavirus 18 in HeLa cells.

    PubMed

    Li, Yanhong; Qi, Hongxue; Li, Xiaobo; Hou, Xueling; Lu, Xueying; Xiao, Xiangwen

    2015-06-01

    Dithiocarbamates (DTCs) exhibit a broad spectrum of antitumor activities, however, their molecular mechanisms of antitumor have not yet been elucidated. Previously, we have synthesized a series of novel dithiocarbamate derivatives. These DTCs were examined for cytotoxic activities against five human cancer cell lines. In this study, one of dithiocarbamate (DTC1) with higher potential for HeLa cells was chosen to investigate molecular mechanisms for its anti-tumor activities. DTC1 could inhibit proliferation, and highly induce apoptosis in HeLa cells by activating caspase-3, -6 and -9; moreover, activities of caspase-3, -6 and -9 were inhibited by pan-caspase inhibitor, Z-VAD-FMK. Furthermore, DTC1 decreased the levels of Bcl-2 and Bcl-xL, and increased expression of cytosol cytochrome c, Bak, Bax and p53 in a time-dependent manner but had no effect on the level of Rb. It was shown that DTC1 induced HeLa cells apoptosis through a p53-dependent pathway as tested by the wild type p53 inhibitor, pifithrin-α. Additionally, the relative expression of E6 and E7 were evaluated in HPV18-positive (HeLa cells) by real-time PCR and western blotting. The results firstly demonstrated that DTC1 suppressed both expression of E6 mRNA and E6 oncoprotein, but had no effect on the expression of E7 mRNA and protein in HPV18. Our results suggested that DTC1 may serve as novel chemotherapeutic agents in the treatment of cervical cancer and potential anti-HPV virus candidates that merit further studies. PMID:25772545

  10. HPV (Human Papillomavirus) vaccine - what you need to know [Gardasil®-9

    MedlinePlus

    ... taken in its entirety from the CDC HPV (Human Papillomavirus) Gardasil-9 Vaccine Information Statement (VIS): www. ... WHY GET VACCINATED? Gardasil-9 prevents human papillomavirus (HPV) ... Vaginal and vulvar cancers in females, and Anal cancer in ...

  11. Therapeutic Vaccine Strategies against Human Papillomavirus

    PubMed Central

    Khallouf, Hadeel; Grabowska, Agnieszka K.; Riemer, Angelika B.

    2014-01-01

    High-risk types of human papillomavirus (HPV) cause over 500,000 cervical, anogenital and oropharyngeal cancer cases per year. The transforming potential of HPVs is mediated by viral oncoproteins. These are essential for the induction and maintenance of the malignant phenotype. Thus, HPV-mediated malignancies pose the unique opportunity in cancer vaccination to target immunologically foreign epitopes. Therapeutic HPV vaccination is therefore an ideal scenario for proof-of-concept studies of cancer immunotherapy. This is reflected by the fact that a multitude of approaches has been utilized in therapeutic HPV vaccination design: protein and peptide vaccination, DNA vaccination, nanoparticle- and cell-based vaccines, and live viral and bacterial vectors. This review provides a comprehensive overview of completed and ongoing clinical trials in therapeutic HPV vaccination (summarized in tables), and also highlights selected promising preclinical studies. Special emphasis is given to adjuvant science and the potential impact of novel developments in vaccinology research, such as combination therapies to overcome tumor immune suppression, the use of novel materials and mouse models, as well as systems vaccinology and immunogenetics approaches. PMID:26344626

  12. Human Papillomavirus Laboratory Testing: the Changing Paradigm.

    PubMed

    Burd, Eileen M

    2016-04-01

    High-risk human papillomaviruses (HPVs) cause essentially all cervical cancers, most anal and oropharyngeal cancers, and some vaginal, vulvar, and penile cancers. Improved understanding of the pathogenesis of infection and the availability of newer tests are changing the approach to screening and diagnosis. Molecular tests to detect DNA from the most common high-risk HPVs are FDA approved for use in conjunction with cytology in cervical cancer screening programs. More-specific tests that detect RNA from high-risk HPV types are now also available. The use of molecular tests as the primary screening tests is being adopted in some areas. Genotyping to identify HPV16 and -18 has a recommended role in triaging patients for colposcopy who are high-risk HPV positive but have normal cytology. There are currently no recommended screening methods for anal, vulvar, vaginal, penile, or oropharyngeal HPV infections. HPV testing has limited utility in patients at high risk for anal cancer, but p16 immunohistochemistry is recommended to clarify lesions in tissue biopsy specimens that show moderate dysplasia or precancer mimics. HPV testing is recommended for oropharyngeal squamous cell tumors as a prognostic indicator. Ongoing research will help to improve the content of future guidelines for screening and diagnostic testing. PMID:26912568

  13. An update on oral human papillomavirus infection.

    PubMed

    Bharti, Ankit H; Chotaliya, Kiran; Marfatia, Y S

    2013-07-01

    Human papillomavirus (HPV) constitutes the majority of newly acquired sexually transmitted infections (STIs) in United States as per the centers for disease control factsheet 2013. Genital HPV is the most common STI with incidence of about 5.5 million world-wide, nearly 75% of sexually active men and women have been exposed to HPV at some point in their lives. Oral Sexual behavior is an important contributor to infection of HPV in the oral mucosa especially in cases known to practice high risk behavior and initiating the same at an early age. HPV infection of the oral mucosa currents is believed to affect 1-50% of the general population, depending on the method used for diagnosis. The immune system clears most HPV naturally within 2 years (about 90%), but the ones that persist can cause serious diseases. HPV is an essential carcinogen being implicated increasingly in association with cancers occurring at numerous sites in the body. Though there does not occur any specific treatment for the HPV infection, the diseases it causes are treatable such as genital warts, cervical and other cancers. PMID:24339456

  14. Optimal control with multiple human papillomavirus vaccines.

    PubMed

    Malik, Tufail; Imran, Mudassar; Jayaraman, Raja

    2016-03-21

    A two-sex, deterministic ordinary differential equations model for human papillomavirus (HPV) is constructed and analyzed for optimal control strategies in a vaccination program administering three types of vaccines in the female population: a bivalent vaccine that targets two HPV types and provides longer duration of protection and cross-protection against some non-target types, a quadrivalent vaccine which targets an additional two HPV types, and a nonavalent vaccine which targets nine HPV types (including those covered by the quadrivalent vaccine), but with lesser type-specific efficacy. Considering constant vaccination controls, the disease-free equilibrium and the effective reproduction number Rv for the autonomous model are computed in terms of the model parameters. Local-asymptotic stability of the disease-free equilibrium is established in terms of Rv. Uncertainty and Sensitivity analyses are carried out to study the influence of various important model parameters on the HPV infection prevalence. Assuming the HPV infection prevalence in the population under the constant control, optimal control theory is used to devise optimal vaccination strategies for the associated non-autonomous model when the vaccination rates are functions of time. The impact of these strategies on the number of infected individuals and the accumulated cost is assessed and compared with the constant control case. Switch times from one vaccine combination to a different combination including the nonavalent vaccine are assessed during an optimally designed HPV immunization program. PMID:26796222

  15. [Human papillomavirus vaccine. Efficacy and safety].

    PubMed

    Bruni, Laia; Serrano, Beatriz; Bosch, Xavier; Castellsagué, Xavier

    2015-05-01

    Human papillomavirus (HPV) related disease remains a major cause of morbidity and mortality worldwide. Prophylactic vaccines have been recognized as the most effective intervention to control for HPV-related diseases. This article reviews the major phaseii/iii trials of the bivalent (HPVs16/18), quadrivalent (HPVs6/11/16/18), and the recently approved 9-valent vaccine (HPVs6/11/16/18/31/33/45/52/58). Large trials have been conducted showing the safety, immunogenicity and high efficacy of the bivalent and quadrivalent vaccines in the prevention of pre-invasive lesions and infection, especially when administered at young ages before exposure to HPV. Trials of the 9-valent vaccine have also demonstrated the safety, immunogenicity and efficacy of the vaccine in the prevention of infection and disease associated with the vaccine types, and its potential to substantially increase the overall prevention of HPV-related diseases. Post-licensure country reports have shown the recent and early impact of these vaccines at population level after the implementation of established HPV vaccination programs, including decreases in the prevalence of vaccine HPV types, the incidence of genital warts, and the incidence of high-grade cervical abnormalities. If widely implemented, current HPV vaccines may drastically reduce the incidence of cervical cancer and other HPV-related cancers and diseases. PMID:25937455

  16. Human papillomavirus vaccination among adolescents in Georgia.

    PubMed

    Underwood, Natasha L; Weiss, Paul; Gargano, Lisa M; Seib, Katherine; Rask, Kimberly J; Morfaw, Christopher; Murray, Dennis; DiClemente, Ralph J; Hughes, James M; Sales, Jessica M

    2015-01-01

    Human papillomavirus (HPV) vaccination coverage for adolescent females and males remains low in the United States. We conducted a 3-arm randomized controlled trial (RCT) conducted in middle and high schools in eastern Georgia from 2011-2013 to determine the effect of 2 educational interventions used to increase adolescent vaccination coverage for the 4 recommended adolescent vaccines: Tdap, MCV4, HPV and influenza. As part of this RCT, this article focuses on: 1) describing initiation and completion of HPV vaccine series among a diverse population of male and female adolescents; 2) assessing parental attitudes toward HPV vaccine; and 3) examining correlates of HPV vaccine series initiation and completion. Parental attitude score was the strongest predictor of HPV vaccine initiation among adolescents (adjusted odds ratio (aOR): 2.08; 95% confidence interval (CI): 1.80, 2.39). Other correlates that significantly predicted HPV series initiation were gender, study year, and intervention arm. Parental attitudes remained a significant predictor of receipt of 3 doses of HPV vaccine along with gender, race, school type and insurance type. This study demonstrates that positive parental attitudes are important predictors of HPV vaccination and critical to increasing coverage rates. Our findings suggest that more research is needed to understand how parental attitudes are developed and evolve over time. PMID:25912372

  17. Human papillomavirus vaccine and systemic lupus erythematosus.

    PubMed

    Gatto, Mariele; Agmon-Levin, Nancy; Soriano, Alessandra; Manna, Raffaele; Maoz-Segal, Ramit; Kivity, Shaye; Doria, Andrea; Shoenfeld, Yehuda

    2013-09-01

    To investigate the association between human papillomavirus (HPV) vaccination and autoimmune manifestations compatible with systemic lupus erythematosus (SLE) or SLE-like disease, the medical history of six women who presented with SLE or SLE-like disease following HPV immunization was collected. Data regarding type of vaccine, number of immunization, family and personal, clinical and serological features, as well as response to treatments were analyzed. In the reported cases, several common features were observed, such as personal or familial susceptibility to autoimmunity or adverse response to a prior dose of the vaccine, both of which may be associated with a higher risk of post-vaccination autoimmunity. Favorable response to immunosuppressant was observed in all patients. In the current study, a temporal association between immunization with HPV vaccine and the appearance of a spectrum of SLE-like conditions is reported. Additionally, among the patients described, several common features were observed that may enable better identification of subjects at risk. Further studies are required to assess the safety of immunization with the HPV vaccine in patients with autoimmune-rheumatic diseases or in subject at risk of autoimmunity as well as the potential beneficial effect of preventive immunosuppressants. PMID:23624585

  18. Safety of human papillomavirus vaccines: a review

    PubMed Central

    Stillo, Michela; Carrillo Santisteve, Paloma; Lopalco, Pier Luigi

    2015-01-01

    Introduction: Between 2006 and 2009, two different human papillomavirus virus (HPV) vaccines were licensed for use: a quadrivalent (qHPVv) and a bivalent (bHPVv) vaccine. Since 2008, HPV vaccination programmes have been implemented in the majority of the industrialized countries. Since 2013, HPV vaccination has been part of the national programs of 66 countries including almost all countries in North America and Western Europe. Despite all the efforts made by individual countries, coverage rates are lower than expected. Vaccine safety represents one of the main concerns associated with the lack of acceptance of HPV vaccination both in the European Union/European Economic Area and elsewhere. Areas covered: Safety data published on bivalent and quadrivalent HPV vaccines, both in pre-licensure and post-licensure phase, are reviewed. Expert opinion: Based on the latest scientific evidence, both HPV vaccines seem to be safe. Nevertheless, public concern and rumors about adverse events (AE) represent an important barrier to overcome in order to increase vaccine coverage. Passive surveillance of AEs is an important tool for detecting safety signals, but it should be complemented by activities aimed at assessing the real cause of all suspect AEs. Improved vaccine safety surveillance is the first step for effective communication based on scientific evidence. PMID:25689872

  19. Current status of human papillomavirus vaccines

    PubMed Central

    Yi, Seokjae

    2014-01-01

    Cervical cancer is a malignant neoplasm arising from cells that originate in the cervix uteri. It is the second most prevalent cancer among women. It can have several causes; an infection with some type of human papillomavirus (HPV) is the greatest risk factor for cervical cancer. Over 100 types of HPVs have been identified, and more than 40 types of HPVs are typically transmitted through sexual contact and infect the anogenital region. Among these, a number of HPVs types, containing types 16 and 18, are classified as "high-risk" HPVs that can cause cervical cancer. The HPVs vaccine prevents infection with certain species of HPVs associated with the development of cervical cancer, genital warts, and some less common cancers. Two HPVs vaccines are currently on the global market: quadrivalent HPVs vaccine and bivalent HPV vaccine that use virus-like particles as a vaccine antigen. This review discusses the current status of HPVs vaccines on the global market, clinical trials, and the future of HPVs vaccine development. PMID:25003090

  20. [Uterine cervical carcinoma and human papillomaviruses].

    PubMed

    Sugase, M

    1992-06-01

    For many years it has been thought that a significant proportion of cervical cancer could be attributed to sexually transmitted agents, such as sperm, smegma, Treponema pallidum, Gonococcus and herpes simplexvirus type 2. Recent advances of molecular biology, however, have revealed that human papillomavirus (HPV) might be the most causative virus of the disease. Since HPV type 16 DNA was found in a patient with cervical cancer in 1983, many HPV types have been cloned from cervical cancers, also from premalignant lesions (intraepithelial neoplasias). In Japan, we have found 6 new types of HPV (HPV 58, 59, 61, 62, 64, 67) in the female genital tract so far. Especially, HPV 58, which was cloned from a patient with cervical squamous cell carcinoma and was already fully sequenced, is thought to be an important agent for the development of cervical cancer as well as HPV 16. Now we are investigating extensively to clarify the real relationship between genital HPV infection and cervical cancer. PMID:1327090

  1. Human papillomavirus vaccination among adolescents in Georgia

    PubMed Central

    Underwood, Natasha L; Weiss, Paul; Gargano, Lisa M; Seib, Katherine; Rask, Kimberly J; Morfaw, Christopher; Murray, Dennis; DiClemente, Ralph J; Hughes, James M; Sales, Jessica M

    2015-01-01

    Human papillomavirus (HPV) vaccination coverage for adolescent females and males remains low in the United States. We conducted a 3-arm randomized controlled trial (RCT) conducted in middle and high schools in eastern Georgia from 2011–2013 to determine the effect of 2 educational interventions used to increase adolescent vaccination coverage for the 4 recommended adolescent vaccines: Tdap, MCV4, HPV and influenza. As part of this RCT, this article focuses on: 1) describing initiation and completion of HPV vaccine series among a diverse population of male and female adolescents; 2) assessing parental attitudes toward HPV vaccine; and 3) examining correlates of HPV vaccine series initiation and completion. Parental attitude score was the strongest predictor of HPV vaccine initiation among adolescents (adjusted odds ratio (aOR): 2.08; 95% confidence interval (CI): 1.80, 2.39). Other correlates that significantly predicted HPV series initiation were gender, study year, and intervention arm. Parental attitudes remained a significant predictor of receipt of 3 doses of HPV vaccine along with gender, race, school type and insurance type. This study demonstrates that positive parental attitudes are important predictors of HPV vaccination and critical to increasing coverage rates. Our findings suggest that more research is needed to understand how parental attitudes are developed and evolve over time. PMID:25912372

  2. Lung adenocarcinoma and human papillomavirus infection.

    PubMed

    Chen, Yen-Ching; Chen, Jen-Hau; Richard, Kradin; Chen, Pao-Yang; Christiani, David C

    2004-09-15

    Over the past three decades, the incidence of lung adenocarcinoma has increased worldwide. Most individuals with lung adenocarcinoma (especially women) are nonsmokers. Reported risk factors for the development of lung adenocarcinoma include cigarette smoking; exposure to cooking fumes, air pollution, second-hand smoke, asbestos, and radon; nutritional status; genetic susceptibility; immunologic dysfunction; tuberculosis infection; and asthma. Human papillomavirus (HPV) infection is a known risk factor for the development of squamous cell carcinoma (SCC), but it has not been thoroughly assessed as a potential risk factor for the development of pulmonary adenocarcinoma. More than 50% of people are infected with HPV during their lifetimes, either via intrauterine or postnatal infection. Recent studies involving Taiwanese patients have demonstrated a possible association between HPV infection and the risk of developing pulmonary adenocarcinoma. HPV transmission pathways have not yet been conclusively identified. The observation of certain types of HPV in association with cervical and oral SCC raises the possibility of sexual transmission of HPV from the cervix to the oral cavity, with subsequent transmission to the larynx and then to the lung. HPV infection and metaplasia in lung tissue may increase an individual's susceptibility to the tumorigenesis of pulmonary adenocarcinoma. Further epidemiologic and pathologic investigations will be necessary to establish a causal relation. PMID:15368331

  3. Knowledge about human papillomavirus and the human papillomavirus vaccine in Belgian students

    PubMed Central

    Deriemaeker, Hanne; Reichman, Gina; Devroey, Dirk; Cammu, Hendrik

    2014-01-01

    Introduction The aim of this study was to examine the knowledge of Belgian university students about the human papillomavirus (HPV) and HPV–vaccination. Material and methods During a period of two months we administered an online questionnaire, which contained 29 questions, to 3332 students of the Free University of Brussels. Of the 433 completed questionnaires, 346 were included by age (18–30 years) and completeness of responded questionnaires. These formed the study group. Results Of the 346 included questionnaires (76% female), 48% were completed by medical students. The majority (65%) knew that both genders could be infected with HPV. Ninety–five percent of all medical students were aware of the existence of HPV, while 92% knew of the possibility to be vaccinated against the virus. Ninety percent of them were aware of the causal relationship between HPV infection and cervical cancer. 46% of the medical students were aware that HPV can cause anogenital cancers, and only 28% knew that HPV–vaccination could protect them against genital warts. Sixty percent of all female students were fully vaccinated against HPV, without any difference between medical and non–medical students. A very small part of all students (3%) believed that vaccination against HPV could enhance a promiscuous lifestyle. Conclusions Almost 80% of respondents were aware of the existence of the human papillomavirus, its morbid potential and the HPV–vaccination. PMID:25667765

  4. Primary human cervical carcinoma cells require human papillomavirus E6 and E7 expression for ongoing proliferation

    SciTech Connect

    Magaldi, Thomas G.; Almstead, Laura L.; Bellone, Stefania; Prevatt, Edward G.; Santin, Alessandro D.; DiMaio, Daniel

    2012-01-05

    Repression of human papillomavirus (HPV) E6 and E7 oncogenes in established cervical carcinoma cell lines causes senescence due to reactivation of cellular tumor suppressor pathways. Here, we determined whether ongoing expression of HPV16 or HPV18 oncogenes is required for the proliferation of primary human cervical carcinoma cells in serum-free conditions at low passage number after isolation from patients. We used an SV40 viral vector expressing the bovine papillomavirus E2 protein to repress E6 and E7 in these cells. To enable efficient SV40 infection and E2 gene delivery, we first incubated the primary cervical cancer cells with the ganglioside GM1, a cell-surface receptor for SV40 that is limiting in these cells. Repression of HPV in primary cervical carcinoma cells caused them to undergo senescence, but the E2 protein had little effect on HPV-negative primary cells. These data suggest that E6 and E7 dependence is an inherent property of human cervical cancer cells.

  5. A prospective analysis of smoking and human papillomavirus (HPV) infection among men in The HPV in Men (HIM) Study

    PubMed Central

    Schabath, Matthew B.; Villa, Luisa L.; Lin, Hui-Yi; Fulp, William J.; Lazcano-Ponce, Eduardo; Salmerón, Jorge; Abrahamsen, Martha E.; Papenfuss, Mary R.; Quiterio, Manuel; Giuliano, Anna R.

    2013-01-01

    At present it is unknown whether the higher prevalence of human papillomavirus (HPV) infection among smokers in men is attributed to a higher probability of acquiring an infection or because of longer infection persistence. Thus, we investigated the role of smoking on the (acquisition) and clearance (persistence) of genital HPV infections among 4,026 men in The HPV in Men (HIM) Study, a multinational prospective study of the natural history of genital HPV infection in men. Genital HPV infections were grouped any-, oncogenic-, and non-oncogenic HPV infections and smoking status was categorized as current-, former, and never smokers. The incidence of any-, oncogenic-, and non-oncogenic HPV infections was significantly higher among current smokers compared to former- and never smokers (P < 0.01). In multivariable analyses adjusting for sexual behavior and potential confounders, when compared to never smokers, current smokers exhibited significantly higher probability of acquiring any- (Hazard Ratio [HR] = 1.23; 95% confidence interval [CI] 1.02 – 1.50) and non-oncogenic (HR = 1.21; 95% CI 1.00 – 1.45) infections and a borderline significant probability for oncogenic infections (HR = 1.18; 95% CI 0.98 – 1.41). Although the median duration of HPV infection was generally longer among current smokers, we found no statistically significant associations in the multivariable analyses. Overall, these results demonstrated that current smoking exhibited the highest incidence and highest probability of acquiring genital HPV infections. PMID:24222514

  6. Human Oncogenic Herpesvirus and Post-translational Modifications - Phosphorylation and SUMOylation.

    PubMed

    Chang, Pei-Ching; Campbell, Mel; Robertson, Erle S

    2016-01-01

    Pathogens, especially viruses, evolve abilities to utilize cellular machineries to facilitate their survival and propagation. Post-translational modifications (PTMs), especially phosphorylation and SUMOylation, that reversibly modulate the function and interactions of target proteins are among the most important features in cell signaling pathways. PTM-dependent events also serve as one of the favorite targets for viruses. Among the seven unambiguous human oncogenic viruses, hepatitis B virus (HBV), hepatitis C virus (HCV), Epstein-Barr virus (EBV), Kaposi's sarcoma-associated herpesvirus (KSHV), human papillomavirus (HPV), Human T lymphotrophic virus-1 (HTLV-1), and Merkel cell polyomavirus (MCPyV), two are herpesviruses. The life cycle of herpesviruses consists of latent and lytic phases and the rapid switch between these states includes global remodeling of the viral genome from heterochromatin-to-euchromatin. The balance between lytic replication and latency is essential for herpesvirus to maintain a persistent infection through a combination of viral propagation and evasion of the host immune response, which consequently may contribute to tumorigenesis. It is no surprise that the swift reversibility of PTMs, especially SUMOylation, a modification that epigenetically regulates chromatin structure, is a major hijack target of the host for oncogenic herpesviruses. In this brief review, we summarize the varied ways in which herpesviruses engage the host immune components through PTMs, focusing on phosphorylation and SUMOylation. PMID:27379086

  7. Human Oncogenic Herpesvirus and Post-translational Modifications – Phosphorylation and SUMOylation

    PubMed Central

    Chang, Pei-Ching; Campbell, Mel; Robertson, Erle S.

    2016-01-01

    Pathogens, especially viruses, evolve abilities to utilize cellular machineries to facilitate their survival and propagation. Post-translational modifications (PTMs), especially phosphorylation and SUMOylation, that reversibly modulate the function and interactions of target proteins are among the most important features in cell signaling pathways. PTM-dependent events also serve as one of the favorite targets for viruses. Among the seven unambiguous human oncogenic viruses, hepatitis B virus (HBV), hepatitis C virus (HCV), Epstein-Barr virus (EBV), Kaposi’s sarcoma-associated herpesvirus (KSHV), human papillomavirus (HPV), Human T lymphotrophic virus-1 (HTLV-1), and Merkel cell polyomavirus (MCPyV), two are herpesviruses. The life cycle of herpesviruses consists of latent and lytic phases and the rapid switch between these states includes global remodeling of the viral genome from heterochromatin-to-euchromatin. The balance between lytic replication and latency is essential for herpesvirus to maintain a persistent infection through a combination of viral propagation and evasion of the host immune response, which consequently may contribute to tumorigenesis. It is no surprise that the swift reversibility of PTMs, especially SUMOylation, a modification that epigenetically regulates chromatin structure, is a major hijack target of the host for oncogenic herpesviruses. In this brief review, we summarize the varied ways in which herpesviruses engage the host immune components through PTMs, focusing on phosphorylation and SUMOylation. PMID:27379086

  8. Model systems of human papillomavirus-associated disease.

    PubMed

    Doorbar, John

    2016-01-01

    Human papillomaviruses (HPVs) cause a range of serious diseases, including the vast majority of cervical cancers, most anal cancers and around half of head and neck cancers. They are also responsible for troublesome benign epithelial lesions, including genital warts and laryngeal papillomas, and in some individuals HPVs lead to recurrent respiratory papillomatosis and other difficult-to-manage diseases. As a result, there is a great need for model systems that accurately mimic papillomavirus infections in humans. This is complicated by the diverse variety of HPVs, which now number over 200 types, and the different strategies they have evolved to persist in the population. The most well-developed models involve the culture of HPV-containing keratinocytes in organotypic raft culture, an approach which appears to accurately mimic the life cycle of several of the high-risk cancer-associated HPV types. Included amongst these are HPV16 and 18, which cause the majority of cervical cancers. The low-risk HPV types persist less well in tissue-culture models, and our ability to study the productive life cycle of these viruses is more limited. Although ongoing research is likely to improve this situation, animal models of papillomavirus disease can provide considerable basic information as to how lesions form, regress and can be controlled by the immune system. The best studied are cottontail rabbit papillomavirus, rabbit oral papillomavirus and, more recently, mouse papillomavirus (MmuPV), the last of which is providing exciting new insights into viral tropisms and immune control. In addition, transgenic models of disease have helped us to understand the consequences of persistent viral gene expression and the importance of co-factors such as hormones and UV irradiation in the development of neoplasia and cancer. It is hoped that such disease models will eventually lead us to better understanding and better treatments for human disease. PMID:26456009

  9. Human papillomavirus (HPV) genome status & cervical cancer outcome - A retrospective study

    PubMed Central

    Das, Poulami; Thomas, Asha; Kannan, Sadhana; Deodhar, Kedar; Shrivastava, Shyam K.; Mahantshetty, Umesh; Mulherkar, Rita

    2015-01-01

    Background & objectives: Persistent infections with high-risk (HR) human papillomaviruses such as HPV 16, 18, 31, 33 and 45 have been identified as the major aetiological factor for cervical cancer. The clinical outcome of the disease is often determined by viral factors such as viral load, physical status and oncogene expression. The aim of the present study was to evaluate the impact of such factors on clinical outcome in HPV16 positive, locally advanced cervical cancer cases. Methods: One hundred and thirty two pretreatment cervical tumour biopsies were selected from patients undergoing radiotherapy alone (n=63) or concomitant chemo-radiation (n=69). All the samples were positive for HPV 16. Quantitative real time-PCR was carried out to determine viral load and oncogene expression. Physical status of the virus was determined for all the samples by the ratio of E2copies/E7copies; while in 73 cases, the status was reanalyzed by more sensitive APOT (amplification of papillomavirus oncogene transcripts) assay. Univariate analysis of recurrence free survival was carried out using Kaplan-Meier method and for multivariate analysis the Cox proportional hazard model was used. Results: The median viral load was 19.4 (IQR, 1.9- 69.3), with viral integration observed in 86 per cent cases by combination of the two methodologies. Both univariate and multivariate analyses identified viral physical status as a good predictor of clinical outcome following radiation treatment, with episomal form being associated with increased recurrence free survival. Interpretation & conclusions: The present study results showed that viral physical status might act as an important prognostic factor in cervical cancer. PMID:26658585

  10. No evidence for human papillomavirus in the etiology of colorectal polyps

    PubMed Central

    Burnett-Hartman, Andrea N.; Newcomb, Polly A.; Mandelson, Margaret T.; Galloway, Denise A.; Madeleine, Margaret M.; Wurscher, Michelle A.; Carter, Joseph J.; Makar, Karen W.; Potter, John D.; Schwartz, Stephen M.

    2011-01-01

    Background While some studies have reported detection of oncogenic human papillomavirus (HPV) in colorectal tumors, others have not. Methods We examined the association between oncogenic HPV infection and colorectal polyps in a case-control study of individuals with colorectal adenomas (n=167), hyperplastic polyps (n=87), and polyp-free controls (n=250). We performed real-time PCR for HPV-16 /18 DNA, and SPF PCR covering 43 HPV types, on lesional and normal colorectal tissue samples. Plasma antibodies for oncogenic HPV types were assessed via a bead-based multiplex Luminex assay. Results HPV DNA was not found in any of the 609 successfully assayed colorectal tissue samples from adenomas, hyperplastic polyps, normal biopsies adjacent to polyps, or normal biopsies of the rectum of disease-free controls. Also, there was no association between HPV seropositivity for all oncogenic HPV types combined, for either polyp type, and for men or women. When analyses were restricted to participants without a previous history of polyps, among men [adenomas (n=31), hyperplastic polyps (n=28), and controls (n=68)], there was an association between seropositivity and hyperplastic polyps when all oncogenic HPV types were combined (odds ratio=3.0; 95% confidence interval: 1.1–7.9). Conclusions Overall, our findings do not support an etiologic relationship between HPV and colorectal adenomas or hyperplastic polyps; however, our finding suggesting an association between HPV seropositivity and hyperplastic polyps in men may warrant further investigations. Impact After stringent controls for contamination and three methods to assess HPV infection, we report no evidence for HPV in the etiology of colorectal neoplasia for either men or women. PMID:21817125

  11. Human papillomavirus causes an angiogenic switch in keratinocytes which is sufficient to alter endothelial cell behavior

    SciTech Connect

    Chen, W.; Li, F.; Mead, L.; White, H.; Walker, J.; Ingram, D.A.; Roman, A.

    2007-10-10

    One of the requirements for tumor growth is the ability to recruit a blood supply, a process known as angiogenesis. Angiogenesis begins early in the progression of cervical disease from mild to severe dysplasia and on to invasive cancer. We have previously reported that expression of human papillomavirus type 16 E6 and E7 (HPV16 E6E7) proteins in primary foreskin keratinocytes (HFKs) decreases expression of two inhibitors and increases expression of two angiogenic inducers [Toussaint-Smith, E., Donner, D.B., Roman, A., 2004. Expression of human papillomavirus type 16 E6 and E7 oncoproteins in primary foreskin keratinocytes is sufficient to alter the expression of angiogenic factors. Oncogene 23, 2988-2995]. Here we report that HPV-induced early changes in the keratinocyte phenotype are sufficient to alter endothelial cell behavior both in vitro and in vivo. Conditioned media from HPV16 E6E7 expressing HFKs as well as from human cervical keratinocytes containing the intact HPV16 were able to stimulate proliferation and migration of human microvascular endothelial cells. In addition, introduction of the conditioned media into immunocompetent mice using a Matrigel plug model resulted in a clear angiogenic response. These novel data support the hypothesis that HPV proteins contribute not only to the uncontrolled keratinocyte growth seen following HPV infection but also to the angiogenic response needed for tumor formation.

  12. Comparative transforming potential of different human papillomaviruses associated with non-melanoma skin cancer

    SciTech Connect

    Massimi, Paola; Thomas, Miranda; Bouvard, Veronique; Ruberto, Irene; Campo, M. Saveria; Tommasino, Massimo; Banks, Lawrence

    2008-02-20

    It is well established that high-risk human papillomaviruses (HPVs) that infect mucosal epithelia are the causative agents of cervical cancer. In contrast, the association of cutaneo-tropic HPV types with the development of non-melanoma skin cancer (NMSC) is less well defined. In this study, we have analysed the in vitro transforming potential of various cutaneous HPV types. Using oncogene cooperation assays with activated ras, we have shown that diverse cutaneous types, including 12, 14, 15, 24, 36 and 49, have significant transforming potential. Interestingly, most of this activity appears to be encoded by the E6 gene product. In contrast, the common HPV-10 exhibits no significant transforming potential in these assays. This difference may be a reflection of different patterns of cellular localization, with transforming E6s being nuclear and non-transforming being cytoplasmic. These results provide molecular support for a role of these viruses in the development of certain human malignancies.

  13. Human papillomavirus promotes Epstein-Barr virus maintenance and lytic reactivation in immortalized oral keratinocytes.

    PubMed

    Makielski, Kathleen R; Lee, Denis; Lorenz, Laurel D; Nawandar, Dhananjay M; Chiu, Ya-Fang; Kenney, Shannon C; Lambert, Paul F

    2016-08-01

    Epstein-Barr virus and human papillomaviruses are human tumor viruses that infect and replicate in upper aerodigestive tract epithelia and cause head and neck cancers. The productive phases of both viruses are tied to stratified epithelia highlighting the possibility that these viruses may affect each other's life cycles. Our lab has established an in vitro model system to test the effects of EBV and HPV co-infection in stratified squamous oral epithelial cells. Our results indicate that HPV increases maintenance of the EBV genome in the co-infected cells and promotes lytic reactivation of EBV in upper layers of stratified epithelium. Expression of the HPV oncogenes E6 and E7 were found to be necessary and sufficient to account for HPV-mediated lytic reactivation of EBV. Our findings indicate that HPV increases the capacity of epithelial cells to support the EBV life cycle, which could in turn increase EBV-mediated pathogenesis in the oral cavity. PMID:27179345

  14. Human papillomavirus (HPV)-induced neoplasia in the urinary bladder: a missing link?

    PubMed

    Alexander, Riley E; Wang, Lisha; Lopez-Beltran, Antonio; Emerson, Robert E; Montironi, Rodolfo; Pedrosa, Jose A; Kaimakliotis, Hristos Z; Koch, Michael O; Cheng, Liang

    2016-06-01

    The discovery that the role human papillomavirus (HPV) plays in the induction of human cancer represents an important achievement in oncologic research. It has taken on even greater importance since the development of vaccines, which promise the hope of preventing these cancers from ever occurring. Because of these important implications, many have attempted to determine a possible role for the virus in cancers of the urinary bladder-an organ in close anatomic proximity to the primary sites of HPV-induced neoplasia and one which already has an established oncogenic infectious agent in Schistosoma haematobium. Here we review the current literature exploring this possible role in the most common subtype of cancer of the urinary bladder, urothelial carcinoma, and two much more rare histologic subtypes that have well established roles for HPV-induced neoplasia in other anatomic sites-squamous cell carcinoma and adenocarcinoma. PMID:26687533

  15. The causal relation between human papillomavirus and cervical cancer

    PubMed Central

    Bosch, F X; Lorincz, A; Muñoz, N; Meijer, C J L M; Shah, K V

    2002-01-01

    The causal role of human papillomavirus infections in cervical cancer has been documented beyond reasonable doubt. The association is present in virtually all cervical cancer cases worldwide. It is the right time for medical societies and public health regulators to consider this evidence and to define its preventive and clinical implications. A comprehensive review of key studies and results is presented. PMID:11919208

  16. Human Papillomavirus Vaccine Intent and Uptake among Female College Students

    ERIC Educational Resources Information Center

    Patel, Divya A.; Zochowski, Melissa; Peterman, Stephanie; Dempsey, Amanda F.; Ernst, Susan; Dalton, Vanessa K.

    2012-01-01

    Objective: To examine human papillomavirus (HPV) vaccine intent and the effect of an educational intervention on vaccine uptake among female college students. Participants: Females aged 18 to 26 attending a university health service gynecology clinic (n = 256). Methods: Participants were randomized to receive either HPV-specific education with a…

  17. Human papillomavirus-associated cancers: A growing global problem

    PubMed Central

    Bansal, Anshuma; Singh, Mini P; Rai, Bhavana

    2016-01-01

    Human papillomavirus (HPV) infection is linked with several cancers such as cancer cervix, vagina, vulva, head and neck, anal, and penile carcinomas. Although there is a proven association of HPV with these cancers, questions regarding HPV testing, vaccination, and treatment of HPV-related cancers continue to remain unanswered. The present article provides an overview of the HPV-associated cancers. PMID:27127735

  18. Maternal acceptance of human papillomavirus vaccine in Malaysia.

    PubMed

    Sam, I-Ching; Wong, Li-Ping; Rampal, Sanjay; Leong, Yin-Hui; Pang, Chan-Fu; Tai, Yong-Ting; Tee, Hwee-Ching; Kahar-Bador, Maria

    2009-06-01

    Acceptability rates of human papillomavirus (HPV) vaccination by 362 Malaysian mothers were 65.7% and 55.8% for daughters and sons, respectively. Younger mothers, and those who knew someone with cancer, were more willing to vaccinate their daughters. If the vaccine was routine and cost free, acceptability rate was 97.8%. PMID:19465327

  19. Human papillomavirus-associated cancers: A growing global problem.

    PubMed

    Bansal, Anshuma; Singh, Mini P; Rai, Bhavana

    2016-01-01

    Human papillomavirus (HPV) infection is linked with several cancers such as cancer cervix, vagina, vulva, head and neck, anal, and penile carcinomas. Although there is a proven association of HPV with these cancers, questions regarding HPV testing, vaccination, and treatment of HPV-related cancers continue to remain unanswered. The present article provides an overview of the HPV-associated cancers. PMID:27127735

  20. Human papillomaviruses and cervical cancer in Bangkok. I. Risk factors for invasive cervical carcinomas with human papillomavirus types 16 and 18 DNA.

    PubMed

    Thomas, D B; Ray, R M; Koetsawang, A; Kiviat, N; Kuypers, J; Qin, Q; Ashley, R L; Koetsawang, S

    2001-04-15

    Personal interviews, tests for antibodies to herpes simplex virus type 2, Treponema pallidum, and hepatitis B, tests for hepatitis B surface antigen (HBsAg), and polymerase chain reaction-based assays for human papillomavirus (HPV) DNA in cervical scrapings were obtained from 190 women with squamous cell and 42 women with adenomatous cervical carcinoma and from 291 hospitalized controls diagnosed in Bangkok, Thailand, between September 1991 and September 1993. Risk was strongly associated with oncogenic HPV types, with types 16 and 18 predominating in squamous and adenomatous lesions, respectively. The 126 cases with HPV-16 and the 42 cases with HPV-18 were compared with 250 controls with no evidence of any HPV. The risk of both viral tumor types increased with decreasing age at first intercourse in this predominantly monogamous population, which may be explained by more visits to prostitutes by the husbands of cases with early than late age at first intercourse. HPV-16 tumors were weakly associated with HBsAg carrier state and smoking. The risk of tumors of both viral types increased with parity and use of oral contraceptives but not with injectable progestogens. Factors that may predispose to persistent, oncogenic HPV-16 or -18 infection may include estrogens or progestins in the presence of estrogens, immunosuppression, and smoking, but other factors related to low socioeconomic status are also involved. PMID:11296143

  1. University Students' Knowledge and Attitudes Regarding Cervical Cancer, Human Papillomavirus, and Human Papillomavirus Vaccines in Turkey

    ERIC Educational Resources Information Center

    Koç, Zeliha

    2015-01-01

    Objectives: The current descriptive study aimed to determine university students' knowledge and attitudes regarding cervical cancer, human papillomavirus (HPV), and HPV vaccines in Turkey. Participants: A total of 800 students participated. Methods: This study was carried out between September 1, 2012, and October 30, 2012, in 8 female…

  2. First Detection of Human Papillomaviruses and Human Polyomaviruses in River Waters in Italy.

    PubMed

    Iaconelli, M; Petricca, S; Libera, S Della; Di Bonito, P; La Rosa, G

    2015-12-01

    Waterborne exposure to human viruses is possible through contact with contaminated water environments and can result in infections associated with a wide range of illnesses, including gastrointestinal, respiratory, ear, ocular, and skin infections. Recently, the occurrence in water environments of two groups of human viruses-both known with oncogenic potential, human polyomaviruses (HPyVs) and papillomaviruses (HPVs)-has been reported worldwide. These viruses, responsible for highly prevalent infections worldwide, have recently been proposed as potentially emerging waterborne pathogens. The objective of the present study was to examine the occurrence of HPyVs and HPVs in surface waters, by monitoring two rivers in Northwestern Italy, by nested PCR assays and sequencing. HPyVs (JC, BK, and Merkel cell polyomavirus) were detected in 10/25 (40%) samples. HPVs (HPV8, 17, 21, 25, 32, 80, 99, 105, and putative new HPVs) were identified in 14/25 (56%) river samples. The number of HPV DNA copies in waters was measured by quantitative real-time PCR. To our knowledge, this is the first detection and quantification of HPVs in surface waters. The possibility that HPyVs and HPVs can be transmitted by the waterborne route deserves to be explored in future studies. PMID:26049729

  3. Induction of human papillomavirus type 16-specific immunologic responses in a normal and an human papillomavirus-infected populations

    PubMed Central

    Cheng, Wen-Fang; Lee, Chien-Nan; Su, Yi-Ning; Chang, Ming-Cheng; Hsiao, Wen-Chun; Chen, Chi-An; Hsieh, Chang-Yao

    2005-01-01

    Human papillomavirus (HPV) infection, especially with the oncogenic genotypes, is the most important risk factor for developing cervical cancer. We focused on generating HPV16 E7-specific cytotoxic CD8+ T lymphocytes and evaluating HPV16 E7-specific immune responses in HPV16-infected and uninfected populations. Peripheral blood mononuclear cells (PBMCs) were first collected from an uninfected group with an human lymphocyte antigen (HLA) A2 haplotype (four volunteers). Mature monocyte-derived dendritic cells (DCs) were generated from the PBMCs and pulsed with one of two HLA-A2-restricted E7 peptides, aa 11–20 [YMLDLQPETT] and aa 86–93 [TLGIVCPI], as antigen presenting cells. The autologous naïve or cultured PBMCs were then cultured with peptide-pulsed DCs to detect the HPV16 E7-specific immune responses by a variety of techniques such as enzyme-linked immunosorbent assay (ELISA), enzyme-linked immunospot (ELISPOT) assay and cytotoxic T lymphocyte assay. Interferon-γ (IFN-γ) from E7-specific cytotoxic CD8+ T lymphocytes stimulated with the respective peptide was detected by ELISA. Using ELISPOT analysis, a marked increase in the number of IFN-γ-secreting CD8+ E7-specific lymphocytes was observed following peptide stimulation. Cultured CD8+ T lymphocytes were highly cytotoxic against the CaSki cells. PBMCs were then colleted from an HPV16-infected population of the HLA-A2 haplotype, including four persons of HPV16 infection only, four with cervical intraepithelial neoplasia (CIN) lesions, and four cervical cancer patients. We then compared the immunologic responses to E7 between HPV16-infected and uninfected populations by ELISA and ELISPOT assay. The E7-specific immunologic responses of the HPV16-infected populations were significantly higher than those of the uninfected population. In addition, persons with an HPV16 infection only or those with CIN lesions generated higher E7-specific immunologic responses than cervical cancer patients. Our results

  4. Genital human papillomavirus infection in women from the Zagreb region.

    PubMed

    Marijan, Tatjana; Vranes, Jasmina; Mlinarić-Dzepina, Ana; Leskovar, Vladimira; Knezević, Jasna; Kvaternik, Matea

    2007-04-01

    Human papillomavirus (HPV) infection is the most common sexually transmitted infection, especially among young, sexually active individuals. As persistent infection with oncogenic types may lead to cervical cancer, HPV testing is a useful tool to screen for women at risk for subsequent development of cervical cancer. The aim of the study was to determine the prevalence of high-risk HPV (hrHPV) infection in different age groups of cytologically selected women from the Zagreb region, and to evaluate the frequency and results of repeat hrHPV testing. During a one-year study period (November 2005 to November 2006), a total of 3,440 cervical samples from women attending gynecological services of public and private health care systems were received. They were tested for 13 hrHPV genotypes by the polymerase chain reaction based AMPLICOR HPV test (Roche Molecular Systems). The overall prevalence of hrHPV was 34.6%. Most samples were obtained from women aged 21-30 years (44.2%), followed by the 31-40 (27.6%), 41-50 (15.7%), 51-60 (5.3%) and 261 (2.4%) age groups. Out of 3,227 cervical samples obtained from women of known age, 4.9% were obtained from the group of girls younger than 21, in which the highest prevalence of hrHPV (49.4%) was found. A similar prevalence was observed in women aged 21-30 (45.1%). The prevalence gradually decreased with age. During the study period, repeat hrHPV testing was performed in samples from 66 women at different intervals. Out of 28 women that were hrHPV negative on initial testing, only five women turned positive on repeat testing. Out of 38 women that were positive on initial testing, in one-third hrHPV could not be detected on repeat testing. As expected, hrHPV infection was highly prevalent in female adolescents and young women. Further investigation on repeat hrHPV testing is needed to assess virus clearance and rate of newly acquired infection. PMID:17600936

  5. Is human papillomavirus vaccination likely to be a useful strategy in India?

    PubMed Central

    Gupta, Sudeep; Kerkar, Rajendra A.; Dikshit, Rajesh; Badwe, Rajendra A.

    2013-01-01

    Two vaccines that protect against infection by some of the oncogenic human papillomavirus (HPV) subtypes have recently been licensed for use in population-based vaccination strategies in many countries. However, these products are being promoted as ‘cervical cancer vaccines’ based on inadequate data. Specifically, there remain several concerns about the duration of immunogenicity, length of follow-up of trial subjects, endpoints chosen in vaccine trials, applicability of trial results to real populations, the safety of these products, and their cost-effectiveness as public health interventions. Furthermore, it is unlikely that vaccination will obviate the need for setting up robust and cost-effective screening programs in countries like India. This article will discuss various aspects of HPV vaccination from a public health perspective, especially from the point of view of its relevance to India and other South Asian countries. PMID:24455622

  6. Transformation of human cells by oncogenic viruses supports permissiveness for parvovirus H-1 propagation.

    PubMed Central

    Faisst, S; Schlehofer, J R; zur Hausen, H

    1989-01-01

    Parvovirus H-1 has been shown to suppress spontaneous and chemically or virally induced tumorigenesis in hamsters. In human cell culture systems propagation of H-1 is restricted to transformed cells, which are killed by H-1 infection, in contrast to normal diploid cells, which are nonpermissive for H-1. By analyzing the permissiveness of a variety of human cells for H-1, it was determined that the majority of tested transformed or immortalized cells which were permissive for H-1 contained the DNA of oncogenic viruses (human papillomavirus, simian virus 40, adenovirus, hepatitis B virus, Epstein-Barr virus, and human T-cell lymphotropic virus type I). Of six transformed cell lines negative for persisting tumor virus DNA, only two were permissive for H-1, while two were semipermissive and two were nonpermissive. Thus, persistence and expression of tumor virus functions appears to promote full permissiveness for H-1 in human cells. However, neither expression of genes of specific viral genomes nor the transformed state of apparently virus-free cells alone was sufficient to render human cells permissive for H-1. Therefore, the effect of tumor virus functions on H-1 in transformed cells seems to be indirect, probably mediated by cellular factors which are induced or switched off during the transformation process. It appears that similar factors are induced or switched off by 5-azacytidine or calcium phosphate, both known inducers of cellular gene expression. Images PMID:2495371

  7. The association of human papillomavirus vaccination with sexual behaviours and human papillomavirus knowledge: a systematic review.

    PubMed

    Coles, Victoria A H; Patel, Ajay S; Allen, Felicity L; Keeping, Sam T; Carroll, Stuart M

    2015-10-01

    Since the 2008 introduction of the human papillomavirus (HPV) vaccination programme for adolescent girls in the UK, parents and other groups have expressed fears that immunisation condones sexual activity, promotes promiscuity and encourages risky sexual behaviour. This study aimed to explore whether HPV vaccination programmes have increased knowledge surrounding HPV and associated disease and whether uptake has influenced sexual behaviour. MEDLINE, Embase, Cochrane Library and PsycINFO electronic databases were interrogated. Studies of behaviour, attitudes and knowledge associated with HPV vaccination (or vaccination intent) in subjects of any age and gender in programmes reflective of UK practice were included in the review (n = 58). The evidence regarding the association of HPV vaccination with high-risk sexual behaviour was varied, primarily due to the heterogeneous nature of the included studies. Young females typically exhibited better knowledge than males, and vaccinated respondents (or those with vaccination intent) had higher levels of knowledge than the unvaccinated. However, knowledge surrounding HPV and genital warts was generally poor. This review highlights the need to provide effective education regarding the HPV vaccine and HPV-associated disease to adolescents of vaccination age, nurses, teachers, parents and guardians to ultimately allow informed decisions to be made regarding receipt of the HPV vaccine. PMID:25300588

  8. Immortalization of human foreskin keratinocytes by various human papillomavirus DNAs corresponds to their association with cervical carcinoma

    SciTech Connect

    Woodworth, C.D.; Doniger, J.; DiPaolo, J.A.

    1989-01-01

    Normal human foreskin keratinocytes cotransfected with the neomycin resistance gene and recombinant human papillomavirus (HPV) DNAs (types 16, 18, 31, and 33) that have a high or moderate association with cervical malignancy acquired immortality and contained integrated and transcriptionally active viral genomes. Only transcripts from the intact E6 and E7 genes were detected in at least one cell line, suggesting that one or both of these genes are responsible for immortalization. Recombinant HPV DNAs with low or no oncogenic potential for cervical cancer (HPV1a, -5, -6b, and -11) induced small G418-resistant colonies that senesced as did the nontransfected cells. These colonies contained only episomal virus DNA; therefore, integration of HPV sequences is important for immortalization of keratinocytes. This study suggests that the virus-encoded immortalization function contributes to the pathogenesis of cervical carcinoma.

  9. Using Organotypic Epithelial Tissue Culture to Study the Human Papillomavirus Life Cycle.

    PubMed

    Lee, Denis; Norby, Kathryn; Hayes, Mitchell; Chiu, Ya-Fang; Sugden, Bill; Lambert, Paul F

    2016-01-01

    Human papillomaviruses (HPVs) are small double-stranded DNA viruses that are associated with greater than 95% of cervical cancers and 20% of head and neck cancers. These cancers arise from persistent infections in which there is continued expression of the HPV E6 and E7 oncogenes, often as a consequence of integration of HPV DNA into the host genome. Such cancers represent "dead ends" for the virus as integration disrupts the viral genome and because the cancers are defective in normal epithelial differentiation, which is required for production of progeny papillomavirus. In order to study the full viral life cycle, from the establishment to maintenance to productive stages, our lab makes use of the organotypic epithelial tissue culture system. This system allows us to mimic the three-dimensional structure of epithelia whose differentiation is tightly linked to the completion of the HPV viral life cycle. In this chapter we describe how various aspects of the HPV life cycle are monitored in raft cultures making use of an immortalized keratinocyte cell line. © 2016 by John Wiley & Sons, Inc. PMID:27153383

  10. Recent advances in the search for antiviral agents against human papillomaviruses

    PubMed Central

    Fradet-Turcotte, Amélie; Archambault, Jacques

    2015-01-01

    Infection by human papillomavirus (HPV) is extremely common and associated with the development of benign warts or malignant lesions of the skin and mucosa. Infection by a high-risk (oncogenic) anogenital HPV type, most often through sexual contacts, is the starting point of virtually all cases of cervical cancers and the majority of anal cancers. The same viral types are also increasingly being linked with a subset of head-and-neck and non-melanoma skin cancers. Although prophylactic vaccines are now available to protect against the four types most commonly found in cervical and anal cancers (HPV16 and HPV18) and anogenital warts (HPV6 and HPV11), these neither protect against all genital HPVs nor are of therapeutic utility for already infected patients. Thus, the need for antiviral agents to treat HPV-associated diseases remains great, but none currently exist. This article reviews the recent progress made towards the development of antiviral agents to treat HPV infections, from target identification and validation to the discovery of lead compounds with therapeutic potential. Emphasis has been placed on novel low-molecular-weight compounds that antagonize HPV proteins or, alternatively, inhibit cellular proteins which have been usurped by papillomaviruses and are mediating their pathogenic effects. PMID:17668552

  11. Human papillomavirus 16 E5 induces bi-nucleated cell formation by cell-cell fusion

    SciTech Connect

    Hu Lulin; Plafker, Kendra; Vorozhko, Valeriya; Zuna, Rosemary E.; Hanigan, Marie H.; Gorbsky, Gary J.; Plafker, Scott M.; Angeletti, Peter C.; Ceresa, Brian P.

    2009-02-05

    Human papillomaviruses (HPV) 16 is a DNA virus encoding three oncogenes - E5, E6, and E7. The E6 and E7 proteins have well-established roles as inhibitors of tumor suppression, but the contribution of E5 to malignant transformation is controversial. Using spontaneously immortalized human keratinocytes (HaCaT cells), we demonstrate that expression of HPV16 E5 is necessary and sufficient for the formation of bi-nucleated cells, a common characteristic of precancerous cervical lesions. Expression of E5 from non-carcinogenic HPV6b does not produce bi-nucleate cells. Video microscopy and biochemical analyses reveal that bi-nucleates arise through cell-cell fusion. Although most E5-induced bi-nucleates fail to propagate, co-expression of HPV16 E6/E7 enhances the proliferation of these cells. Expression of HPV16 E6/E7 also increases bi-nucleated cell colony formation. These findings identify a new role for HPV16 E5 and support a model in which complementary roles of the HPV16 oncogenes lead to the induction of carcinogenesis.

  12. Oncogenic long noncoding RNA FAL1 in human cancer

    PubMed Central

    Zhong, Xiaomin; Hu, Xiaowen; Zhang, Lin

    2015-01-01

    Long non-coding RNAs (lncRNAs) are defined as RNA transcripts larger than 200 nucleotides that do not appear to have protein-coding potential. Accumulating evidence indicates that lncRNAs are involved in tumorigenesis. Our work reveals that lncRNA FAL1 (focally amplified lncRNA on chromosome 1) is frequently and focally amplified in human cancers and mediates oncogenic functions. PMID:27308441

  13. Papillomaviruses: Molecular and clinical aspects

    SciTech Connect

    Howley, P.M.; Broker, T.R.

    1985-01-01

    This book contains nine sections, each consisting of several papers. The section headings are : Papillomaviruses and Human Genital Tract Diseases;Papillomaviruses and Human Cutaneous Diseases, Papillomaviruses and Human Oral and Laryngeal Diseases;Therapeutic Approaches to Papillomavirus Infections;Animal Papillomaviruses;Molecular Biology;Transcription, Replication, and Genome Organization;Epithelial Cell Culture;Papillomavirus Transformation;and Viral Vectors.

  14. Incidence and clearance of oral human papillomavirus infection in men: the HIM cohort study

    PubMed Central

    Kreimer, Aimée R.; Pierce Campbell, Christine M.; Lin, Hui-Yi; Fulp, William; Papenfuss, Mary R.; Abrahamsen, Martha; Hildesheim, Allan; Villa, Luisa L.; Salmerón, Jorge J.; Lazcano-Ponce, Eduardo; Giuliano, Anna R.

    2013-01-01

    Background Oral human papillomavirus (HPV) infection causes a subset of oropharyngeal cancers. These cancers disproportionately affect men, are increasing in incidence, and have no proven prevention methods. We aimed to establish the natural history of oral HPV infection in men. Methods To estimate incidence and clearance of HPV infections, men residing in Brazil, Mexico, and the USA who were HIV negative and reported no history of anogenital cancer were recruited into the HPV Infection in Men (HIM) cohort study. A subset of the cohort who provided two or more oral rinse-and-gargle samples with valid HPV results and who completed a minimum of 2 weeks of follow-up were included in this analysis. Oral rinse-and-gargle samples and questionnaire data were obtained every 6 months for up to 4 years. Samples were analysed for the presence of oncogenic and non-oncogenic HPV infections by the linear array method. Findings 1626 men aged 18–73 years and with a median follow-up of 12·7 months (IQR 12·1–14·7) were included in the analysis. During the first 12 months of follow-up, 4·4% (95% CI 3·5–5·6; n=115 incident infections) of men acquired an incident oral HPV infection, 1·7% (1·2–2·5; n=53 incident infections) an oral oncogenic HPV infection, and 0·6% (0·3–1·1; n=18 incident infections) an oral HPV 16 infection. Acquisition of oral oncogenic HPV was significantly associated with smoking and not being married or cohabiting, but was similar across countries, age groups, and reported sexual behaviours. Median duration of infection was 6·9 months (95 % CI 6·2–9·3; n=45 cleared infections) for any HPV, 6·3 months (6·0–9·9; n=18 cleared infections) for oncogenic HPV, and 7·3 months (6·0–not estimable; n=5 cleared infections) for HPV 16. Eight of the 18 incident oral HPV 16 infections persisted for two or more study visits. Interpretation Newly acquired oral oncogenic HPV infections in healthy men were rare and most were cleared within 1 year

  15. Human Papillomavirus Type 16 E7 Oncoprotein Causes a Delay in Repair of DNA Damage

    PubMed Central

    Park, Jung Wook; Nickel, Kwangok P.; Torres, Alexandra D.; Lee, Denis; Lambert, Paul F.; Kimple, Randall J.

    2014-01-01

    Background and Purpose Patients with Human papillomavirus related (HPV+) head and neck cancers (HNCs) demonstrate improved clinical outcomes compared to traditional HPV negative (HPV−) HNC patients. We have recently shown that HPV+ HNC cells are more sensitive to radiation than HPV− HNC cells. However, roles of HPV oncogenes in regulating the response of DNA damage repair remain unknown. Material and Methods Using immortalized normal oral epithelial cell lines, HPV+ HNC derived cell lines, and HPV16 E7-transgenic mice we assessed the repair of DNA damage using γ-H2AX foci, single and split dose clonogenic survival assays, and immunoblot. The ability of E7 to modulate expression of proteins associated with DNA repair pathways was assessed by immunoblot. Results HPV16 E7 increased retention of γ-H2AX nuclear foci and significantly decreased sublethal DNA damage repair. While phospho-ATM, phospho-ATR, Ku70, and Ku80 expressions were not altered by E7, Rad51 was induced by E7. Correspondingly, HPV+ HNC cell lines showed retention of Rad51 after γ-radiation. Conclusions Our findings provide further understanding as to how HPV16 E7 manipulates cellular DNA damage responses that may underlie its oncogenic potential and influence the altered sensitivity to radiation seen in HPV+ HNC as compared to HPV− HNC. PMID:25216575

  16. Role of human papillomavirus and tumor suppressor genes in oral cancer

    PubMed Central

    Manvikar, Vardendra; Kulkarni, Rama; Koneru, Anila; Vanishree, M

    2016-01-01

    The incidence of oral cancer remains high and is associated with many deaths in both Western and Asian countries. Several risk factors for the development of oral cancer are now well known, including smoking, drinking and consumption of smokeless tobacco products. Genetic predisposition to oral cancer has been found in certain cases, but its components are not yet entirely clear. In accordance with the multi-step theory of carcinogenesis, the natural history of oral cancer seems to gradually evolve through transitional precursor lesions from normal epithelium to a full-blown metastatic phenotype. A number of genomic lesions accompany this transformation and a wealth of related results has appeared in recent literature and is being summarized here. Furthermore, several key genes have been implicated, especially well-known tumor suppressors such as the cyclin-dependent kinase inhibitors, TP53 and RB1 and oncogenes such as the cyclin family, epidermal growth factor receptor and RAS. Viral infections, particularly oncogenic human papillomavirus subtypes and Epstein–Barr virus, can have a tumorigenic effect on oral epithelia and their role is discussed, along with potential therapeutic interventions. A brief explanatory theoretical model of oral carcinogenesis is provided and potential avenues for further research are highlighted. PMID:27194871

  17. Human papillomavirus type 16 E7 perturbs DREAM to promote cellular proliferation and mitotic gene expression

    PubMed Central

    DeCaprio, James A.

    2014-01-01

    Study of the small DNA tumor viruses continues to provide valuable new insights into oncogenesis and fundamental biological processes. While much has already been revealed about how the human papillomaviruses (HPVs) can transform cells and contribute to cervical and oropharyngeal cancer, there clearly is much more to learn. In this issue of Oncogene, Pang et al. demonstrate that the high-risk HPV16 E7 oncogene can promote cellular proliferation by interacting with the DREAM (DP, RB-like, E2F and MuvB) complex at two distinct phases of the cell cycle (1). Consistent with earlier work, HPV16 E7 can bind to the retinoblastoma tumor suppressor (RB) family member p130 (RBL2) protein and promote its proteasome-mediated destruction thereby disrupting the DREAM complex and prevent exit from the cell cycle into quiescence. In addition, they demonstrate that HPV16 E7 can bind to MuvB core complex in association with BMYB and FOXM1 and activate gene expression during the G2 and M phase of the cell cycle. Thus, HPV16 E7 acts to prevent exit from the cell cycle entry and promotes mitotic proliferation and may account for the high levels of FOXM1 often observed in poor risk cervical cancers. PMID:24166507

  18. Human papillomavirus type 16 E7 perturbs DREAM to promote cellular proliferation and mitotic gene expression.

    PubMed

    DeCaprio, J A

    2014-07-31

    The study of the small DNA tumor viruses continues to provide valuable new insights into oncogenesis and fundamental biological processes. Although much has already been revealed about how the human papillomaviruses (HPVs) can transform cells and contribute to cervical and oropharyngeal cancer, there clearly is much more to learn. In this issue of Oncogene, Pang et al., doi:10.1038/onc.2013.426, demonstrate that the high-risk HPV16 E7 oncogene can promote cellular proliferation by interacting with the DREAM (DP, RB-like, E2F and MuvB) complex at two distinct phases of the cell cycle. Consistent with earlier work, HPV16 E7 can bind to the retinoblastoma tumor suppressor (RB) family member p130 (RBL2) protein and promote its proteasome-mediated destruction thereby disrupting the DREAM complex and can prevent exit from the cell cycle into quiescence. In addition, they demonstrate that HPV16 E7 can bind to MuvB core complex in association with BMYB and FOXM1 and activate gene expression during the G2 and M phase of the cell cycle. Thus, HPV16 E7 acts to prevent exit from the cell cycle entry and promotes mitotic proliferation and may account for the high levels of FOXM1 often observed in poor-risk cervical cancers. PMID:24166507

  19. Male Human Papillomavirus Prevalence and Association With Condom Use in Brazil, Mexico, and the United States

    PubMed Central

    Repp, Kimberly K.; Nielson, Carrie M.; Fu, Rongwei; Schafer, Sean; Lazcano-Ponce, Eduardo; Salmerón, Jorge; Quiterio, Manuel; Villa, Luisa L.

    2012-01-01

    Background. Reported associations of condom use and human papillomavirus (HPV) infection have been inconsistent. We investigated self-reported frequency of condom use and detection of genital HPV among men. Methods. A cross-sectional analysis was conducted in men aged 18–70 years from Brazil, Mexico, and the United States. Men completed questionnaires on sexual history, condom use, and sociodemographic characteristics. Among 2621 men reporting recent vaginal sex, prevalence of any HPV, any oncogenic type, and nononcogenic types only was estimated by frequency of condom use (“always” or “not always”). Multivariable models were used to estimate prevalence ratios (PRs) for HPV according to frequency of condom use. Results. The prevalence of any HPV was 70.5%; any oncogenic type, 34%, and nononcogenic types only, 22.2%. The adjusted PR for always vs not always using condoms was 0.87 (95% confidence interval [CI], .77–.97) for all countries combined. The association was stronger in the United States (PR, 0.70; CI, .55–.90) than in Brazil (PR, 0.84; CI, .71–1.01) or Mexico (PR, 1.05; CI, .89–1.25) (P for interaction = .025). Conclusions. HPV prevalence was high even among those who reported always using condoms, and its associations with always using condoms varied among countries. PMID:22396601

  20. Human Papillomavirus: Current and Future RNAi Therapeutic Strategies for Cervical Cancer

    PubMed Central

    Jung, Hun Soon; Rajasekaran, Nirmal; Ju, Woong; Shin, Young Kee

    2015-01-01

    Human papillomaviruses (HPVs) are small DNA viruses; some oncogenic ones can cause different types of cancer, in particular cervical cancer. HPV-associated carcinogenesis provides a classical model system for RNA interference (RNAi) based cancer therapies, because the viral oncogenes E6 and E7 that cause cervical cancer are expressed only in cancerous cells. Previous studies on the development of therapeutic RNAi facilitated the advancement of therapeutic siRNAs and demonstrated its versatility by siRNA-mediated depletion of single or multiple cellular/viral targets. Sequence-specific gene silencing using RNAi shows promise as a novel therapeutic approach for the treatment of a variety of diseases that currently lack effective treatments. However, siRNA-based targeting requires further validation of its efficacy in vitro and in vivo, for its potential off-target effects, and of the design of conventional therapies to be used in combination with siRNAs and their drug delivery vehicles. In this review we discuss what is currently known about HPV-associated carcinogenesis and the potential for combining siRNA with other treatment strategies for the development of future therapies. Finally, we present our assessment of the most promising path to the development of RNAi therapeutic strategies for clinical settings. PMID:26239469

  1. Role of human papillomavirus and tumor suppressor genes in oral cancer.

    PubMed

    Manvikar, Vardendra; Kulkarni, Rama; Koneru, Anila; Vanishree, M

    2016-01-01

    The incidence of oral cancer remains high and is associated with many deaths in both Western and Asian countries. Several risk factors for the development of oral cancer are now well known, including smoking, drinking and consumption of smokeless tobacco products. Genetic predisposition to oral cancer has been found in certain cases, but its components are not yet entirely clear. In accordance with the multi-step theory of carcinogenesis, the natural history of oral cancer seems to gradually evolve through transitional precursor lesions from normal epithelium to a full-blown metastatic phenotype. A number of genomic lesions accompany this transformation and a wealth of related results has appeared in recent literature and is being summarized here. Furthermore, several key genes have been implicated, especially well-known tumor suppressors such as the cyclin-dependent kinase inhibitors, TP53 and RB1 and oncogenes such as the cyclin family, epidermal growth factor receptor and RAS. Viral infections, particularly oncogenic human papillomavirus subtypes and Epstein-Barr virus, can have a tumorigenic effect on oral epithelia and their role is discussed, along with potential therapeutic interventions. A brief explanatory theoretical model of oral carcinogenesis is provided and potential avenues for further research are highlighted. PMID:27194871

  2. The human minisatellite consensus at breakpoints of oncogene translocations.

    PubMed Central

    Krowczynska, A M; Rudders, R A; Krontiris, T G

    1990-01-01

    A reexamination of human minisatellite (hypervariable) regions following the cloning and sequencing of the new minisatellite, VTR1.1, revealed that many of these structures possessed a strongly conserved copy of the chi-like octamer, GC[A/T]GG[A/T]GG. In oncogene translocations apparently created by aberrant VDJ recombinase activity, this VTR octamer was often found within a few bases of the breakpoint (p less than 10(-10)). Three bcl2 rearrangements which occurred within 2 bp of one another were located precisely adjacent to this consensus; it defined the 5' border of that oncogene's major breakpoint cluster. Several c-myc translocations also occurred within 2 bp of this sequence. While the appearance of a chi-like element in polymorphic minisatellite sequences is consistent with a role promoting either recombination or replication slippage, the existence of such elements at sites of somatic translocations suggests chi function in site-specific recombination, perhaps as a subsidiary recognition signal in immunoglobulin gene rearrangement. We discuss the implications of these observations for mechanisms by which oncogene translocations and minisatellite sequences are generated. Images PMID:1969618

  3. Progressive squamous epithelial neoplasia in K14-human papillomavirus type 16 transgenic mice.

    PubMed Central

    Arbeit, J M; Münger, K; Howley, P M; Hanahan, D

    1994-01-01

    To model human papillomavirus-induced neoplastic progression, expression of the early region of human papillomavirus type 16 (HPV16) was targeted to the basal cells of the squamous epithelium in transgenic mice, using a human keratin 14 (K14) enhancer/promoter. Twenty-one transgenic founder mice were produced, and eight lines carrying either wild-type or mutant HPV16 early regions that did not express the E1 or E2 genes were established. As is characteristic of human cancers, the E6 and E7 genes remained intact in these mutants. The absence of E1 or E2 function did not influence the severity of the phenotype that eventually developed in the transgenic mice. Hyperplasia, papillomatosis, and dysplasia appeared at multiple epidermal and squamous mucosal sites, including ear and truncal skin, face, snout and eyelids, and anus. The ears were the most consistently affected site, with pathology being present in all lines with 100% penetrance. This phenotype also progressed through discernible stages. An initial mild hyperplasia was followed by hyperplasia, which further progressed to dysplasia and papillomatosis. During histopathological progression, there was an incremental increase in cellular DNA synthesis, determined by 5-bromo-2'-deoxyuridine incorporation, and a profound perturbation in keratinocyte terminal differentiation, as revealed by immunohistochemistry to K5, K14, and K10 and filaggrin. These K14-HPV16 transgenic mice present an opportunity to study the role of the HPV16 oncogenes in the neoplastic progression of squamous epithelium and provide a model with which to identify genetic and epigenetic factors necessary for carcinogenesis. Images PMID:7515971

  4. Comparison of liver oncogenic potential among human RAS isoforms

    PubMed Central

    Chung, Sook In; Moon, Hyuk; Ju, Hye-Lim; Kim, Dae Yeong; Cho, Kyung Joo; Ribback, Silvia; Dombrowski, Frank; Calvisi, Diego F.; Ro, Simon Weonsang

    2016-01-01

    Mutation in one of three RAS genes (i.e., HRAS, KRAS, and NRAS) leading to constitutive activation of RAS signaling pathways is considered a key oncogenic event in human carcinogenesis. Whether activated RAS isoforms possess different oncogenic potentials remains an unresolved question. Here, we compared oncogenic properties among RAS isoforms using liver-specific transgenesis in mice. Hydrodynamic transfection was performed using transposons expressing short hairpin RNA downregulating p53 and an activated RAS isoform, and livers were harvested at 23 days after gene delivery. No differences were found in the hepatocarcinogenic potential among RAS isoforms, as determined by both gross examination of livers and liver weight per body weight ratio (LW/BW) of mice expressing HRASQ61L, KRAS4BG12V and NRASQ61K. However, the tumorigenic potential differed significantly between KRAS splicing variants. The LW/BW ratio in KRAS4AG12V mice was significantly lower than in KRAS4BG12V mice (p < 0.001), and KRAS4AG12V mice lived significantly longer than KRRAS4BG12V mice (p < 0.0001). Notably, tumors from KRAS4AG12V mice displayed higher expression of the p16INK4A tumor suppressor when compared with KRAS4BG12V tumors. Forced overexpression of p16INK4A significantly reduced tumor growth in KRAS4BG12V mice, suggesting that upregulation of p16INK4A by KRAS4AG12V presumably delays tumor development driven by the latter oncogene. PMID:26799184

  5. A risk for non-sexual transmission of human papillomavirus?

    PubMed

    Ryndock, Eric J; Meyers, Craig

    2014-10-01

    Human papillomaviruses (HPVs) are estimated to be the most common sexually transmitted virus in humans. The virus is of great interest as it is the etiological agent of cervical cancer. Sexual transmission of HPV is generally accepted, however, non-sexual transmission of the virus is often debated. Here, we review the evidence from basic research and clinical studies that show HPV can survive well outside of its host to potentially be transmitted by non-sexual means. In doing so, we hope to discover problems in current prevention practices and show a need for better disinfectants to combat the spread of HPV. PMID:25199987

  6. Associations of health behaviors with human papillomavirus vaccine uptake, completion, and intentions among female undergraduate students.

    PubMed

    Winger, Joseph G; Christy, Shannon M; Mosher, Catherine E

    2016-09-01

    This study explored associations between health behaviors and human papillomavirus vaccine receipt/intentions among female undergraduates. Participants (N = 286) completed a survey assessing human papillomavirus vaccine uptake (receiving 1-3 shots vs no shots), completion (receiving 3 shots vs 1-2 shots), and intentions as well as various health behaviors. Human papillomavirus vaccine uptake and completion were associated with receipt of other preventive medical care; completion was associated with having a regular healthcare provider. Among unvaccinated students (n = 115), increased human papillomavirus vaccine intentions were associated with flu shot and human immunodeficiency virus test receipt. Findings suggest promoting human papillomavirus vaccination with other preventive medical care might improve vaccine receipt. PMID:25649428

  7. The role of human cervical cancer oncogene in cancer progression.

    PubMed

    Li, Xin-Yu; Wang, Xin

    2015-01-01

    Human cervical cancer oncogene (HCCR) was identified by differential display RT-PCR by screened abnormally expressed genes in cervical human cancers. The overexpressed gene is not only identified in cervical tissues, but also in various human cancers as leukemia/lymphoma, breast, stomach, colon, liver, kidney and ovarian cancer. For its special sensitivities and specificities in human breast cancer and hepatocellular carcinoma, it is expected to be a new biomarker to replace or combine with the existing biomarkers in the diagnose. The HCCR manifests as a negative regulator of the p53 tumor suppressor gene, and its expression is regulated by the PI3K/Akt signaling pathway, modulated by TCF/β-catenin, it also participates in induction of the c-kit proto-oncogene, in activation of PKC and telomerase activities, but the accurate biochemical mechanisms of how HCCR contributes to the malignancies is still unknown. The aim of this review is to summarize the roles of HCCR in cancer progression and the molecular mechanisms involved. PMID:26309489

  8. Human Papillomavirus (HPV) and Genital Warts

    MedlinePlus

    ... page. Skip Navigation U.S. Department of Health and Human Services • National Institutes of Health Temas de Salud ... RELATED GOVERNMENT SITES U.S. Department of Health and Human Services National Institutes of Health USA.gov

  9. Abnormal structure of the canine oncogene, related to the human c-yes-1 oncogene, in canine mammary tumor tissue.

    PubMed

    Miyoshi, N; Tateyama, S; Ogawa, K; Yamaguchi, R; Kuroda, H; Yasuda, N; Shimizu, T

    1991-12-01

    Cellular oncogenes of genomic DNA in 6 canine primary mammary tumors were screened by Southern blot analysis, using 7 oncogene probes. A canine genomic oncogene related to the human c-yes-1 oncogene was detected as abnormal bands in solid carcinoma genomic DNA digested with EcoRI, HindIII, HindIII-EcoRI, or HindIII-BamHI. Comparison was made between other tumor specimens and control specimens obtained from 4 clinically normal dogs--1 mixed breed and 3 Shiba Inu dogs (the same breed as the dog from which the solid carcinoma was obtained). These abnormal bands were 0.1 to 1 kilobase shorter than the normal gene. However, digestion of genomic DNA obtained from normal WBC of this dog also produced all of the abnormal bands as observed in digested DNA from the solid carcinoma tissue. Therefore, in this dog, the genomic DNA of all somatic cells from the ontogenic stage still had the abnormal sequences related to the human c-yes-1 oncogene, and it is possible that this abnormal structure may have some role (eg, as an initiator) in tumorigenesis or the progression of this tumor. PMID:1789521

  10. The Moral Justification for a Compulsory Human Papillomavirus Vaccination Program

    PubMed Central

    2009-01-01

    Compulsory human papillomavirus (HPV) vaccination of young girls has been proposed as a public health intervention to reduce the threat of the disease. Such a program would entail a symbiotic relationship between scientific interests in reducing mortality and morbidity and philosophical interests in promoting morality. This proposal raises the issue of whether government should use its police powers to restrict liberty and parental autonomy for the purpose of preventing harm to young people. I reviewed the scientific literature that questions the value of a HPV vaccination. Applying a principle-based approach to moral reasoning, I concluded that compulsory HPV vaccinations can be justified on moral, scientific, and public health grounds. PMID:19197085

  11. Porokeratoma: A Possible Association with Human Papillomavirus Infection.

    PubMed

    Caseiro Silverio, Patricia; Pham, Xuan-Cuong; Kaya, Gürkan

    2015-01-01

    Porokeratoma is a rare, relatively newly described and still unclear entity. Here, we describe the case of a 52-year-old male patient who presented with four well-defined, verrucous and hyperkeratotic lesions. Microscopically, one of the lesions showed acanthopapillomatosis overlying compact orthokeratosis. Prominent broad and confluent cornoid lamellae were present, with no granular layer and some dyskeratotic keratinocytes. PCR sequencing and in situ hybridization revealed the presence of human papillomavirus (HPV) type 16 in the lesion. The association of porokeratoma and HPV infection has not previously been reported. PMID:27047933

  12. Porokeratoma: A Possible Association with Human Papillomavirus Infection

    PubMed Central

    Caseiro Silverio, Patricia; Pham, Xuan-Cuong; Kaya, Gürkan

    2015-01-01

    Porokeratoma is a rare, relatively newly described and still unclear entity. Here, we describe the case of a 52-year-old male patient who presented with four well-defined, verrucous and hyperkeratotic lesions. Microscopically, one of the lesions showed acanthopapillomatosis overlying compact orthokeratosis. Prominent broad and confluent cornoid lamellae were present, with no granular layer and some dyskeratotic keratinocytes. PCR sequencing and in situ hybridization revealed the presence of human papillomavirus (HPV) type 16 in the lesion. The association of porokeratoma and HPV infection has not previously been reported. PMID:27047933

  13. Concomitant anal and cervical human papillomavirusV infections and intraepithelial neoplasia in HIV-infected and uninfected women

    PubMed Central

    Hessol, Nancy A.; Holly, Elizabeth A.; Efird, Jimmy T.; Minkoff, Howard; Weber, Kathleen M.; Darragh, Teresa M.; Burk, Robert D.; Strickler, Howard D.; Greenblatt, Ruth M.; Palefsky, Joel M.

    2014-01-01

    Objective To assess factors associated with concomitant anal and cervical human papillomavirus (HPV) infections in HIV-infected and at-risk women. Design A study nested within the Women’s Interagency HIV Study (WIHS), a multi-center longitudinal study of HIV-1 infection in women conducted in six centers within the United States. Methods Four hundred and seventy HIV-infected and 185 HIV-uninfected WIHS participants were interviewed and examined with anal and cervical cytology testing. Exfoliated cervical and anal specimens were assessed for HPV using PCR and type-specific HPV testing. Women with abnormal cytologic results had colposcopy or anoscopy-guided biopsy of visible lesions. Logistic regression analyses were performed and odds ratios (ORs) measured the association for concomitant anal and cervical HPV infection. Results One hundred and sixty-three (42%) HIV-infected women had detectable anal and cervical HPV infection compared with 12 (8%) of the HIV-uninfected women (P <0.001). HIV-infected women were more likely to have the same human papillomavirus (HPV) genotype in the anus and cervix than HIV-uninfected women (18 vs. 3%, P <0.001). This was true for both oncogenic (9 vs. 2%, P = 0.003) and nononcogenic (12 vs. 1%, P <0.001) HPV types. In multivariable analysis, the strongest factor associated with both oncogenic and nononcogenic concomitant HPV infection was being HIV-infected (OR = 4.6 and OR = 16.9, respectively). In multivariable analysis of HIV-infected women, CD4+ cell count of less than 200 was the strongest factor associated with concomitant oncogenic (OR = 4.2) and nononcogenic (OR = 16.5) HPV infection. Conclusion HIV-infected women, particularly those women with low CD4+ cell counts, may be good candidates for HPV screening and monitoring for both cervical and anal disease PMID:23803793

  14. Effects of telomerase and viral oncogene expression on the in vitro growth of human chondrocytes.

    PubMed

    Martin, James A; Mitchell, Calista J; Klingelhutz, Aloysius J; Buckwalter, Joseph A

    2002-02-01

    Senescent chondrocytes accumulate with aging in articular cartilage, a process that interferes with cartilage homeostasis and increases the risk of cartilage degeneration. We showed previously that chondrocyte telomere length declines with donor age, which suggests that the aging process is telomere dependent. From these results we hypothesized that telomerase should delay the onset of senescence in cultured chondrocytes. Population doubling limits (PDL) were determined for chondrocytes expressing telomerase. We found that telomerase alone did not extend PDL beyond controls that senesced after 25 population doublings. The human papillomavirus 16 oncogenes E6 and E7 were transduced into the same cell population to investigate this telomere-independent form of senescence further. Chondrocytes expressing E6 and E7 grew longer than the telomerase cDNA (hTERT) cells but still senesced at 55 population doublings. In contrast, chondrocytes expressing telomerase with E6 and E7 grew vigorously past 100 population doublings. We conclude that although telomerase is necessary for the indefinite extension of chondrocyte life span, telomere-independent senescence limits PDL in vitro and may play a role in the age-related accumulation of senescent chondrocytes in vivo. PMID:11818423

  15. Human papillomavirus and the development of non-melanoma skin cancer.

    PubMed Central

    Harwood, C A; McGregor, J M; Proby, C M; Breuer, J

    1999-01-01

    Human papillomaviruses (HPV) are increasingly recognised as important human carcinogens. The best established association with human malignancy is that of high-risk mucosal HPV types and anogenital cancer. HPV-induced transformation of anogenital epithelia has been the subject of intense research which has identified the cellular tumour suppressor gene products, p53 and pRB, as important targets for the viral oncoproteins E6 and E7 respectively. Certain HPV types are also strongly associated with the development of non-melanoma skin cancer in the inherited disorder epidermodysplasia verruciformis (EV). However, in contrast with anogenital malignancy the oncogenic mechanisms of EV-HPV types remain uncertain, and there appears to be a crucial additional requirement for ultraviolet radiation. Cutaneous HPV types in the general population are predominantly associated with benign viral warts, but a role in non-melanoma skin cancer has recently been postulated. Polymerase chain reaction based HPV detection techniques have shown a high prevalence of HPV DNA, particularly in skin cancers from immunosuppressed patients and to a lesser extent in malignancies from otherwise immunocompetent individuals. No particular HPV type has yet emerged as predominant, and the role of HPV in cutaneous malignancy is unclear at present. It remains to be established whether HPV plays an active or purely a passenger role in the evolution of non-melanoma skin cancer. PMID:10474513

  16. Secreted primary human malignant mesothelioma exosome signature reflects oncogenic cargo.

    PubMed

    Greening, David W; Ji, Hong; Chen, Maoshan; Robinson, Bruce W S; Dick, Ian M; Creaney, Jenette; Simpson, Richard J

    2016-01-01

    Malignant mesothelioma (MM) is a highly-aggressive heterogeneous malignancy, typically diagnosed at advanced stage. An important area of mesothelioma biology and progression is understanding intercellular communication and the contribution of the secretome. Exosomes are secreted extracellular vesicles shown to shuttle cellular cargo and direct intercellular communication in the tumour microenvironment, facilitate immunoregulation and metastasis. In this study, quantitative proteomics was used to investigate MM-derived exosomes from distinct human models and identify select cargo protein networks associated with angiogenesis, metastasis, and immunoregulation. Utilising bioinformatics pathway/network analyses, and correlation with previous studies on tumour exosomes, we defined a select mesothelioma exosomal signature (mEXOS, 570 proteins) enriched in tumour antigens and various cancer-specific signalling (HPGD/ENO1/OSMR) and secreted modulators (FN1/ITLN1/MAMDC2/PDGFD/GBP1). Notably, such circulating cargo offers unique insights into mesothelioma progression and tumour microenvironment reprogramming. Functionally, we demonstrate that oncogenic exosomes facilitate the migratory capacity of fibroblast/endothelial cells, supporting the systematic model of MM progression associated with vascular remodelling and angiogenesis. We provide biophysical and proteomic characterisation of exosomes, define a unique oncogenic signature (mEXOS), and demonstrate the regulatory capacity of exosomes in cell migration/tube formation assays. These findings contribute to understanding tumour-stromal crosstalk in the context of MM, and potential new diagnostic and therapeutic extracellular targets. PMID:27605433

  17. Secreted primary human malignant mesothelioma exosome signature reflects oncogenic cargo

    PubMed Central

    Greening, David W.; Ji, Hong; Chen, Maoshan; Robinson, Bruce W. S.; Dick, Ian M.; Creaney, Jenette; Simpson, Richard J.

    2016-01-01

    Malignant mesothelioma (MM) is a highly-aggressive heterogeneous malignancy, typically diagnosed at advanced stage. An important area of mesothelioma biology and progression is understanding intercellular communication and the contribution of the secretome. Exosomes are secreted extracellular vesicles shown to shuttle cellular cargo and direct intercellular communication in the tumour microenvironment, facilitate immunoregulation and metastasis. In this study, quantitative proteomics was used to investigate MM-derived exosomes from distinct human models and identify select cargo protein networks associated with angiogenesis, metastasis, and immunoregulation. Utilising bioinformatics pathway/network analyses, and correlation with previous studies on tumour exosomes, we defined a select mesothelioma exosomal signature (mEXOS, 570 proteins) enriched in tumour antigens and various cancer-specific signalling (HPGD/ENO1/OSMR) and secreted modulators (FN1/ITLN1/MAMDC2/PDGFD/GBP1). Notably, such circulating cargo offers unique insights into mesothelioma progression and tumour microenvironment reprogramming. Functionally, we demonstrate that oncogenic exosomes facilitate the migratory capacity of fibroblast/endothelial cells, supporting the systematic model of MM progression associated with vascular remodelling and angiogenesis. We provide biophysical and proteomic characterisation of exosomes, define a unique oncogenic signature (mEXOS), and demonstrate the regulatory capacity of exosomes in cell migration/tube formation assays. These findings contribute to understanding tumour-stromal crosstalk in the context of MM, and potential new diagnostic and therapeutic extracellular targets. PMID:27605433

  18. In vitro and in vivo growth suppression of human papillomavirus 16-positive cervical cancer cells by CRISPR/Cas9.

    PubMed

    Zhen, Shuai; Hua, Ling; Takahashi, Y; Narita, S; Liu, Yun-Hui; Li, Yan

    2014-08-01

    Deregulated expression of high-risk human papillomavirus oncogenes (E6 and E7) is a pivotal event for pathogenesis and progression in cervical cancer. Both viral oncogenes are therefore regarded as ideal therapeutic targets. In the hope of developing a gene-specific therapy for HPV-related cancer, we established CRISPR/Cas9 targeting promoter of HPV 16 E6/E7 and targeting E6, E7 transcript, transduced the CRISPR/Cas9 into cervical HPV-16-positive cell line SiHa. The results showed that CRISPR/Cas9 targeting promoter, as well as targeting E6 and E7 resulted in accumulation of p53 and p21 protein, and consequently remarkably reduced the abilities of proliferation of cervical cancer cells in vitro. Then we inoculated subcutaneously cells into nude mice to establish the transplanted tumor animal models, and found dramatically inhibited tumorigenesis and growth of mice incubated by cells with CRISPR/Cas9 targeting (promoter+E6+E7)-transcript. Our results may provide evidence for application of CRISPR/Cas9 targeting HR-HPV key oncogenes, as a new treatment strategy, in cervical and other HPV-associated cancer therapy. PMID:25044113

  19. Stranglehold on the spindle assembly checkpoint: the human papillomavirus E2 protein provokes BUBR1-dependent aneuploidy.

    PubMed

    Tan, Chye Ling; Teissier, Sébastien; Gunaratne, Jayantha; Quek, Ling Shih; Bellanger, Sophie

    2015-01-01

    The Human Papillomavirus (HPV) E2 protein, which inhibits the E6 and E7 viral oncogenes, is believed to have anti-oncogenic properties. Here, we challenge this view and show that HPV-18 E2 over-activates the Spindle Assembly Checkpoint (SAC) and induces DNA breaks in mitosis followed by aneuploidy. This phenotype is associated with interaction of E2 with the Mitotic Checkpoint Complex (MCC) proteins Cdc20, MAD2 and BUBR1. While BUBR1 silencing rescues the mitotic phenotype induced by E2, p53 silencing or presence of E6/E7 (inactivating p53 and increasing BUBR1 levels respectively) both amplify it. This work pinpoints E2 as a key protein in the initiation of HPV-induced cervical cancer and identifies the SAC as a target for oncogenic pathogens. Moreover, our results suggest a role of p53 in regulating the mitotic process itself and highlight SAC over-activation in a p53-negative context as a highly pathogenic event. PMID:25789401

  20. Stranglehold on the spindle assembly checkpoint: the human papillomavirus E2 protein provokes BUBR1-dependent aneuploidy

    PubMed Central

    Tan, Chye Ling; Teissier, Sébastien; Gunaratne, Jayantha; Quek, Ling Shih; Bellanger, Sophie

    2015-01-01

    The Human Papillomavirus (HPV) E2 protein, which inhibits the E6 and E7 viral oncogenes, is believed to have anti-oncogenic properties. Here, we challenge this view and show that HPV-18 E2 over-activates the Spindle Assembly Checkpoint (SAC) and induces DNA breaks in mitosis followed by aneuploidy. This phenotype is associated with interaction of E2 with the Mitotic Checkpoint Complex (MCC) proteins Cdc20, MAD2 and BUBR1. While BUBR1 silencing rescues the mitotic phenotype induced by E2, p53 silencing or presence of E6/E7 (inactivating p53 and increasing BUBR1 levels respectively) both amplify it. This work pinpoints E2 as a key protein in the initiation of HPV-induced cervical cancer and identifies the SAC as a target for oncogenic pathogens. Moreover, our results suggest a role of p53 in regulating the mitotic process itself and highlight SAC over-activation in a p53-negative context as a highly pathogenic event. PMID:25789401

  1. Transcriptional regulation of genes involved in keratinocyte differentiation by human papillomavirus 16 oncoproteins.

    PubMed

    Gyöngyösi, Eszter; Szalmás, Anita; Ferenczi, Annamária; Póliska, Szilárd; Kónya, József; Veress, György

    2015-02-01

    The life cycle of human papillomaviruses (HPVs) is strictly linked to the differentiation of their natural host cells. The HPV E6 and E7 oncoproteins can delay the normal differentiation program of keratinocytes; however, the exact mechanisms responsible for this have not yet been identified. The goal of this study was to investigate the effects of HPV16 oncoproteins on the expression of genes involved in keratinocyte differentiation. Primary human keratinocytes transduced by LXSN (control) retroviruses or virus vectors expressing HPV16 E6, E7 or E6/E7 genes were subjected to gene expression profiling. The results of microarray analysis showed that HPV 16 E6 and E7 have the capacity to downregulate the expression of several genes involved in keratinocyte differentiation. Quantitative real-time polymerase chain reaction (qRT-PCR) assays were performed to confirm the microarray data. To investigate the effects of the HPV oncoproteins on the promoters of selected keratinocyte differentiation genes, luciferase reporter assays were performed. Our results suggest that the HPV 16 E6 and/or E7 oncogenes are able to downregulate the expression of several genes involved in keratinocyte differentiation (such as desmocollin 1, keratin 4, S100 calcium-binding protein A8 and small proline-rich protein 1A), at least partially by downregulating their promoter activity. This activity of the HPV oncoproteins may have a role in the productive virus life cycle, and also in virus-induced carcinogenesis. PMID:25488293

  2. Requirement for Estrogen Receptor Alpha in a Mouse Model for Human Papillomavirus-Associated Cervical Cancer

    PubMed Central

    Chung, Sang-Hyuk; Wiedmeyer, Kerri; Shai, Anny; Korach, Kenneth S.; Lambert, Paul F.

    2008-01-01

    The majority of human cervical cancers are associated with the high-risk human papillomaviruses (HPVs), which encode the potent E6 and E7 oncogenes. Upon prolonged treatment with physiological levels of exogenous estrogen, K14E7 transgenic mice expressing HPV-16 E7 oncoprotein in their squamous epithelia succumb to uterine cervical cancer. Furthermore, prolonged withdrawal of exogenous estrogen results in complete or partial regression of tumors in this mouse model. In the current study we investigated whether estrogen receptor alpha (ERα) is required for the development of cervical cancer in K14E7 transgenic mice. We demonstrate that exogenous estrogen fails to promote either dysplasia or cervical cancer in K14E7/ERα−/− mice despite the continued presence of the presumed cervical cancer precursor cell type, reserve cells, and evidence for E7 expression therein. We also observed that cervical cancers in our mouse models are strictly associated with atypical squamous metaplasia (ASM), which is believed to be the precursor for cervical cancer in women. Consistently, E7 and exogenous estrogen failed to promote ASM in the absence of ERα. We conclude that ERα plays a crucial role at an early stage of cervical carcinogenesis in this mouse model. PMID:19047174

  3. Rat embryo fibroblast cells expressing human papillomavirus 1a genes exhibit altered growth properties and tumorigenicity.

    PubMed Central

    Green, M; Brackmann, K H; Loewenstein, P M

    1986-01-01

    Human papillomavirus 1a (HPV1a) induces benign tumors (papillomas or warts) in humans under natural conditions of infection but has not been found to replicate significantly in cell culture or in experimental animals. To establish model systems to study the oncogenic properties and expression of HPV genes, we established cell lines by cotransfecting the 3Y1 rat fibroblast cell line with HPV1a DNA constructs containing an intact early gene region and the Tn5 neomycin resistance gene. Most cell lines selected for expression of the neomycin resistance gene by treatment with the antibiotic G-418 contained viral DNA in a high-molecular-weight form. The growth characteristics of several cell lines containing high copy numbers of HPV1a DNA were studied further. They were shown to differ from the parental cell line and from G-418-resistant cell lines that did not incorporate viral DNA in the following properties: morphological alteration, increased cell density at confluence, growth in 0.5% serum, efficient anchorage-independent growth in soft agar, and rapid formation of tumors in nude mice. Those cell lines that possessed altered growth properties and tumorigenicity were found to express abundant quantities of polyadenylated virus-specific RNA species in the cytoplasm. Images PMID:3023676

  4. Human papillomavirus in the HIV-infected host: epidemiology and pathogenesis in the antiretroviral era.

    PubMed

    Brickman, Cristina; Palefsky, Joel M

    2015-03-01

    Human papillomavirus (HPV) infection is associated with essentially all cervical cancers, 80-90 % of anal cancers, and a high proportion of oropharyngeal, vaginal, penile, and vulvar cancers. Malignancy is preceded by the development of precancerous lesions termed high-grade squamous intraepithelial lesions (HSIL). Men and women with human immunodeficiency virus (HIV) infection are at high risk of HPV-related malignancies. The incidence of anal cancer in particular has markedly risen during the antiretroviral era due to the increased longevity of patients with HIV and the absence of anal malignancy screening programs. HIV infection may facilitate initial HPV infection by disrupting epithelial cell tight junctions. Once infection is established, HIV may promote HSIL development via the up-regulation of HPV oncogene expression and impairment of the immune response needed to clear the lesion. HIV-infected women should be screened for cervical HSIL and cancer, and HIV-infected men and women should be considered for anal screening programs. PMID:25644977

  5. Deregulation of the miRNAs Expression in Cervical Cancer: Human Papillomavirus Implications

    PubMed Central

    Gómez-Gómez, Yazmín; Organista-Nava, Jorge; Gariglio, Patricio

    2013-01-01

    MicroRNAs (miRNAs) are a class of small non coding RNAs of 18–25 nucleotides in length. The temporal or short-lived expression of the miRNAs modulates gene expression post transcriptionally. Studies have revealed that miRNAs deregulation correlates and is involved with the initiation and progression of human tumors. Cervical cancer (CC) displays notably increased or decreased expression of a large number of cellular oncogenic or tumor suppressive miRNAs, respectively. However, understanding the potential role of miRNAs in CC is still limited. In CC, the high-risk human papillomaviruses (HR-HPVs) infection can affect the miRNAs expression through oncoprotein E6 and E7 that contribute to viral pathogenesis, although other viral proteins might also be involved. This deregulation in the miRNAs expression has an important role in the hallmarks of CC. Interestingly, the miRNA expression profile in CC can discriminate between normal and tumor tissue and the extraordinary stability of miRNAs makes it suitable to serve as diagnostic and prognostic biomarkers of cancer. In this review, we will summarize the role of the HR-HPVs in miRNA expression, the role of miRNAs in the hallmarks of CC, and the use of miRNAs as potential prognostic biomarkers in CC. PMID:24490161

  6. Human papillomavirus vaccine: A boon or curse

    PubMed Central

    Chawla, Sumit; Singh, Inderjeet; Jain, Rambilas; Mehta, Bharti; Kumari, Sneh; Sahoo, Soumya Swaroop

    2015-01-01

    Cervical cancer is the second most common cancer among women worldwide, with about 493,000 new cases diagnosed annually. Of 274,000 deaths due to cervical cancer each year, more than 80% occur in developing countries, and this proportion is expected to increase to 90% by 2020. Up to 70% of sexually active women will become infected with human papilloma virus (HPV) during their lifetime. Even though screening reduces the risk of cervical cancer, it does not prevent HPV infection or development of precancerous lesions which need careful follow-up and often need excision. It was observed in a study, pre-adolescent vaccination alone reduced cancer incidence by 44% and was more effective than screening alone. A combined approach of pre-adolescent vaccination and screening of adult women was more effective than either alone. The high probability of acquiring HPV infection once, one has become sexually active raises the question of whether the vaccine will be effective if given to girls who have already been infected with HPV type 16 or 18. In April 2010, The Indian parliament's Standing Committee on Health, began probing the use of HPV vaccines in 2 states after the reported deaths of 7 girls, and concluded that “safety and rights of children were highly compromised and violated.” Though the question of immunization of older girls and women deserves attention, from a public health perspective, the first priority in resource-poor settings would be to vaccinate young adolescent girls. PMID:25668662

  7. Novel Functions of the Human Papillomavirus E6 Oncoproteins.

    PubMed

    Wallace, Nicholas A; Galloway, Denise A

    2015-11-01

    Human papillomaviruses (HPVs) infect the epidermis as well as mucous membranes of humans. They are the causative agents of anogenital tract and some oropharyngeal cancers. Infections begin in the basal epithelia, where the viral genome replicates slowly along with its host cell. As infected cells begin to differentiate and progress toward the periphery, the virus drives proliferation in cells that would otherwise be quiescent. To uncouple differentiation from continued cellular propagation, HPVs express two oncoproteins, HPV E6 and E7. This review focuses on high-risk α-HPV E6, which in addition to supporting viral replication has transforming properties. HPV E6 promotes p53 degradation and activates telomerase, but the multifaceted oncoprotein has numerous other functions that are highlighted here. PMID:26958922

  8. Papillomavirus E6 proteins

    SciTech Connect

    Howie, Heather L.; Katzenellenbogen, Rachel A.; Galloway, Denise A.

    2009-02-20

    The papillomaviruses are small DNA viruses that encode approximately eight genes, and require the host cell DNA replication machinery for their viral DNA replication. Thus papillomaviruses have evolved strategies to induce host cell DNA synthesis balanced with strategies to protect the cell from unscheduled replication. While the papillomavirus E1 and E2 genes are directly involved in viral replication by binding to and unwinding the origin of replication, the E6 and E7 proteins have auxillary functions that promote proliferation. As a consequence of disrupting the normal checkpoints that regulate cell cycle entry and progression, the E6 and E7 proteins play a key role in the oncogenic properties of human papillomaviruses with a high risk of causing anogenital cancers (HR HPVs). As a consequence, E6 and E7 of HR HPVs are invariably expressed in cervical cancers. This article will focus on the E6 protein and its numerous activities including inactivating p53, blocking apoptosis, activating telomerase, disrupting cell adhesion, polarity and epithelial differentiation, altering transcription and reducing immune recognition.

  9. Optical detection of nanoparticle-enhanced human papillomavirus genotyping microarrays.

    PubMed

    Li, Xue Zhe; Kim, Sookyung; Cho, Wonhyung; Lee, Seung-Yop

    2013-02-01

    In this study, we propose a new detection method of nanoparticle-enhanced human papillomavirus genotyping microarrays using a DVD optical pick-up with a photodiode. The HPV genotyping DNA chip was labeled using Au/Ag core-shell nanoparticles, prepared on a treatment glass substrate. Then, the bio information of the HPV genotyping target DNA was detected by measuring the difference of the optical signals between the DNA spots and the background parts for cervical cancer diagnosis. Moreover the approximate linear relationship between the concentration of the HPV genotyping target DNA and the optical signal depending on the density of Au/Ag core-shell nanoparticles was obtained by performing a spot finding algorithm. It is shown that the nanoparticle-labeled HPV genotyping target DNA can be measured and quantified by collecting the low-cost photodiode signal on the treatment glass chip, replacing high-cost fluorescence microarray scanners using a photomultiplier tube. PMID:23413051

  10. Recent advances in managing human papillomavirus-positive oropharyngeal tumors

    PubMed Central

    Riccio, Stefano; Colombo, Sarah; Pompilio, Madia; Formillo, Paolo

    2010-01-01

    Human papillomavirus (HPV) is detected in a subset of patients with head and neck squamous cell carcinoma, most frequently in tumors in the Waldeyer's ring (palatine tonsil and base of tongue). Several studies suggest that patients with HPV-positive tumors have better survival with either concurrent chemoradiation therapy or surgery followed by radiation compared with HPV-negative patients. However, some possible confounding clinicopathologic variables may challenge the validity of this statement, for example, some authors used the TNM (tumor, node, metastasis) grouping stage while others used the primary tumor (T stage), and other studies have demonstrated that tumors with advanced T stage were less likely to be infected with HPV. A large clinical trial with stratification of patients according to all known tumor prognostic factors is crucial to solve the question. PMID:20948869

  11. Overview: Detection of Human Papillomavirus in Clinical Samples.

    PubMed

    Prakrankamanant, Preeda; Wongsena, Metee

    2016-01-01

    Human papillomavirus (HPV) is the most common sexually-transmitted virus and it is known that persistent infection by high-risk HPV is a necessary factor for cervical carcinogenesis. Although cytological screening has decreased the incidence of cervical cancer, the sensitivity and specificity of testing is limited. To date, HPV-driven molecular techniques have provided a number of potential biomarkers for both diagnostic and prognostic use in clinical management. In addition, they can provide insights into the biology of HPV-induced cancers leading to non-surgical therapy. This review summarizes current knowledge of detection methods for HPV and related biomarkers that can be used to discriminate lesions with a high risk of progression of cervical cancer. PMID:26817243

  12. Malakoplakia of the esophagus caused by human papillomavirus infection.

    PubMed

    Yang, Ya-Li; Xie, Yu-Cheng; Li, Xiao-Ling; Guo, Jing; Sun, Tao; Tang, Jing

    2012-12-01

    Malakoplakia is a rare granulomatous disease probably caused by infection and characterized histologically by Michaelis-Gutmann bodies. We report a more rarely seen case esophageal malakoplakia in a 54-year-old woman. She presented with coughing while eating and drinking. Gastroscopy showed yellow nodules in the esophagus, and endoscopic ultrasonography showed a space-occupying lesion in the substratum of the esophageal mucosa. All findings highly resembled esophageal cancer. Histopathological examination finally indentified this space-occupying lesion as malakoplakia and not cancer. Immunohistochemistry showed that she had human papillomavirus (HPV) infection in the esophagus, which indicates that infection was responsible for the malakoplakia. This is believed to be the first case of malakoplakia in the esophagus, and more importantly, we established that HPV infection was the initiator of esophageal malakoplakia. PMID:23236248

  13. Social representations of human papillomavirus in Bogotá, Colombia.

    PubMed

    Wiesner, Carolina; Acosta, Jesús; Díaz Del Castillo, Adriana; Tovar, Sandra

    2012-01-01

    Identifying DNA of Human papillomavirus (HPV) has been proposed as a new screening method for cervical cancer control. Conventionally, health education for screening programs is based on scientific information without considering any community cognitive processes. We examine HPV social representations of 124 men and women from diverse educational status living in Bogotá, Colombia. The social representation of HPV involves a series of figurative nuclei derived from meanings linked to scientific information. While women focused on symbols associated to contagion, men focused on its venereal character. Figurative nuclei also included long-term uncertainty, need or urgent treatment, and feelings of imminent death associated with cancer and chronic sexually transmitted infections. The social representation of HPV impeded many participants from clearly understanding written information about HPV transmission, clearance, and cancer risk; they are built into a framework of values, which must be deconstructed to allow women full participation in HPV screening programs. PMID:22288472

  14. Young Hispanic Men and Human Papillomavirus Vaccination Choices.

    PubMed

    Thomas, Tami L; Stephens, Dionne P; Johnson-Mallard, Versie; Higgins, Melinda

    2016-03-01

    This exploratory descriptive study examined perceived vulnerabilities to human papillomavirus (HPV) and the correlation to factors influencing vaccine beliefs and vaccine decision making in young Hispanic males attending a large public urban university. Only 24% of participants believed that the HPV vaccine could prevent future problems, and 53% said they would not be vaccinated. The best predictors of HPV vaccination in young Hispanic men were agreement with doctor recommendations and belief in the vaccine's efficacy. Machismo cultural norms influence young Hispanic men's HPV-related decision making, their perceptions of the vaccine, and how they attitudinally act on what little HPV information they have access to. This study provides culturally relevant information for the development of targeted health education strategies aimed at increasing HPV vaccination in young Hispanic men. PMID:24841473

  15. Human papillomavirus tumor infection in esophageal squamous cell carcinoma

    PubMed Central

    Ludmir, Ethan B.; Stephens, Sarah J.; Palta, Manisha; Willett, Christopher G.

    2015-01-01

    The association between human papillomavirus (HPV) and esophageal squamous cell carcinoma (ESCC) has been recognized for over three decades. Recently, multiple meta-analyses have drawn upon existing literature to assess the strength of the HPV-ESCC linkage. Here, we review these analyses and attempt to provide a clinically-relevant overview of HPV infection in ESCC. HPV-ESCC detection rates are highly variable across studies. Geographic location likely accounts for a majority of the variation in HPV prevalence, with high-incidence regions including Asia reporting significantly higher HPV-ESCC infection rates compared with low-incidence regions such as Europe, North America, and Oceania. Based on our examination of existing data, the current literature does not support the notion that HPV is a prominent carcinogen in ESCC. We conclude that there is no basis to change the current clinical approach to ESCC patients with respect to tumor HPV status. PMID:26029456

  16. Progress and prospects for L2-based human papillomavirus vaccines.

    PubMed

    Jiang, Rosie T; Schellenbacher, Christina; Chackerian, Bryce; Roden, Richard B S

    2016-07-01

    Human papillomavirus (HPV) is a worldwide public health problem, particularly in resource-limited countries. Fifteen high-risk genital HPV types are sexually transmitted and cause 5% of all cancers worldwide, primarily cervical, anogenital and oropharyngeal carcinomas. Skin HPV types are generally associated with benign disease, but a subset is linked to non-melanoma skin cancer. Licensed HPV vaccines based on virus-like particles (VLPs) derived from L1 major capsid antigen of key high risk HPVs are effective at preventing these infections but do not cover cutaneous types and are not therapeutic. Vaccines targeting L2 minor capsid antigen, some using capsid display, adjuvant and fusions with early HPV antigens or Toll-like receptor agonists, are in development to fill these gaps. Progress and challenges with L2-based vaccines are summarized. PMID:26901354

  17. The transmembrane channel-like protein family and human papillomaviruses

    PubMed Central

    Horton, Jaime S; Stokes, Alexander J

    2014-01-01

    Epidermodysplasia verruciformis (EV) is a rare genodermatosis characterized by increased sensitivity to infection by the β-subtype of human papillomaviruses (β-HPVs), causing persistent, tinea versicolor-like dermal lesions. In a majority of affected individuals, these macular lesions progress to invasive cutaneous squamous cell carcinoma (CSCC) in sun-exposed areas. While mutations in transmembrane channel-like 6 (TMC6 / EVER1) and 8 (TMC8 / EVER2) have been causally linked to EV, their molecular functions are unclear. It is likely that their protective effects involve regulation of the β-HPV life cycle, host keratinocyte apoptosis vs. survival balance and/or T-cell interaction with infected host cells. PMID:24800179

  18. Human papillomavirus vaccine trials and tribulations: Vaccine efficacy.

    PubMed

    Handler, Nancy S; Handler, Marc Z; Majewski, Slawomir; Schwartz, Robert A

    2015-11-01

    As of December 2014, there were 3 approved vaccines for human papillomavirus (HPV): bivalent Cervarix (GlaxoSmithKline, New York, NY), quadrivalent Gardasil (Merck and Co, Kenilworth, NJ), and 9-valent Gardasil-9 (Merck and Co). The average cost per dose is $120, with a recommended 3-dose course. The quadrivalent vaccine is the most widely administered worldwide. As with the bivalent and 9-valent vaccines, the vaccine is considered safe, although concerns have been raised. In addition to immunization against the targeted HPV types, there is evidence that there is cross protection against other types of HPV. This continuing medical education review evaluates the differences in vaccines that are currently on the market; part II focuses on the cost-effectiveness of vaccination, the HPV vaccination programs currently instituted around the globe, efficacy, and safety. PMID:26475535

  19. The Spanish human papillomavirus vaccine consensus group: a working model.

    PubMed

    Cortés-Bordoy, Javier; Martinón-Torres, Federico

    2010-08-01

    Successful implementation of Human Papillomavirus (HPV) vaccine in each country can only be achieved from a complementary and synergistic perspective, integrating all the different points of view of the diverse related professionals. It is this context where the Spanish HPV Vaccine Consensus Group (Grupo Español de Consenso sobre la Vacuna VPH, GEC-VPH) was created. GEC-VPH philosophy, objectives and experience are reported in this article, with particular attention to the management of negative publicity and anti-vaccine groups. Initiatives as GEC-VPH--adapted to each country's particular idiosyncrasies--might help to overcome the existing barriers and to achieve wide and early implementation of HPV vaccination. PMID:20484987

  20. Human papillomavirus as a target for management, prevention and therapy.

    PubMed

    Crosbie, Emma J; Kitchener, Henry C

    2012-01-01

    The discovery that human papillomavirus (HPV) is the necessary causal factor in cervical carcinogenesis has made it a target for prophylactic and therapeutic vaccines, as well as a diagnostic tool in cervical screening. Whilst prophylactic vaccination has proven very effective in terms of preventing cervical cancer precursor lesions, therapeutic strategies have presented far greater challenges. HPV testing has shown itself to be extremely valuable in the triage of low grade cytological abnormalities, test of cure following treatment of cervical intraepithelial neoplasia (CIN), and will, over the next 10 years, gradually replace cytology as the mainstay of primary cervical screening. In this review, the latest evidence supporting HPV as both a biomarker of risk for cervical cancer and a target for prophylactic and therapeutic vaccination is presented. PMID:22690976

  1. Human papillomavirus status in extragenital nonmelanoma skin cancers.

    PubMed

    Drvar, Daniela Ledic; Lipozenčić, Jasna; Sabol, Ivan; Mokos, Zrinka Bukvic; Ilic, Ivana; Grce, Magdalena

    2014-01-01

    About 5% of all cancers worldwide can be attributed to human papillomaviruses (HPVs); namely, six sites are strongly associated with HPV infections: cervix, penis, vulva, vagina, anus, and oropharynx. Nonmelanoma skin cancers (NMSC), basal cell carcinoma (BCC), and squamous cell carcinoma (SCC) are the most common malignancies in Caucasians. In fact, there is an intense connection between sunlight exposure, fair skin, HPV, and development of NMSC. We have conducted a pilot study that included tissue samples from 26 carcinoma patients, of which there were 13 BCC and 13 SCC. HPV detection and typing was done with DNA amplification and sequencing, respectively. In total, 23.1% of SCC samples (3/13) and 7.7% of BCC samples (1/13) were positive for HPV DNA. The importance of understanding all aspects of NMSC carcinogenesis may be to reveal novel therapeutic options or preventive measures for HPV containing NMSC patients. PMID:24559560

  2. Molecular analysis of human papillomavirus in never-smokers with non-small cell lung cancer

    PubMed Central

    ISA, SHUN-ICHI; KURAHARA, YU; YAMAMOTO, SATOMI; TAMIYA, AKIHIRO; OMACHI, NAOKI; ASAMI, KAZUHIRO; OKISHIO, KYOICHI; UTSUMI, TOMOKI; ITO, NORIMASA; YOON, HYUNG-EUN; MATSUMURA, AKIHIDE; ATAGI, SHINJI; KAWAGUCHI, TOMOYA

    2015-01-01

    The causes of lung cancer in never-smokers remain unclear. The potential contribution of human papillomavirus (HPV) to the carcinogenesis of non-small cell lung cancer (NSCLC) has been reported. In 2008, a prospective registry of never-smokers with NSCLC was established at the Kinki-Chuo Chest Medical Center, Sakai, Osaka, Japan. Never-smokers with NSCLC were consecutively enrolled onto the registry. Of these patients, 114 with large tumor specimens, the majority of which were surgical tissues, were selected. In total, 23 of the most clinically relevant HPV types were assayed using polymerase chain reaction amplification of the viral genome. Following exclusion of samples with suboptimal quality, DNA was extracted from 96 formalin-fixed paraffin-embedded samples. These 96 cases consisted of 82 females (85.4%) and 14 males (14.6%), with a median age of 67 years (range, 29–83). Almost all cases (93.8%) were of the adenocarcinoma histological subtype. Despite confirmation of the quality and amount of DNA, HPV type 6 was detected in only one case (1.1%). Furthermore, no other samples examined were positive for any other HPV types. The results therefore suggest that HPV does not play a major role as the driving oncogenic event in never-smokers with NSCLC. PMID:25621070

  3. YY1 represses human papillomavirus type 16 transcription by quenching AP-1 activity.

    PubMed Central

    O'Connor, M J; Tan, S H; Tan, C H; Bernard, H U

    1996-01-01

    YY1 is a multifunctional transcription factor that has been shown to regulate the expression of a number of cellular and viral genes, including the human papillomavirus (HPV) oncogenes E6 and E7. In this study, we have analyzed the YY1-mediated repression of the HPV type 16 (HPV-16) E6-E7 promoter. A systematic analysis to identify YY1 sites present in the HPV-16 long control region showed that of 30 potential YY1 binding motifs, 24 bound purified recombinant YY1 protein, but only 10 of these were able to bind YY1 when nuclear extracts of HeLa cells were used. Of these, only a cluster of five sites, located in the vicinity of an AP-1 motif, were found to be responsible for repressing the HPV-16 P97 promoter. All five sites were required for repression, the mutation of any one site giving rise to a four- to sixfold increase in transcriptional activity. The target for YY1-mediated repression was identified as being a highly conserved AP-1 site, and we propose that AP-1 may represent a common target for YY1 repression. We also provide data demonstrating that YY1 can bind the transcriptional coactivator CREB-binding protein and propose a potentially novel mechanism by which YY1 represses AP-1 activity as a result of this YY1-CREB-binding protein interaction. PMID:8794287

  4. A comprehensive review on host genetic susceptibility to human papillomavirus infection and progression to cervical cancer

    PubMed Central

    Chattopadhyay, Koushik

    2011-01-01

    Cervical cancer is the second most common cancer in women worldwide. This is caused by oncogenic types of human papillomavirus (HPV) infection. Although large numbers of young sexually active women get HPV-infected, only a small fraction develop cervical cancer. This points to different co-factors for regression of HPV infection or progression to cervical cancer. Host genetic factors play an important role in the outcome of such complex or multifactor diseases such as cervical cancer and are also known to regulate the rate of disease progression. The aim of this review is to compile the advances in the field of host genetics of cervical cancer. MEDLINE database was searched using the terms, ‘HPV’, ‘cervical’, ‘CIN’, ‘polymorphism(s)’, ‘cervical’+ *the name of the gene* and ‘HPV’+ *the name of the gene*. This review focuses on the major host genes reported to affect the progression to cervical cancer in HPV infected individuals. PMID:22345983

  5. Epidemiologic Approaches to Evaluating the Potential for Human Papillomavirus Type Replacement Postvaccination

    PubMed Central

    Tota, Joseph E.; Ramanakumar, Agnihotram V.; Jiang, Mengzhu; Dillner, Joakim; Walter, Stephen D.; Kaufman, Jay S.; Coutlée, François; Villa, Luisa L.; Franco, Eduardo L.

    2013-01-01

    Currently, 2 vaccines exist that prevent infection by the genotypes of human papillomavirus (HPV) responsible for approximately 70% of cervical cancer cases worldwide. Although vaccination is expected to reduce the prevalence of these HPV types, there is concern about the effect this could have on the distribution of other oncogenic types. According to basic ecological principles, if competition exists between ≥2 different HPV types for niche occupation during natural infection, elimination of 1 type may lead to an increase in other type(s). Here, we discuss this issue of “type replacement” and present different epidemiologic approaches for evaluation of HPV type competition. Briefly, these approaches involve: 1) calculation of the expected frequency of coinfection under independence between HPV types for comparison with observed frequency; 2) construction of hierarchical logistic regression models for each vaccine-targeted type; and 3) construction of Kaplan-Meier curves and Cox models to evaluate sequential acquisition and clearance of HPV types according to baseline HPV status. We also discuss a related issue concerning diagnostic artifacts arising when multiple HPV types are present in specific samples (due to the inability of broad-spectrum assays to detect certain types present in lower concentrations). This may result in an apparent increase in previously undetected types postvaccination. PMID:23660798

  6. Transcriptional Repression of E-Cadherin by Human Papillomavirus Type 16 E6

    PubMed Central

    D'Costa, Zarina J.; Jolly, Carol; Androphy, Elliot J.; Mercer, Andrew; Matthews, Charles M.; Hibma, Merilyn H.

    2012-01-01

    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 human papillomavirus (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-2′-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. PMID:23189137

  7. Hypermutation in the E2 gene of human papillomavirus type 16 in cervical intraepithelial neoplasia.

    PubMed

    Kukimoto, Iwao; Mori, Seiichiro; Aoyama, Satoru; Wakae, Kousho; Muramatsu, Masamichi; Kondo, Kazunari

    2015-10-01

    Persistent infection with oncogenic human papillomavirus (HPV) causes cervical cancer. However, viral genetic changes during cervical carcinogenesis are not fully understood. Recent studies have revealed the presence of adenine/thymine-clustered hypermutation in the long control region of the HPV16 genome in cervical intraepithelial neoplasia (CIN) lesions, and suggested that apolipoprotein B mRNA editing enzyme, catalytic polypeptide-like (APOBEC) proteins, which play a key role in innate immunity against retroviral infection, potentially introduce such hypermutation. This study reports for the first time the detection of adenine/thymine-clustered hypermutation in the E2 gene of HPV16 isolated from clinical specimens with low- and high-grade CIN lesions (CIN1/3). Differential DNA denaturation PCR, which utilizes lower denaturation temperatures to selectively amplify adenine/thymine-rich DNA, identified clusters of adenine/thymine mutations in the E2 gene in 4 of 11 CIN1 (36.4%), and 6 of 27 CIN3 (22.2%) samples. Interestingly, the number of mutations per sample was higher in CIN3 than in CIN1. Although the relevance of E2 hypermutation in cervical carcinogenesis remains unclear, the observed hypermutation patterns strongly imply involvement of APOBEC3 proteins in editing the HPV16 genome during natural viral infection. PMID:25914233

  8. A Low Density Microarray Method for the Identification of Human Papillomavirus Type 18 Variants

    PubMed Central

    Meza-Menchaca, Thuluz; Williams, John; Rodríguez-Estrada, Rocío B.; García-Bravo, Aracely; Ramos-Ligonio, Ángel; López-Monteon, Aracely; Zepeda, Rossana C.

    2013-01-01

    We describe a novel microarray based-method for the screening of oncogenic human papillomavirus 18 (HPV-18) molecular variants. Due to the fact that sequencing methodology may underestimate samples containing more than one variant we designed a specific and sensitive stacking DNA hybridization assay. This technology can be used to discriminate between three possible phylogenetic branches of HPV-18. Probes were attached covalently on glass slides and hybridized with single-stranded DNA targets. Prior to hybridization with the probes, the target strands were pre-annealed with the three auxiliary contiguous oligonucleotides flanking the target sequences. Screening HPV-18 positive cell lines and cervical samples were used to evaluate the performance of this HPV DNA microarray. Our results demonstrate that the HPV-18's variants hybridized specifically to probes, with no detection of unspecific signals. Specific probes successfully reveal detectable point mutations in these variants. The present DNA oligoarray system can be used as a reliable, sensitive and specific method for HPV-18 variant screening. Furthermore, this simple assay allows the use of inexpensive equipment, making it accessible in resource-poor settings. PMID:24077317

  9. Activation of miR-9 by human papillomavirus in cervical cancer

    PubMed Central

    Wang, Yuhui; Schwarz, Julie K.; Chen, Jason J.; Grigsby, Perry W.; Wang, Xiaowei

    2014-01-01

    Cervical cancer is the third most common cancer in women worldwide, leading to about 300,000 deaths each year. Most cervical cancers are caused by human papillomavirus (HPV) infection. However, persistent transcriptional activity of HPV oncogenes, which indicates active roles of HPV in cervical cancer maintenance and progression, has not been well characterized. Using our recently developed assays for comprehensive profiling of HPV E6/E7 transcripts, we have detected transcriptional activities of 10 high-risk HPV strains from 87 of the 101 cervical tumors included in the analysis. These HPV-positive patients had significantly better survival outcome compared with HPV-negative patients, indicating HPV transcriptional activity as a favorable prognostic marker for cervical cancer. Furthermore, we have determined microRNA (miRNA) expression changes that were correlated with tumor HPV status. Our profiling and functional analyses identified miR-9 as the most activated miRNA by HPV E6 in a p53-independent manner. Further target validation and functional studies showed that HPV-induced miR-9 activation led to significantly increased cell motility by downregulating multiple gene targets involved in cell migration. Thus, our work helps to understand the molecular mechanisms as well as identify potential therapeutic targets for cervical cancer and other HPV-induced cancers. PMID:25344913

  10. Incidence and clinical management of oral human papillomavirus infection in men: a series of key short messages.

    PubMed

    Videla, Sebastián; Darwich, Laila; Cañadas, MariPaz; Clotet, Bonaventura; Sirera, Guillem

    2014-08-01

    Oral human papillomavirus (HPV) infections are less prevalent than genital and anal infections. However, the incidence of oropharyngeal squamous cell carcinomas has increased significantly over the last 2 decades in several countries. At least 90% of these cancers are associated with oncogenic type HPV16. Oral HPV infections are notably more frequent in men than in women, and the incidence of HPV-positive oropharyngeal squamous cell carcinomas has increased, predominantly among mid-adult men. Nevertheless, little is known about the progression of oral HPV infection to cancer, and it remains unclear which medical interventions should be applied to modify the natural history of the disease. This narrative review aimed at non-experts in HPV infection provides an update on oral HPV infection and its clinical management in men. Furthermore, using the cervix as a reference anatomical site, the lessons learned from investigations on cervical HPV infection are also addressed. PMID:24865412

  11. Home-Based or Clinic-Based Human Papillomavirus (HPV) Screening

    ClinicalTrials.gov

    2016-01-28

    Atypical Squamous Cell of Undetermined Significance; Cervical Carcinoma; Cervical Intraepithelial Neoplasia Grade 2/3; Health Status Unknown; Human Papillomavirus Infection; Low Grade Cervical Squamous Intraepithelial Neoplasia; Stage 0 Cervical Cancer

  12. HPV (Human Papillomavirus) vaccine - what you need to know [Gardasil®-9

    MedlinePlus

    ... is taken in its entirety from the CDC HPV (Human Papillomavirus) Gardasil-9 Vaccine Information Statement (VIS): www.cdc.gov/vaccines/hcp/vis/vis-statements/hpv-gardasil-9.html . CDC review information for HPV ...

  13. Human papillomavirus genotypes in human immunodeficiency virus-positive patients with anal pathology in Madrid, Spain

    PubMed Central

    2013-01-01

    Background We studied anal specimens to determine the distribution of human papillomavirus (HPV) genotypes and co-infection occurrence. This information will contribute to the knowledge of HPV genotype distributions and provide an estimate of the prevalence of different oncogenic HPV genotypes found in patients in Madrid (Spain). Methods We studied a total of 82 anal biopsies from the Hospital General Universitario Gregorio Marañón of Madrid. These included 4 specimens with benign lesions, 52 specimens with low-grade anal squamous intraepithelial lesion, 24 specimens with high-grade anal squamous intraepithelial lesions and 2 specimens with invasive anal carcinoma. HPV genotyping was performed with PCR amplification and reverse dot blot hybridization. Results We detected 33 different HPV genotypes, including 16 HPVs associated with a high risk of carcinogenesis, 3 HPVs associated with a highly likely risk of carcinogenesis and 14 HPVs associated with a low-risk of carcinogenesis. In two specimens, an uncharacterized HPV genotype was detected. The most frequent HPV genotypes found were HPV-16 (10.3%; 95% CI: 6.6%-15.1%), HPV-52 (8.5%; 95% CI: 5.2%-13%) and HPV-43/44 (7.6%; 95% CI: 4.5%-11.9%). HPV-18 was only detected in 0.9% (95% CI: 0.1%-3.2%) of the total viruses detected in all lesions. HPV co-infections were found in 83.9% of all types of lesions. The majority of cases (90.2%) were concomitantly infected with the human immunodeficiency virus (HIV). Conclusion The prevalence of high-risk carcinogenic genotypes in anal pathological samples was remarkable. Therefore, further studies that include a greater number of samples, particularly invasive carcinoma cases are needed to evaluate the potential influence of these HPV genotypes in the appearance of anal carcinomas. Also, the influence of other accompanying infections should be evaluated clarify the appearance of this type of carcinoma. Virtual slides The virtual slide(s) for this article can be found here

  14. Laboratory production in vivo of infectious human papillomavirus type 11

    SciTech Connect

    Kreider, J.W.; Howett, M.K.; Leure-Dupree, A.E.; Zaino, R.J.; Weber, J.A.

    1987-02-01

    Human papillomaviruses (HPV) induce among patients natural lesions which produce small amounts of virus. Infection of human cell cultures does not lead to the multiplication of virus, which also does not replicate in experimental animals. The authors have developed a unique system for the laboratory production of HPV type 11 (HPV-11). Fragments of human neonatal foreskin were infected with an extract of naturally occurring human vulvar condylomata and grafted beneath the renal capsule of athymic mice. Later (3 to 5 months), condylomatous cysts developed from those grafts. Nuclei of koilocytotic cells contained large amounts of capsid antigen and intranuclear virions. The experimentally induced condylomata were homogenized, and the virions were extracted and used to infect another generation of human foreskin grafts in athymic mice. The HPV-11 DNA content and infectivity of the natural and experimental condylomata were similar. Extracts of experimental condylomata were subjected to differential ultracentrifugation and sedimentation in CsCl density gradients. A single, opalescent band was visible at a density of 1.34 g/ml. It contained HPV virions with HPV-11 DNA. This report is the first demonstration of the laboratory production of an HPV.

  15. GENES FOR TUMOR MARKERS ARE CLUSTERED WITH CELLULAR PROTO-ONCOGENES ON HUMAN CHROMOSOMES

    EPA Science Inventory

    The relative mapping positions of genes for polypeptides expressed abnormally in tumors (tumor markers) and cellular proto-oncogenes were analyzed and a remarkable degree of co-mapping of tumor marker genes with oncogenes in the human karyotype were found. It is proposed that abe...

  16. Cloning of monomeric human papillomavirus type 16 DNA integrated within cell DNA from a cervical carcinoma

    SciTech Connect

    Matsukura, T.; Kanda, T.; Furuno, A.; Yoshikawa, H.; Kawana, T.; Yoshiike, K.

    1986-06-01

    The authors have molecularly cloned and characterized monomeric human papillomavirus type 16 DNA with flanking cell DNA sequences from a cervical carcinoma. Determination of nucleotide sequence around the junctions of human papillomavirus and cell DNAs revealed that at the site of integration within cell DNA the cloned viral DNA had a deletion between nucleotides 1284 and 4471 (numbering system from K. Seedorf, G. Kraemmer, M. Duerst, S. Suhai, and W.G. Roewkamp), which includes the greater part of E1 gene and the entire E2 gene. In the remaining part of the E1 gene, three guanines were found at the location where two guanines at nucleotides 1137 and 1138 have been recorded. This additional guanine shifted the reading frame and erased an interruption in the E1 gene. The data strongly suggest that, like other papillomaviruses, human papillomavirus type 16 has an uninterrupted E1 gene.

  17. Use of human papillomavirus vaccine in HIV-infected men for the prevention of anal dysplasia and cancer.

    PubMed

    Cachay, Edward R; Mathews, Wm Christopher

    2014-01-01

    There are two commercially available vaccines licensed worldwide for the prevention of cervical cancer and other human papillomavirus-associated cancers such as anal cancer. However, only two countries have implemented healthcare programs that include human papillomavirus vaccination for boys and men. Although most of the human papillomavirus-related cancers in the world are attributable to cervical cancer, in developed countries anal cancer accounts for a larger proportion of human papillomavirus-related cancers. Most cases of anal cancer occur in HIV-infected men who have sex with men. In this review, we discuss the burden of human papillomavirus-related cancers in men, the most plausible immune mechanism associated with the high efficacy of the human papillomavirus vaccine, and address key issues of vaccination for HIV-infected men. Finally, we review cost-effectiveness considerations for the use of the vaccine in boys and recent guidelines for vaccination in boys, with attention to HIV-infected men. PMID:24818632

  18. Human papillomavirus alters microRNA profiles in squamous cell carcinoma of the head and neck (SCCHN) cell lines

    PubMed Central

    Wald, Abigail I.; Hoskins, Elizabeth E.; Wells, Susanne I.; Ferris, Robert L.; Khan, Saleem A.

    2010-01-01

    Background Human papillomavirus (HPV) positive cases of squamous cell carcinoma of the head and neck (SCCHN) have a much better disease outcome compared to SCCHN cases lacking HPVs. Differences in microRNA (miRNA) expression may affect their clinical outcomes. Methods miRNA expression was studied using microarrays and quantitative RT-PCR in HPV-16 positive and HPV-negative SCCHN cell lines. The role of HPV-16 E6 and E7 oncogenes in altering miRNA expression was investigated using human foreskin keratinocytes (HFKs). Results MiRNAs miR-363, miR-33 and miR-497 were upregulated while miR-155, miR-181a, miR-181b, miR-29a, miR-218, miR-222, miR-221 and miR-142-5p were downregulated in HPV-positive cells compared to both HPV-negative SCCHN and normal oral keratinocytes. HPV-16 E6 oncogene altered miRNA expression in HFKs and in an HPV-16 positive cell line with E6 knockdown using siRNA. Conclusions MiRNAs differentially expressed in the presence of HPV-16 may provide biomarkers for SCCHN and identify cellular pathways targeted by this virus. PMID:20652977

  19. Transforming properties of Felis catus papillomavirus type 2 E6 and E7 putative oncogenes in vitro and their transcriptional activity in feline squamous cell carcinoma in vivo.

    PubMed

    Altamura, Gennaro; Corteggio, Annunziata; Pacini, Laura; Conte, Andrea; Pierantoni, Giovanna Maria; Tommasino, Massimo; Accardi, Rosita; Borzacchiello, Giuseppe

    2016-09-01

    Felis catus papillomavirus type 2 (FcaPV2) DNA is found in feline cutaneous squamous cell carcinomas (SCCs); however, its biological properties are still uncharacterized. In this study, we successfully expressed FcaPV2 E6 and E7 putative oncogenes in feline epithelial cells and demonstrated that FcaPV2 E6 binds to p53, impairing its protein level. In addition, E6 and E7 inhibited ultraviolet B (UVB)-triggered accumulation of p53, p21 and pro-apoptotic markers such as Cleaved Caspase3, Bax and Bak, suggesting a synergistic action of the virus with UV exposure in tumour pathogenesis. Furthermore, FcaPV2 E7 bound to feline pRb and impaired pRb levels, resulting in upregulation of the downstream pro-proliferative genes Cyclin A and Cdc2. Importantly, we demonstrated mRNA expression of FcaPV2 E2, E6 and E7 in feline SCC samples, strengthening the hypothesis of a causative role in the development of feline SCC. PMID:27236740

  20. Epidemiology of mucosal human papillomavirus infection and associated diseases.

    PubMed

    Trottier, Helen; Burchell, Ann N

    2009-01-01

    This article describes the epidemiology of mucosal human papillomavirs (HPV) in adults and children, its mode of transmission and its associated diseases. Over 40 genotypes of HPV infect the epithelial lining of the anogenital tract and other mucosal areas of the body. HPV is the most common sexually transmitted infection globally, with high prevalences found in both females and males. The predominant route of transmission is via sexual contact, although mother-to-child transmission is also possible. HPV infection may exist asymptomatically or may induce the formation of benign or malignant tumours in the genital, oral or conjunctival mucosa. Although most infections clear spontaneously, those that persist result in substantial morbidity and invoke high costs associated with the treatment of clinically relevant lesions. Some 13-18 mucosal HPV types are considered to have high oncogenic potential. HPV is recognized unequivocally as the main causal factor for cervical cancer, and is further responsible for a substantial proportion of many other anogenital neoplasms and head and neck cancers. Infections with HPV types that have low oncogenic risk, such as HPV-6 and 11, are associated with benign lesions of the anogenital areas known as condylomata acuminata (genital warts), oral papillomas, conjunctival papillomas, as well as low-grade squamous intra-epithelial lesions of the cervix. Perinatally acquired HPV can also cause recurrent respiratory papillomatosis in infants and young children. The implementation of HPV vaccination therefore has the potential to prevent a substantial proportion of HPV-related disease in the future. PMID:19684442

  1. Cancerl cells 5. Papillomaviruses

    SciTech Connect

    Steinberg, B.M.; Brandsma, J.L. ); Taichman, L.B. )

    1987-01-01

    This book contains over 30 selections. Some of the titles are: Elements that Control the Transcription of Genital Human Papillomavirus Type 18; Human Paillomavirus Gene Expression; RNA Probes to Analyze Human Papillomavirus Gene Expression in Squamous Papilloma of the Respiratory Tract; Expression of Human Papillomavirus Type-1 E4 Gene Products in Warts; and Underreplication of Human Papillomavirus Type-1 DNA in Cultures of Foreskin Keratinocytes.

  2. CpG methylation in human papillomavirus (HPV) type 31 long control region (LCR) in cervical infections associated with cytological abnormalities.

    PubMed

    László, Brigitta; Ferenczi, Annamária; Madar, László; Gyöngyösi, Eszter; Szalmás, Anita; Szakács, Levente; Veress, György; Kónya, József

    2016-08-01

    The mechanisms that regulate papillomavirus gene expression include DNA methylation. The transcription of papillomavirus oncogenes E6 and E7 is controlled by certain regulatory elements in the LCR, which include binding sites for the E2 protein, a viral regulator of oncogene expression. In HPV-31-infected exfoliated cervical cells, the CpG methylation of the entire LCR was determined by next-generation sequencing after bisulfite modification. Six of the 22 cases had methylated CpG sites in the HPV-31 LCR, including position 7479 and/or 7485, at the promoter distal E2 binding site, thus suggesting a potential regulatory mechanism for papillomavirus transcription. PMID:27098644

  3. Oncogenic roles of carbonic anhydrase 8 in human osteosarcoma cells.

    PubMed

    Wang, Tze-Kai; Lin, Yu-Ming; Lo, Che-Min; Tang, Chih-Hsin; Teng, Chieh-Lin Jerry; Chao, Wei-Ting; Wu, Min Huan; Liu, Chin-San; Hsieh, Mingli

    2016-06-01

    Carbonic anhydrase 8 (CA8), a member of the carbonic anhydrase family, is one of the three isozymes that do not catalyze the reversible hydration of carbon dioxide due to the lack of one important histidine. In the present study, we observed increased expression of CA8 in more aggressive types of human osteosarcoma (OS) cells and found that CA8 expression is correlated with disease stages, such that more intense expression occurs in the disease late stage. We also demonstrated that overexpression of CA8 in human OS (HOS) cells significantly increased cell proliferation both in vitro and in vivo. Downregulated CA8 sensitized cells to apoptotic stress induced by staurosporine and cisplatin, suggesting a specific role of CA8 to protect cells from stresses. In addition, downregulation of CA8 in HOS cells reduced cell invasion and colony formation ability in soft agar and further decreased matrix metalloproteinase 9 and focal adhesion kinase expression, indicating that CA8 might facilitate cancer cell invasion via the activation of FAK-MMP9 signaling. Interestingly, HOS cells with CA8 knockdown showed a significant decrease in glycolytic activity and cell death under glucose withdrawal, further indicating that CA8 may be involved in regulating aerobic glycolysis and enhancing cell viability. Knockdown of CA8 significantly decreased phosphorylated Akt expression suggesting that the oncogenic role of CA8 may be mediated by the regulation of Akt activation through p-Akt induction. Importantly, the inhibition of glycolysis by 2-deoxyglucose sensitized CA8 HOS-CA8-myc cells to cisplatin treatment under low glucose condition, highlighting a new therapeutic option for OS cancer. PMID:26711783

  4. [Natural history of the infection for human papillomavirus: an actualization].

    PubMed

    Martínez, Gerardo González; Troconis, José Núñez

    2014-03-01

    In recent years, there have been major advances in our understanding of the biology and natural history of Human Papilloma Virus (HPV). Most papillomavirus infections are transmitted by close contact of either skin to skin or mucosa to mucosa. Sexual intercourse is not a requirement for genital HPV infection. Digital-oral infections occur and there is evidence that digital-genital and oral-genital contacts can result in the transmission of HPV, although in a relatively low percentage. Vertical transmission from mother to fetus is a common route of infection; in fact, it is recognized that more than 80% of infants born from mothers infected with genital HPV will be positive for HPV DNA determination in the nasal-pharyngeal region and oral mucosa. Women with transient infections often develop cytological abnormalities that take place while there is active HPV replication. This occurs because productive HPV infections result in cytological abnormalities in infected epithelial cells. The strong association between the risk of HPV infection and increased immune suppression, supports a direct biological effect of Human Immunodeficiency Virus (HIV) infection on the natural history of HPV. PMID:24758104

  5. Prevalence of and risk factors for anal human papillomavirus in men having sex with women: A cross–national study

    PubMed Central

    Nyitray, Alan G.; Smith, Dan’elle; Villa, Luisa; Lazcano-Ponce, Eduardo; Abrahamsen, Martha; Papenfuss, Mary; Giuliano, Anna R.

    2010-01-01

    Background While the primary cause of anal cancer is human papillomavirus (HPV) infection in the anal canal, little attention has been paid to the epidemiology of anal HPV in men having sex with women (MSW). Methods Anal canal exfoliated cells from 903 MSW in Brazil (São Paulo), Mexico (Cuernavaca) and the United States (Tampa) were tested for HPV DNA. Results HPV prevalence in the anal canal (12.0%) was similar in MSW in each city (P=0.77) while 7.0% had oncogenic types. Men in Tampa had a four–fold higher prevalence of HPV 16 than men in São Paulo or Cuernavaca (P<0.001). Duration of relationship with a primary sex partner and ever having oral or anal sex with a man was associated with any HPV type and any oncogenic type while lifetime number of female sex partners was associated with any HPV type. Conclusions Anal canal HPV is commonly found in MSW and the prevalence of HPV 16 may differ substantially by geography. Men with a larger number of female sex partners, in a sexual relationship of <1 year duration, and with a history of oral or anal sex with men were most likely to have an anal HPV infection. PMID:20367457

  6. Prevalence and concordance of human papillomavirus infection at multiple anatomic sites among HIV-infected women from Chennai, India.

    PubMed

    Menezes, Lynette J; Poongulali, Selvamuthu; Tommasino, Massimo; Lin, Hui-Yi; Kumarasamy, Nagalingeswaran; Fisher, Kate J; Saravanan, Shanmugam; Gheit, Tarik; Ezhilarasi, Chandrasekaran; Jeeva, Arumugham; Lu, Beibei; Giuliano, Anna R

    2016-06-01

    Human papillomavirus (HPV) infection at the cervix, anus and oropharynx has been rarely concurrently estimated among HIV-infected women. Using multiplex polymerase chain reaction testing, we prospectively evaluated HPV genotype distribution across three anatomic sites among 50 eligible HIV-infected women from Chennai, India, who provided biological specimens and answered a sexual behaviour questionnaire. We also assessed clinical and behavioural factors related to HPV prevalence. Oncogenic HPV prevalence was comparable between the anus and cervix at 52.2% and 52.0% and lower at the oropharynx at 13.2%; 78% of women with a cervical HPV infection had the same type in the anus. Newly acquired oncogenic HPV infections were lower at cervix (24%) than anus (35%) at three months. 'Any type' cervical HPV prevalence was higher among women with low education and less than five years since HIV diagnosis. CD4+ count and antiretroviral therapy status were not associated with HPV prevalence at the three anatomic sites; however, enrolment cervical HPV16 prevalence was elevated among women with nadir CD4+ <200 cells/µL and enrolment CD4+ <350 cells/µL. Regular cervical screening is essential in HIV-infected Indian women irrespective of CD4+ count and antiretroviral therapy status. Additional research clarifying the natural history of anal HPV infection is also needed in this population. PMID:26002318

  7. Association between Toll-like Receptors expression and Human Papillomavirus Type 16 Persistence

    PubMed Central

    Daud, Ibrahim I.; Scott, Mark E.; Ma, Yifei; Shiboski, Stephen; Farhat, Sepideh; Moscicki, Anna-Barbara

    2010-01-01

    The mechanisms involved in mucosal immune control of cervical human papillomavirus (HPV) infection remain ill-defined. Because Toll-like receptors (TLRs) are key players in innate immune responses, we investigated the association between TLR expression and viral persistence or clearance in young women with incident infections with oncogenic HPV types 16 or 51. Messenger RNA expression of TLR1, TLR2, TLR3, TLR4, TLR6, TLR7, TLR8, and TLR9 was measured by quantitative reverse transcription-PCR using human endocervical specimens, collected before and following viral acquisition, in a cohort well characterized for HPV infections. Wilcoxon rank sum test was used to compare the change seen from pre-infection to incident infection between women who subsequently cleared infection with those who did not. HPV 16 infections that cleared were significantly (P < 0.05) associated with an increase in expression of the four viral nucleic acid-sensing TLRs (TLR3, TLR7, TLR8 and TLR9) as well as TLR2 upon viral acquisition. Similar associations were not observed for HPV 51. In women who subsequently cleared their HPV 16 infection, changes in TLR1, TLR3, TLR7, and TLR8 expression levels between pre-incident and incident visits were significantly correlated with parallel changes in the levels of interferon-α2, measured by immunoassay in cervical lavage specimens. This study suggests that dampened TLR expression in the cervical mucosa is a type-specific mechanism by which HPV 16 interferes with innate immune responses, contributing to viral persistence, and that TLR upregulation and resultant cytokine induction is important in subsequent viral clearance. PMID:20473890

  8. Risk of human papillomavirus-related cancers among kidney transplant recipients and patients receiving chronic dialysis - an observational cohort study

    PubMed Central

    2013-01-01

    Background Individuals with end-stage renal disease (ESRD) have excess risk of various cancer types. However, the total burden of human papillomavirus-related cancers remains unknown. Methods We performed a nationwide observational cohort study during 1994–2010. For each person with ESRD, we sampled 19 population controls (without ESRD) matched on age, gender and municipality. Participants were followed until first diagnosis of human papillomavirus-related cancer, death, emigration, or 31 December 2010, whichever came first. Human papillomavirus-related cancers were extracted from Danish medical administrative databases. We considered cancers of the cervix, vulva, vagina, penis, anus, and subsets of head and neck cancers as human papillomavirus-related. We calculated incidence rates of human papillomavirus-related cancer and used Poisson regression to identify risk factors for human papillomavirus-related cancer. Results Among 12,293 persons with ESRD and 229,524 population controls we identified 62 and 798 human papillomavirus-related cancers, respectively. Incidence rates of human papillomavirus-related- cancer were 102 per 100,000 person-years (95% confidence interval [CI]; 79.5-131) among persons with ESRD and 40.8 per 100,000 person-years (95% CI; 38.1-43.7) among population controls. ESRD patients had 4.54 (95% CI, 2.48-8.31) fold increased risk of anal cancer and 5.81 fold (95% CI; 3.36-10.1) increased risk of vulvovaginal cancer. Adjusted for age, comorbidity, and sex, ESRD patients had 2.41 (95% CI; 1.83-3.16) fold increased risk of any human papillomavirus-related cancer compared with population controls. Compared with dialysis patients renal transplant recipients had an age-adjusted non-significant 1.53 (95% CI, 0.91-2.58) fold higher risk of human papillomavirus-related cancer. Conclusions Persons with ESRD have excess risk of potentially vaccine-preventable human papillomavirus-related cancers. PMID:23834996

  9. Adeno-associated virus type 2 rep protein inhibits human papillomavirus type 16 E2 recruitment of the transcriptional coactivator p300.

    PubMed

    Marcello, A; Massimi, P; Banks, L; Giacca, M

    2000-10-01

    Infection by human adeno-associated virus type 2 (AAV2) is a possible protective factor in the development of cervical carcinomas associated with human papillomaviruses (HPV). The replicative proteins of AAV2 (Rep) have been implicated in the inhibition of papillomavirus replication and transforming activities, although the molecular events underlying these effects are poorly understood. We observed that each of the four forms of AAV2 Rep inhibited the E1- and E2-driven replication of oncogenic HPV type 16 (HPV16). Rep40, corresponding to the C-terminal domain of all Rep proteins, inhibited both HPV DNA replication and HPV16 E2-mediated transactivation. Rep40 specifically bound the N-terminal transactivation domain of HPV16 E2 both in vitro and in vivo. This interaction was found to specifically disrupt the binding of E2 to the cellular transcriptional coactivator p300. Accordingly, the inhibitory effect of Rep on HPV16 E2 transactivation was rescued by the overexpression of p300. These data indicate a novel role of Rep in the down-regulation of papillomaviruses through inhibition of complex formation between the HPV16 E2 transcriptional activator and its cellular coactivator, p300. PMID:10982355

  10. Trials and projects on cervical cancer and human papillomavirus prevention in sub-Saharan Africa.

    PubMed

    Adefuye, Peter O; Broutet, Nathalie J; de Sanjosé, Silvia; Denny, Lynette A

    2013-12-29

    Cervical cancer is the leading cause of cancer morbidity and mortality in women in sub-Saharan Africa (SSA), accounting for about 50,000 deaths annually. Until recently, cytology was the gold standard for screening and prevention of cervical cancer. This method of screening has not been successful in SSA due to a lack of human, financial and material resources and poor health care infrastructure. It is estimated that less than 5% of at risk women have ever being screened. In the past two decades alternative approaches to cytology for cervical cancer screening have been evaluated in low- and medium-income countries. Visual inspection with acetic acid (VIA) and/or Lugol's iodine (VILI) have been shown to have adequate sensitivity, although low specificity, in a number of cross-sectional research and demonstration projects. Visual inspection methods require minimal resources, are technologically accessible, and are feasible for screening for precancerous lesions. Linking screening with VIA/VILI to treatment with cryotherapy may enable screening and treatment to take place in one visit, but this is likely to result in large numbers of women being subjected to unnecessary treatment. A number of studies have shown that cryotherapy is not associated with significant side effects or complications and is well tolerated. Creating the infrastructure for screening of older women is considered desirable, despite the limitations of visual inspection methods as screening tests. Understanding the role of human papillomavirus (HPV) infection in the etiology of cervical cancer and the discovery of HPV rapid test kits, as well as the development of vaccines against the HPV oncogenic types, have created new opportunities for prevention of cervical cancer. Trials and projects have established (and are still ongoing) the feasibility of using these molecular tests for screening. The ultimate in prevention method is primary prevention, offered by the advent of prophylactic vaccines

  11. Human Papillomavirus Type 18 E6 and E7 Genes Integrate into Human Hepatoma Derived Cell Line Hep G2

    PubMed Central

    Ma, Tianzhong; Su, Zhongjing; Chen, Ling; Liu, Shuyan; Zhu, Ningxia; Wen, Lifeng; Yuan, Yan; Lv, Leili; Chen, Xiancai; Huang, Jianmin; Chen, Haibin

    2012-01-01

    Background and Objectives Human papillomaviruses have been linked causally to some human cancers such as cervical carcinoma, but there is very little research addressing the effect of HPV infection on human liver cells. We chose the human hepatoma derived cell line Hep G2 to investigate whether HPV gene integration took place in liver cells as well. Methods We applied PCR to detect the possible integration of HPV genes in Hep G2 cells. We also investigated the expression of the integrated E6 and E7 genes by using RT-PCR and Western blotting. Then, we silenced E6 and E7 expression and checked the cell proliferation and apoptosis in Hep G2 cells. Furthermore, we analyzed the potential genes involved in cell cycle and apoptosis regulatory pathways. Finally, we used in situ hybridization to detect HPV 16/18 in hepatocellular carcinoma samples. Results Hep G2 cell line contains integrated HPV 18 DNA, leading to the expression of the E6 and E7 oncogenic proteins. Knockdown of the E7 and E6 genes expression reduced cell proliferation, caused the cell cycle arrest at the S phase, and increased apoptosis. The human cell cycle and apoptosis real-time PCR arrays analysis demonstrated E6 and E7-mediated regulation of some genes such as Cyclin H, UBA1, E2F4, p53, p107, FASLG, NOL3 and CASP14. HPV16/18 was found in only 9% (9/100) of patients with hepatocellular carcinoma. Conclusion Our investigations showed that HPV 18 E6 and E7 genes can be integrated into the Hep G2, and we observed a low prevalence of HPV 16/18 in hepatocellular carcinoma samples. However, the precise risk of HPV as causative agent of hepatocellular carcinoma needs further study. PMID:22655088

  12. Detection and typing of common human papillomaviruses among Jordanian patients.

    PubMed

    Al Bdour, Suzan; Akkash, Laith; Shehabi, Asem A

    2013-06-01

    The epidemiology of human papillomaviruses (HPVs) genotype distribution of cutaneous warts in Jordanian patients were studied. A total of 200 samples were collected using skin swabs from patients with warts attending the dermatology clinic at the Jordan University Hospital over the period of June 2010 to October 2010. Another 100 control samples were taken from healthy Jordanian individuals with no current or previous history of warts. DNA extraction and sequencing was carried out using PCR with the FAP primer pair to detect HPV DNA, followed by multiple-type-specific (Multiplex) PCR combined with DNA sequencing. The prevalence of HPV among Jordanian patients tested with warts diagnosed clinically was 82% (157/192); of these 45% (87/192) were detected by FAP PCR method, and 37% (70/192) were detected by multiplex PCR method. Sequencing of the FAP positive samples shows that HPV 2 was associated with the highest prevalence (36%), followed by HPV 27 (28%) and HPV 57 (21%). A total of 6% of healthy persons were positive for HPV DNA. In conclusion, this study demonstrates that alpha HPV types (HPV 2, HPV 27, and HPV 57) are associated with the most prevalent cutaneous warts in Jordanian patients. PMID:23588732

  13. Amplification of human papillomavirus DNA sequences by using conserved primers.

    PubMed Central

    Gregoire, L; Arella, M; Campione-Piccardo, J; Lancaster, W D

    1989-01-01

    The polymerase chain reaction has potential for use in the detection of small amounts of human papillomavirus (HPV) viral nucleic acids present in clinical specimens. However, new HPV types for which no probes exist would remain undetected by using type-specific primers for the polymerase chain reaction before hybridization. Primers corresponding to highly conserved HPV sequences may be useful for detecting low amounts of known HPV DNA as well as new HPV types. Here we analyze a pair of primers derived from conserved sequences within the E1 open reading frame for HPV sequence amplification by using the polymerase chain reaction. The longest perfect homology among HPV sequences is a 12-mer within the first exon of E1M. A region of conserved amino acids coded by the E1 open reading frame allowed the detection of another highly conserved region about 850 base pairs downstream. Two 21-mers derived from these conserved regions were used to amplify sequences from all HPV DNAs used as templates. The amplified DNA was shown to be specific for HPV sequences within the E1 open reading frame. DNA from HPVs whose sequences were not available were amplified by using these two primers. HPV DNA sequences in clinical specimens could also be amplified with the primers. Images PMID:2556429

  14. Human papillomavirus infections in nonsexually active perinatally HIV infected children.

    PubMed

    Moscicki, Anna-Barbara; Puga, Ana; Farhat, Sepideh; Ma, Yifei

    2014-02-01

    Although human papillomavirus (HPV) infections are common in HIV-infected adults, little is known about children. Our objective was to examine the prevalence of and risks for HPV of the oral mucosal and external genital areas in nonsexually active (NSA) perinatally (P) HIV+ children and compare with HIV-exposed but uninfected (HEU) children. A convenience sample attending a pediatric clinic were enrolled. Samples for HPV were obtained from the oral and anogenital areas and tested for one of 37 HPV types. The mean age of the 48 PHIV+ children was 14.3±3.9 years vs. 6.2±4.8 for the 52 HEU (p<0.001). Of the 23 PHIV+ girls, 30.4% had anogenital and 17% had oral HPV, and of the 27 HEU girls, 2 (7.4%) anogenital and 0 had oral HPV. Of the boys, 4/23 (17.4%) and 1/25 (4%) PHIV+ had anogenital and oral HPV, respectively, and 3/24 (12.5%) and 1/25 (4%) HEU had anogenital and oral HPV, respectively. Rates of HPV did not differ by age among the PHIV+, whereas older HEU were more likely to have HPV than younger HEU (p=0.07). This large age gap precluded statistical comparison by HIV status. The presence of HPV in NSA PHIV+ children may have implications regarding HPV vaccination efficacy. PMID:24460009

  15. Target Cell Cyclophilins Facilitate Human Papillomavirus Type 16 Infection

    PubMed Central

    Sapp, Martin

    2009-01-01

    Following attachment to primary receptor heparan sulfate proteoglycans (HSPG), human papillomavirus type 16 (HPV16) particles undergo conformational changes affecting the major and minor capsid proteins, L1 and L2, respectively. This results in exposure of the L2 N-terminus, transfer to uptake receptors, and infectious internalization. Here, we report that target cell cyclophilins, peptidyl-prolyl cis/trans isomerases, are required for efficient HPV16 infection. Cell surface cyclophilin B (CyPB) facilitates conformational changes in capsid proteins, resulting in exposure of the L2 N-terminus. Inhibition of CyPB blocked HPV16 infection by inducing noninfectious internalization. Mutation of a putative CyP binding site present in HPV16 L2 yielded exposed L2 N-terminus in the absence of active CyP and bypassed the need for cell surface CyPB. However, this mutant was still sensitive to CyP inhibition and required CyP for completion of infection, probably after internalization. Taken together, these data suggest that CyP is required during two distinct steps of HPV16 infection. Identification of cell surface CyPB will facilitate the study of the complex events preceding internalization and adds a putative drug target for prevention of HPV–induced diseases. PMID:19629175

  16. A review of methods for detect human Papillomavirus infection

    PubMed Central

    2012-01-01

    Human Papillomavirus (HPV) is the most common sexually transmitted virus. Worldwide, the most common high-risk (HR)-HPV are -16/18, and approximately 70% of cervical cancers (CC) are due to infection by these genotypes. Persistent infection by HR-HPV is a necessary but not sufficient cause of this cancer, which develops over a long period through precursor lesions, which can be detected by cytological screening. Although this screening has decreased the incidence of CC, HPV-related cervical disease, including premalignant and malignant lesions, continues to be a major burden on health-care systems. Although not completely elucidated, the HPV-driven molecular mechanisms underlying the development of cervical lesions have provided a number of potential biomarkers for both diagnostic and prognostic use in the clinical management of women with HPV-related cervical disease, and these biomarkers can also be used to increase the positive predictive value of current screening methods. In addition, they can provide insights into the biology of HPV-induced cancer and thus lead to the development of nonsurgical therapies. Considering the importance of detecting HPV and related biomarkers, a variety of methods are being developed for these purposes. This review summarizes current knowledge of detection methods for HPV, and related biomarkers that can be used to discriminate lesions with a high risk of progression to CC. PMID:23131123

  17. Human papillomavirus variants among Inuit women in northern Quebec, Canada

    PubMed Central

    Gauthier, Barbara; Coutlée, Francois; Franco, Eduardo L.; Brassard, Paul

    2015-01-01

    Background Inuit communities in northern Quebec have high rates of human papillomavirus (HPV) infection, cervical cancer and cervical cancer–related mortality as compared to the Canadian population. HPV types can be further classified as intratypic variants based on the extent of homology in their nucleotide sequences. There is limited information on the distribution of intratypic variants in circumpolar areas. Objective Our goal was to describe the HPV intratypic variants and associated baseline characteristics. Design We collected cervical cell samples in 2002–2006 from 676 Inuit women between the ages of 15 and 69 years in Nunavik. DNA isolates from high-risk HPVs were sequenced to determine the intratypic variant. Results There were 149 women that were positive for HPVs 16, 18, 31, 33, 35, 45, 52, 56 or 58 during follow-up. There were 5 different HPV16 variants, all of European lineage, among the 57 women positive for this type. There were 8 different variants of HPV18 present and all were of European lineage (n=21). The majority of samples of HPV31 (n=52) were of lineage B. The number of isolates and diversity of the other HPV types was low. Age was the only covariate associated with HPV16 variant category. Conclusions These frequencies are similar to what was seen in another circumpolar region of Canada, although there appears to be less diversity as only European variants were detected. This study shows that most variants were clustered in one lineage for each HPV type. PMID:26653084

  18. [Cervical infection epidemiology of human papillomavirus in Ushuaia, Argentina].

    PubMed

    Sijvarger, C C; González, J V; Prieto, A; Messmer, A G; Mallimaci, M C; Alonio, V L; Teyssié, A R; Picconi, M A

    2006-01-01

    Genital infection with human papillomavirus (HPV) is decisive in the causation of cervical cancer. In order to evaluate the epidemiology of HPV infection in Ushuaia, Province of Tierra del Fuego, Argentina, 132 endocervical cytobrushes from preneoplastic and neoplastic cases and controls were studied. Detection and typing of the viral genome was performed by polymerase chain reaction, combined with a restriction fragment length polymorphism assay or hybridization. The overall prevalence of HPV infection was 41% in the population examined, with a frequency of 26% in the controls and 71% in the cases under study. The 14-24 age group showed the highest HPV prevalence. The most common viral types in the infected population were HPV 16 (23%), HPV 18 (11%), HPV 33 (8%) and HPV 35 (8%), while high risk viral types were detected in 30% of the samples, 16% of the controls and 60% of the cases. This study provides the first data on the predominant viral types in Ushuaia. Our results show lower levels of infection than in regions with a high incidence of cervical cancer, HPV 16 being the most prevalent viral type. This research may be useful for selecting a specific vaccine targeting the population examined. PMID:16784128

  19. Immunogenicity of quadrivalent human papillomavirus vaccine in organ transplant recipients.

    PubMed

    Kumar, D; Unger, E R; Panicker, G; Medvedev, P; Wilson, L; Humar, A

    2013-09-01

    Solid organ transplant recipients are at risk of morbidity from human papillomavirus (HPV)-related diseases. Quadrivalent HPV vaccine is recommended for posttransplant patients but there are no data on vaccine immunogenicity. We determined the immunogenicity of HPV vaccine in a cohort of young adult transplant patients. Patients were immunized with three doses of quadrivalent HPV vaccine containing viral types 6, 11, 16 and 18. Immunogenicity was determined by type-specific viral-like protein ELISA. Four weeks after the last dose of vaccine, a vaccine response was seen in 63.2%, 68.4%, 63.2% and 52.6% for HPV 6, 11, 16 and 18, respectively. Factors that led to reduced immunogenicity were vaccination early after transplant (p = 0.019), having a lung transplant (p = 0.007) and having higher tacrolimus levels (p = 0.048). At 12 months, there were significant declines in antibody titer for all HPV types although the number of patients who remained seropositive did not significantly differ. The vaccine was safe and well tolerated. We show suboptimal immunogenicity of HPV vaccine in transplant patients. This is important for counseling patients who choose to receive this vaccine. Further studies are needed to determine an optimal HPV vaccine type and schedule for this population. PMID:23837399

  20. Argentina's Successful Implementation Of A National Human Papillomavirus Vaccination Program.

    PubMed

    Patel, Hannah; Wilson, Ellen; Vizzotti, Carla; Parston, Greg; Prestt, Jessica; Darzi, Ara

    2016-02-01

    Every year around fourteen million people globally are infected with human papillomavirus (HPV), the sexually transmitted virus that is the cause of most cervical cancers. A number of vaccines have been developed to protect against HPV, but in many countries, HPV vaccination rates have been low compared with rates for other recommended vaccines. Parental concerns, cost, and lack of information and awareness among both health professionals and parents are cited as important barriers to HPV vaccination. In Argentina the HPV vaccine has been provided to all eleven-year-old girls since 2011 as part of a comprehensive national program to prevent cervical cancer. Coverage increased from negligible levels before 2011 to a national average of 87.9 percent for the first dose, 71.6 percent for the second dose, and 52.2 percent for the third dose in 2013. There was a large variance in HPV vaccine coverage across the country's provinces. This article describes key strategies to overcome barriers to implementation of HPV vaccination and provides recommendations for policy makers. PMID:26858384

  1. Human Papillomavirus in Brazilian women with and without cervical lesions

    PubMed Central

    2011-01-01

    Background Human Papillomavirus (HPV) high-risk (HR) types are the causal factor for cervical cancer and premalignant dysplasia. Data on frequency of HPV types provide a basis to design and evaluate HPV prevention programs. Taking into account the heterogeneity of HPV types across and within populations this study aims to access the HPV frequency in Brazilian women. Results We identified 24 different types of HPV, including a Betapapillomavirus and a likely new type, previously reported, from 132 women positive for the virus analysed by Hybrid Capture II assay. These women were infected by a single or multiple HPV types and 142 HPV strains were identified. HR types were found in 75% of women and HPV types 16, 18, 45, 58, and 66 had the highest frequency. Significant differences in frequency of HR HPV types were found for presence of cervical lesions, and for different HPV species and women age. Conclusions Compared with previous studies in Brazil, our data indicated differences in frequency and HPV type diversity, a significant association of other HR-types but HPV16 and 18 and cervical lesions, and a trend for distinct distribution of HPV types by age. PMID:21208414

  2. Gnathic and peripheral ameloblastomas lack human papillomavirus DNA.

    PubMed

    Verduin, Lindsey; Bishop, Justin; Mills, Stacey E

    2015-10-01

    Human papillomavirus (HPV) has been associated with a variety of head and neck neoplasms, including squamous cell carcinomas and Schneiderian papillomas. Ameloblastomas can arise from either the gnathic bones or peripheral soft tissues. Peripheral sinonasal ameloblastomas share clinical features with Schneiderian papillomas. A small number of reports have described detection of HPV DNA within ameloblastomas. However, Most of these cases was reported in the 1990s, used the polymerase chain reaction technique, and only examined gnathic tumors. The current study was designed to determine whether low- or high-risk HPV DNA could be detected in gnathic or peripheral ameloblastomas using in situ hybridization. Twenty-nine examples of gnathic osseous and peripheral head and neck ameloblastomas were obtained from the authors' archives (University of Virginia and the Johns Hopkins Hospital). High-risk HPV DNA was not detected in any of the 29 tumors analyzed. Low-risk HPV DNA was identified in only 1 tumor, which was peripheral in origin, and from an immunocompromised patient. We believe that the HPV in this case represents a background "passenger" infection. This study demonstrates that HPV of either high- or low-risk subtypes is unlikely to play a role in the pathogenesis of sinonasal ameloblastomas. PMID:26190154

  3. Therapeutic vaccines against human papillomavirus and cervical cancer.

    PubMed

    Cid-Arregui, Angel

    2009-01-01

    Cervical cancer and its precursor intra-epithelial lesions are linked to infection by a subset of so-called "highrisk" human papillomavirus types, which are estimated to infect nearly four hundred million women worldwide. Two prophylactic vaccines have been commercialized recently targeting HPV16 and 18, the most prevalent viral types found in cervical cancer, which operate through induction of capsid-specific neutralizing antibodies. However, in patients with persistent infection these vaccines have not been found to protect against progression to neoplasia. Attempts are being made to develop therapeutic vaccines targeting nonstructural early viral proteins. Among these, E6 and E7 are the preferred targets, since they are essential for induction and maintenance of the malignant phenotype and are constitutively expressed by the transformed epithelial cells. Here are reviewed the most relevant potential vaccines based on HPV early antigens that have shown efficacy in preclinical models and that are being tested in clinical studies, which should determine their therapeutic capacity for eradicating HPV-induced premalignant and malignant lesions and cure cervical cancer. PMID:19915722

  4. Correlates of human papillomavirus vaccine completion among adolescent girl initiators

    PubMed Central

    Rahman, Mahbubur; Laz, Tabassum H.; McGrath, Christine J.; Berenson, Abbey B.

    2016-01-01

    OBJECTIVE To examine correlates of vaccine series completion among young adolescent US girls who initiated the human papillomavirus (HPV) vaccine. METHODS We analyzed National Immunization Survey-Teens 2012 provider-verified data to examine correlates of HPV vaccine completion among 13-17 year old girls who initiated HPV vaccine in 2012 (N=4,548). RESULTS The weighted vaccine series completion rate among 13-17 year old girl initiators was 66.7% (95% confidence interval (CI), 64.0-69.3). Adolescent girls who were older, residents of the Northeast (adjusted prevalence ratio (aPR) 1.36, 95% CI 1.07-1.73), and had provider-verified seasonal influenza vaccination in the past year (aPR 1.67, 95% CI 1.32-2.11) and provider recommendation (aPR 1.40, 95% CI 1.10-1.77) were more likely to complete the 3-dose vaccine series. CONCLUSIONS Parents of younger adolescent girls need to be educated about the importance of completing the 3-dose HPV vaccine series. Provider recommendation for the vaccine would also facilitate series completion. PMID:25848128

  5. Adolescent Premature Ovarian Insufficiency Following Human Papillomavirus Vaccination

    PubMed Central

    Ward, Harvey Rodrick Grenville

    2014-01-01

    Three young women who developed premature ovarian insufficiency following quadrivalent human papillomavirus (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. PMID:26425627

  6. Lessons from the failure of human papillomavirus vaccine state requirements.

    PubMed

    Schwartz, J L; Caplan, A L; Faden, R R; Sugarman, J

    2007-12-01

    The licensure in 2006 of a vaccine against the subtypes of human papillomavirus (HPV) responsible for the majority of cervical cancers and genital warts was heralded as a watershed moment for vaccination, cancer prevention, and global health. A safe and effective vaccine against HPV has long been viewed as an enormous asset to cervical cancer prevention efforts worldwide. This is particularly true for places lacking robust Pap screening programs where cervical cancer has the greatest prevalence and mortality. Well before its licensure, however, some observers noted significant obstacles that would need to be addressed in order for an HPV vaccination program to succeed. These included the vaccine's relatively high cost, availability, and opposition from socially conservative groups. Such concerns associated with the implementation of HPV vaccination were soon overwhelmed by the furor that followed the unexpectedly early efforts by the US state governments to require the vaccine as a condition of attendance in public schools, proposals imprecisely referred to as "mandates." In this study, we review the controversy surrounding this debate and its effects on important ethical and public health issues that still need to be addressed. PMID:17971822

  7. Human Papillomavirus Infection, Infertility, and Assisted Reproductive Outcomes

    PubMed Central

    Pereira, Nigel; Kucharczyk, Katherine M.; Estes, Jaclyn L.; Gerber, Rachel S.; Lekovich, Jovana P.; Elias, Rony T.; Spandorfer, Steven D.

    2015-01-01

    The human papillomavirus (HPV) is a sexually transmitted infection common among men and women across all geographic and socioeconomic subgroups worldwide. Recent evidence suggests that HPV infection may affect fertility and alter the efficacy of assisted reproductive technologies. In men, HPV infection can affect sperm parameters, specifically motility. HPV-infected sperm can transmit viral DNA to oocytes, which may be expressed in the developing blastocyst. HPV can increase trophoblastic apoptosis and reduce the endometrial implantation of trophoblastic cells, thus increasing the theoretical risk of miscarriage. Vertical transmission of HPV during pregnancy may be involved in the pathophysiology of preterm rupture of membranes and spontaneous preterm birth. In patients undergoing intrauterine insemination for idiopathic infertility, HPV infection confers a lower pregnancy rate. In contrast, the evidence regarding any detrimental impact of HPV infection on IVF outcomes is inconclusive. It has been suggested that vaccination could potentially counter HPV-related sperm impairment, trophoblastic apoptosis, and spontaneous miscarriages; however, these conclusions are based on in vitro studies rather than large-scale epidemiological studies. Improvement in the understanding of HPV sperm infection mechanisms and HPV transmission into the oocyte and developing blastocyst may help explain idiopathic causes of infertility and miscarriage. PMID:26609434

  8. Development of a highly thermostable, adjuvanted human papillomavirus vaccine.

    PubMed

    Hassett, Kimberly J; Meinerz, Natalie M; Semmelmann, Florian; Cousins, Megan C; Garcea, Robert L; Randolph, Theodore W

    2015-08-01

    A major impediment to economical, worldwide vaccine distribution is the requirement for a "cold chain" to preserve antigenicity. We addressed this problem using a model human papillomavirus (HPV) vaccine stabilized by immobilizing HPV16 L1 capsomeres, i.e., pentameric subunits of the virus capsid, within organic glasses formed by lyophilization. Lyophilized glass and liquid vaccine formulations were incubated at 50°C for 12weeks, and then analyzed for retention of capsomere conformational integrity and the ability to elicit neutralizing antibody responses after immunization of BALB/c mice. Capsomeres in glassy-state vaccines retained tertiary and quaternary structure, and critical conformational epitopes. Moreover, glassy formulations adjuvanted with aluminum hydroxide or aluminum hydroxide and glycopyranoside lipid A were not only as immunogenic as the commercially available HPV vaccine Cervarix®, but also retained complete neutralizing immunogenicity after high-temperature storage. The thermal stability of such adjuvanted vaccine powder preparations may thus eliminate the need for the cold chain. PMID:25998700

  9. The association between human papillomavirus infection and female lung cancer

    PubMed Central

    Lin, Frank Cheau-Feng; Huang, Jing-Yang; Tsai, Stella Ching-Shao; Nfor, Oswald Ndi; Chou, Ming-Chih; Wu, Ming-Fang; Lee, Chun-Te; Jan, Cheng-Feng; Liaw, Yung-Po

    2016-01-01

    Abstract Lung cancer is the leading cause of cancer deaths among Taiwanese women. Human papillomavirus (HPV) has been detected in lung cancer tissues. The aim of this study was to investigate the association between HPV infection and lung cancer among the Taiwanese women. The analytical data were collected from the longitudinal health insurance databases (LHID 2005 and 2010) of the National Health Insurance Research Database (NHIRD). The study participants were 30 years and older and included 24,162 individuals who were identified with HPV infection from 2001 to 2004 and 1,026,986 uninfected individuals. Lung cancer incidence among infected and uninfected individuals was compared using the univariate and multivariate regression models. Among the total participants, 24,162 individuals were diagnosed with HPV. After adjusting for age, gender, low income, residential area, and comorbidity, the risk of lung cancer was higher in women (hazard ratio [HR] 1.263, 95% CI 1.015–1.571), while all cancer risks were high in both men and women with corresponding hazard ratios (HR) of 1.161 (95% CI 1.083–1.245) and HR 1.240 (95% CI 1.154–1.331), respectively. This study showed a significant increase in lung cancer risk among Taiwanese women who were exposed to HPV infection. PMID:27281096

  10. Human papillomavirus and breast cancer in Iran: a meta- analysis

    PubMed Central

    Haghshenas, Mohammad Reza; Mousavi, Tahoora; Moosazadeh, Mahmood; Afshari, Mahdi

    2016-01-01

    Objective(s): This study aims to investigate the relationship between human papillomavirus (HPV) and breast cancer using meta- analysis. Materials and Methods: Relevant studies were identified reviewing the national and international databases. We also increased the search sensitivity by investigating the references as well as interview with research centers and experts. Finally, quality assessment and implementation of inclusion/exclusion criteria determined the eligible articles for meta-analysis. Based on the heterogeneity observed among the results of the primary studies, random effects model was used to estimate the pooled prevalence of HPV infection and also pooled odds ratio between HPV and developing breast cancer using Stata SE V. 11 software. Results: This meta- analysis included 11 primary studies investigating the HPV infection prevalence among 1539 Iranian women. Pooled prevalence (95% confidence interval) of HPV infection among Iranian women with breast cancer was estimated as of 23.6% (6.7- 40.5), while, the odds ratio (95% confidence interval) between HPV infection and developing breast cancer was estimated as of 5.7% (0.7- 46.8). Conclusion: This meta- analysis showed a high prevalence of HPV infection among women with breast cancer. We also found that the odds of developing breast cancer among women with breast cancer was more than that of women without breast cancer. PMID:27114791

  11. Human Papillomavirus Vaccine: State of the Art and Future Perspectives.

    PubMed

    Panatto, Donatella; Amicizia, Daniela; Bragazzi, Nicola Luigi; Rizzitelli, Emanuela; Tramalloni, Daniela; Valle, Ivana; Gasparini, Roberto

    2015-01-01

    Human Papillomavirus (HPV) is a widely distributed and common virus, that causes benign lesions (such as warts and papillomas) but, if not cleared, can lead to malignant lesions as well, such as intraepithelial lesions and neoplasia. An extensive body of researches has demonstrated that E1 and E2 are involved in viral transcription and replication, E5, E6, and E7 act as oncoproteins, whilst L1 and L2 contribute to the formation of the capsid. However, this view has been recently challenged, since also E2 could play a role in HPV-induced carcinogenesis. Therefore, a complex picture is emerging, opening new ways and perspectives. The present article provides an overview of the biology of HPV, paying particular attention to its structural details and molecular mechanisms. The article also shows how this knowledge has been exploited for developing effective vaccines, both prophilactic/preventive and therapeutic ones. L1-based prophylactic vaccines, like Gardasil, Cervarix, and Gardasil 9, have been already licensed, whilst L2-based second generation preventive vaccines are still under clinical trials. New, highly immunogenic and effective vaccines can be further developed thanks to computer-aided design and bioinformatics/computational biology. The optimization of combinational therapies is another promising opportunity. PMID:26572981

  12. Variants of human papillomavirus type 16 predispose toward persistent infection.

    PubMed

    Zhang, Lei; Liao, Hong; Yang, Binlie; Geffre, Christopher P; Zhang, Ai; Zhou, Aizhi; Cao, Huimin; Wang, Jieru; Zhang, Zhenbo; Zheng, Wenxin

    2015-01-01

    A cohort study of 292 Chinese women was conducted to determine the relationship between human papillomavirus (HPV) type 16 variants and persistent viral infection. Enrolled patients were HPV16 positive and had both normal cytology and histology. Flow-through hybridization and gene chip technology was used to identify the HPV type. A PCR sequencing assay was performed to find HPV16 E2, E6 and E7 gene variants. The associations between these variants and HPV16 persistent infection was analyzed by Fisher's exact test. It was found that the variants T178G, T350G and A442C in the E6 gene, as well as C3158A and G3248A variants in the E2 gene were associated with persistent HPV16 infection. No link was observed between E7 variants and persistent viral infection. Our findings suggest that detection of specific HPV variants would help identify patients who are at high risk for viral persistence and development of cervical neoplasia. PMID:26339417

  13. High-Risk Human Papillomavirus Targets Crossroads in Immune Signaling

    PubMed Central

    Tummers, Bart; Van Der Burg, Sjoerd H.

    2015-01-01

    Persistent infections with a high-risk type human papillomavirus (hrHPV) can progress to cancer. High-risk HPVs infect keratinocytes (KCs) and successfully suppress host immunity for up to two years despite the fact that KCs are well equipped to detect and initiate immune responses to invading pathogens. Viral persistence is achieved by active interference with KCs innate and adaptive immune mechanisms. To this end hrHPV utilizes proteins encoded by its viral genome, as well as exploits cellular proteins to interfere with signaling of innate and adaptive immune pathways. This results in impairment of interferon and pro-inflammatory cytokine production and subsequent immune cell attraction, as well as resistance to incoming signals from the immune system. Furthermore, hrHPV avoids the killing of infected cells by interfering with antigen presentation to antigen-specific cytotoxic T lymphocytes. Thus, hrHPV has evolved multiple mechanisms to avoid detection and clearance by both the innate and adaptive immune system, the molecular mechanisms of which will be dealt with in detail in this review. PMID:26008697

  14. Human papillomavirus type 16 DNA in periungual squamous cell carcinomas

    SciTech Connect

    Moy, R.L.; Eliezri, Y.D.; Bennett, R.G. ); Nuovo, G.J.; Siverstein, S. Columbia Univ., New York, NY ); Zitelli, J.A. )

    1989-05-12

    Ten squamous cell carcinomas (in situ or invasive) of the fingernail region were analyzed for the presence of DNA sequences homologous to human papilloma-virus (HPV) by dot blot hybridization. In most patients, the lesions were verrucae of long-term duration that were refractory to conventional treatment methods. Eight of the lesions contained HPV DNA sequences, and in six of these the sequences were related to HPV 16 as deduced from low-stringency nucleic acid hybridization followed by low- and high-stringency washes. Furthermore, the restriction endonuclease digestion pattern of DNA isolated from four of these lesions was diagnostic of episomal HPV 16. The high-frequency association of HPV 16 with periungual squamous cell carcinoma is similar to that reported for HPV 16 with squamous cell carcinomas on mucous membranes at other sites, notably the genital tract. The findings suggest that HPV 16 may play an important role in the development of squamous cell carcinomas of the finger, most notably those lesions that are chronic and located in the periungual area.

  15. Emerging landscape of oncogenic signatures across human cancers

    PubMed Central

    Ciriello, Giovanni; Miller, Martin L; Aksoy, Bülent Arman; Senbabaoglu, Yasin; Schultz, Nikolaus; Sander, Chris

    2014-01-01

    Cancer therapy is challenged by the diversity of molecular implementations of oncogenic processes and by the resulting variation in therapeutic responses. Projects such as The Cancer Genome Atlas (TCGA) provide molecular tumor maps in unprecedented detail. The interpretation of these maps remains a major challenge. Here we distilled thousands of genetic and epigenetic features altered in cancers to ~500 selected functional events (SFEs). Using this simplified description, we derived a hierarchical classification of 3,299 TCGA tumors from 12 cancer types. The top classes are dominated by either mutations (M class) or copy number changes (C class). This distinction is clearest at the extremes of genomic instability, indicating the presence of different oncogenic processes. The full hierarchy shows functional event patterns characteristic of multiple cross-tissue groups of tumors, termed oncogenic signature classes. Targetable functional events in a tumor class are suggestive of class-specific combination therapy. These results may assist in the definition of clinical trials to match actionable oncogenic signatures with personalized therapies. PMID:24071851

  16. In vitro and in vivo growth suppression of human papillomavirus 16-positive cervical cancer cells by CRISPR/Cas9

    SciTech Connect

    Zhen, Shuai; Hua, Ling; Takahashi, Y.; Narita, S.; Liu, Yun-Hui; Li, Yan

    2014-08-08

    Highlights: • Established CRISPR/Cas9 targeting promoter of HPV 16 and targeting E6, E7 transcript. • CRISPR/Cas9 resulted in accumulation of p53 and p21, reduced the proliferation of cervical cancer cells. • Finding inhibited tumorigenesis and growth of mice incubated by cells with CRISPR/Cas9. • CRISPR/Cas9 will be a new treatment strategy, in cervical and other HPV-associated cancer therapy. - Abstract: Deregulated expression of high-risk human papillomavirus oncogenes (E6 and E7) is a pivotal event for pathogenesis and progression in cervical cancer. Both viral oncogenes are therefore regarded as ideal therapeutic targets. In the hope of developing a gene-specific therapy for HPV-related cancer, we established CRISPR/Cas9 targeting promoter of HPV 16 E6/E7 and targeting E6, E7 transcript, transduced the CRISPR/Cas9 into cervical HPV-16-positive cell line SiHa. The results showed that CRISPR/Cas9 targeting promoter, as well as targeting E6 and E7 resulted in accumulation of p53 and p21 protein, and consequently remarkably reduced the abilities of proliferation of cervical cancer cells in vitro. Then we inoculated subcutaneously cells into nude mice to establish the transplanted tumor animal models, and found dramatically inhibited tumorigenesis and growth of mice incubated by cells with CRISPR/Cas9 targeting (promoter+E6+E7)-transcript. Our results may provide evidence for application of CRISPR/Cas9 targeting HR-HPV key oncogenes, as a new treatment strategy, in cervical and other HPV-associated cancer therapy.

  17. Human Papillomavirus and Epstein-Barr virus co-infection in Cervical Carcinoma in Algerian women

    PubMed Central

    2013-01-01

    Background Despite the fact that the implication of human papillomavirus (HPV) in the carcinogenesis and prognosis of cervical cancer is well established, the impact of a co-infection with high risk HPV (HR-HPV) and Epstein-Barr virus (EBV) is still not fully understood. Methods Fifty eight randomly selected cases of squamous cell carcinomas (SCC) of the uterine cervix, 14 normal cervices specimens, 21 CIN-2/3 and 16 CIN-1 cases were examined for EBV and HPV infections. Detection of HR-HPV specific sequences was carried out by PCR amplification using consensus primers of Manos and by Digene Hybrid Capture. The presence of EBV was revealed by amplifying a 660 bp specific EBV sequence of BALF1. mRNA expression of LMP-1 in one hand and protein levels of BARF-1, LMP-1 and EBNA-1 in the other hand were assessed by RT-PCR and immunoblotting and/or immunohischemistry respectively. Results HR-HPV infection was found in patients with SCC (88%), low-grade (75%) and high grade (95%) lesions compared to only 14% of normal cervix cases. However, 69%, 12.5%, 38.1%, and 14% of SCC, CIN-1, CIN-2/3 and normal cervix tissues, respectively, were EBV infected. The highest co-infection (HR-HPV and EBV) was found in squamous cell carcinoma cases (67%). The latter cases showed 27% and 29% expression of EBV BARF-1 and LMP-1 oncogenes respectively. Conclusion The high rate of HR-HPV and EBV co-infection in SCC suggests that EBV infection is incriminated in cervical cancer progression. This could be taken into account as bad prognosis in this type of cancer. However, the mode of action in dual infection in cervical oncogenesis needs further investigation. PMID:24252325

  18. Innovative DNA vaccine for human papillomavirus (HPV)-associated head and neck cancer.

    PubMed

    Wu, A; Zeng, Q; Kang, T H; Peng, S; Roosinovich, E; Pai, S I; Hung, C-F

    2011-03-01

    Human papillomavirus (HPV), particularly type 16, has been associated with a subset of head and neck cancers. The viral-encoded oncogenic proteins E6 and E7 represent ideal targets for immunotherapy against HPV-associated head and neck cancers. DNA vaccines have emerged as attractive approaches for immunotherapy due to its simplicity, safety and ease of preparation. Intradermal administration of DNA vaccine by means of gene gun represents an efficient method to deliver DNA directly into dendritic cells for priming antigen-specific T cells. We have previously shown that a DNA vaccine encoding an invariant chain (Ii), in which the class II-associated Ii peptide (CLIP) region has been replaced by a Pan-DR-epitope (PADRE) sequence to form Ii-PADRE, is capable of generating PADRE-specific CD4+ T cells in vaccinated mice. In the current study, we hypothesize that a DNA vaccine encoding Ii-PADRE linked to E6 (Ii-PADRE-E6) will further enhance E6-specific CD8+ T cell immune responses through PADRE-specific CD4+ T-helper cells. We found that mice vaccinated with Ii-PADRE-E6 DNA generated comparable levels of PADRE-specific CD4+ T-cell immune responses, as well as significantly stronger E6-specific CD8+ T-cell immune responses and antitumor effects against the lethal challenge of E6-expressing tumor compared with mice vaccinated with Ii-E6 DNA. Taken together, our data indicate that vaccination with Ii-E6 DNA with PADRE replacing the CLIP region is capable of enhancing the E6-specific CD8+ T-cell immune response generated by the Ii-E6 DNA. Thus, Ii-PADRE-E6 represents a novel DNA vaccine for the treatment of HPV-associated head and neck cancer and other HPV-associated malignancies. PMID:20981112

  19. Review of the current knowledge on the epidemiology, pathogenesis, and prevention of human papillomavirus infection.

    PubMed

    Asiaf, Asia; Ahmad, Shiekh T; Mohammad, Sheikh O; Zargar, Mohammad A

    2014-05-01

    Human papillomavirus (HPV) infection is a central and necessary, although not sufficient, cause of cervical cancer. Besides HPV, the additional multiple risk factors related with the onset of cervical cancer are early-age sexual activities; high number of sexual partners, which is the most salient risk factor; suppression and alteration of the immune status; long-term use of oral contraceptives; and other hormonal influences. The tumor-suppressor proteins p53 and pRb are degraded and destabilized through ubiquitination by viral oncoproteins E6 and E7. Over 95% of cervical cancer cases worldwide test positive for oncogenic HPV DNA. Although cervical screening procedures have been successful in reducing the disease burden associated with HPV infection because of lack of resources or inadequate infrastructure many countries have failed to reduce cervical cancer mortality. Therefore, prevention may be a valuable strategy for reducing the economic and disease burden of HPV infection. At present, two successful prophylactic HPV vaccines are available, quadrivalent (HPV16/18/6/11) 'Gardasil' and bivalent (HPV16/18) 'Cervarix' for vaccinating young adolescent girls at or before the onset of puberty. Recent data indicate that vaccination prevents the development of cervical lesions in women who have not already acquired the vaccine-specific HPV types. Moreover, several therapeutic vaccines that are protein/peptide-based, DNA-based, or cell-based are in clinical trials but are yet to establish their efficacy; these vaccines are likely to provide important future health benefits. The therapeutic vaccination mode of prevention is a promising area of research, as revealed in preclinical trials; however, clinical trials based on large populations are warranted before reaching a valid conclusion. This review summarizes the studies on the epidemiology of HPV infection, the pathogenesis of viral oncoproteins in the oncogenesis of cervical cancer, the economic and health burden of

  20. Virus-like particles for the prevention of human papillomavirus-associated malignancies

    PubMed Central

    Wang, Joshua W.; Roden, Richard B.S.

    2013-01-01

    As compared to peptide/protein-based vaccines, naked DNA vectors and even traditional attenuated or inactived virus vaccines, virus-like particles (VLPs) are an attractive vaccine platform because they offer a combination of safety, ease of production, and both high density B cell epitope display and intracellular presentation of T cell epitopes that induce potent humoral and cellular immune responses respectively. Indeed, human papillomavirus (HPV) vaccines based on VLP production by recombinant expression of major capsid antigen L1 in yeast (Gardasil®, Merck & Co.) or insect cells (Cervarix®, GlaxoSmithKline) have been licensed for the prevention of cervical and anogenital infection and disease associated with the genotypes targeted by each vaccine. These HPV vaccines however have not been demonstrated as effective to treat existing infections, and efforts to develop a therapeutic HPV vaccine continue. Furthermore, current HPV L1-VLP vaccines provide type-restricted protection, requiring highly multivalent formulations to broaden coverage to the dozen or more oncogenic HPV genotypes. This raises the complexity and cost of vaccine production. The lack of access to screening and high disease burden in developing countries has spurred efforts to develop second generation HPV vaccines that are more affordable, induce wider protective coverage and offer therapeutic coverage against HPV-associated malignancies. Given the previous success with L1 VLP-based vaccines against HPV, VLPs have been also adopted as platforms for many second generation HPV and non-HPV vaccine candidates with both prophylactic and therapeutic intent. Here we examine the progress and challenges of these efforts, with a focus on how they inform VLP vaccine design. PMID:23414405

  1. Combined P16 and human papillomavirus testing predicts head and neck cancer survival.

    PubMed

    Salazar, Christian R; Anayannis, Nicole; Smith, Richard V; Wang, Yanhua; Haigentz, Missak; Garg, Madhur; Schiff, Bradley A; Kawachi, Nicole; Elman, Jordan; Belbin, Thomas J; Prystowsky, Michael B; Burk, Robert D; Schlecht, Nicolas F

    2014-11-15

    While its prognostic significance remains unclear, p16(INK4a) protein expression is increasingly being used as a surrogate marker for oncogenic human papillomavirus (HPV) infection in head and neck squamous cell carcinomas (HNSCC). To evaluate the prognostic utility of p16 expression in HNSCC, we prospectively collected 163 primary tumor specimens from histologically confirmed HNSCC patients who were followed for up to 9.4 years. Formalin fixed tumor specimens were tested for p16 protein expression by immunohistochemistry (IHC). HPV type-16 DNA and RNA was detected by MY09/11-PCR and E6/E7 RT-PCR on matched frozen tissue, respectively. P16 protein expression was detected more often in oropharyngeal tumors (53%) as compared with laryngeal (24%), hypopharyngeal (8%) or oral cavity tumors (4%; p<0.0001). With respect to prognosis, p16-positive oropharyngeal tumors exhibited significantly better overall survival than p16-negative tumors (log-rank test p=0.04), whereas no survival benefit was observed for nonoropharyngeal tumors. However, when both p16 and HPV DNA test results were considered, concordantly positive nonoropharyngeal tumors had significantly better disease-specific survival than concordantly negative nonoropharyngeal tumors after controlling for sex, nodal stage, tumor size, tumor subsite, primary tumor site number, smoking and drinking [adjusted hazard ratio (HR)=0.04, 0.01-0.54]. Compared with concordantly negative nonoropharyngeal HNSCC, p16(+)/HPV16(-) nonoropharyngeal HNSCC (n=13, 7%) demonstrated no significant improvement in disease-specific survival when HPV16 was detected by RNA (adjusted HR=0.83, 0.22-3.17). Our findings show that p16 IHC alone has potential as a prognostic test for oropharyngeal cancer survival, but combined p16/HPV testing is necessary to identify HPV-associated nonoropharyngeal HNSCC with better prognosis. PMID:24706381

  2. Link between chronic inflammation and human papillomavirus-induced carcinogenesis (Review)

    PubMed Central

    FERNANDES, JOSÉ VERÍSSIMO; DE MEDEIROS FERNANDES, THALES ALLYRIO ARAÚJO; DE AZEVEDO, JENNER CHRYSTIAN VERÍSSIMO; COBUCCI, RICARDO NEY OLIVEIRA; DE CARVALHO, MARIA GORETTI FREIRE; ANDRADE, VANIA SOUSA; DE ARAÚJO, JOSÉLIO MARIA GALVÃO

    2015-01-01

    Inflammation is a defense strategy against invading agents and harmful molecules that is activated immediately following a stimulus, and involves the release of cytokines and chemokines, which activate the innate immune response. These mediators act together to increase blood flow and vascular permeability, facilitating recruitment of effector cells to the site of injury. Following resolution of the injury and removal of the stimulus, inflammation is disabled, but if the stimulus persists, inflammation becomes chronic and is strongly associated with cancer. This is likely to be due to the fact that the inflammation leads to a wound that does not heal, requiring a constant renewal of cells, which increases the risk of neoplastic transformation. Debris from phagocytosis, including the reactive species of oxygen and nitrogen that cause damage to DNA already damaged by the leukotrienes and prostaglandins, has an impact on inflammation and various carcinogenic routes. There is an association between chronic inflammation, persistent infection and cancer, where oncogenic action is mediated by autocrine and paracrine signals, causing changes in somatic cells under the influence of the microbial genome or of epigenetic factors. Among the infectious agents associated with cancer, certain genotypes of human papillomavirus (HPV) stand out. HPV is responsible for virtually all cases of cervical cancer and a lower proportion of cancers of the vagina, vulva, anus, penis and a number of extragenital cancers. In the present review, recent advances in the mechanisms involved in the inflammatory response are presented with their participation in the process of carcinogenesis, emphasizing the role of chronic inflammation in the development of HPV-induced cervical cancer. PMID:25663851

  3. Human papillomavirus type-18 prevalence in oesophageal cancer in the Chinese population: a meta-analysis.

    PubMed

    Guo, L W; Zhang, S K; Liu, S Z; Chen, Q; Zhang, M; Quan, P L; Lu, J B; Sun, X B

    2016-02-01

    Globally, the prevalence of oesophageal cancer cases is particularly high in China. Since 1982, oncogenic human papillomavirus (HPV) has been hypothesized as a risk factor for oesophageal cancer, but no firm evidence of HPV infection in oesophageal cancer has been established to date. We aimed to conduct a meta-analysis to estimate the high-risk HPV-18 prevalence of oesophageal cancer in the Chinese population. Eligible studies published from 1 January 2005 to 12 July 2014 were retrieved via computer searches of English and Chinese literature databases (including Medline, EMBASE, Chinese National Knowledge Infrastructure and Wanfang Data Knowledge Service Platform). A random-effects model was used to calculate pooled prevalence and corresponding 95% confidence intervals (CIs). A total of 2556 oesophageal cancer cases from 19 studies were included in this meta-analysis. Overall, the pooled HPV-18 prevalence in oesophageal cancer cases was 4·1% (95% CI 2·7-5·5) in China, 6·1% (95% CI 2·9-9·3) in fresh or frozen biopsies and 4·0% (95% CI 2·3-5·8) in paraffin-embedded fixed biopsies, 8·2% (95% CI 4·6-11·7) by the E6/E7 region and 2·2% (95% CI 0·9-3·6) by the L1 region of the HPV gene. This meta-analysis indicated that China has a moderate HPV-18 prevalence of oesophageal cancer compared to cervical cancer, although there is variation between different variables. Further studies are needed to elucidate the role of HPV in oesophagus carcinogenesis with careful consideration of study design and laboratory detection method, providing more accurate assessment of HPV status in oesophageal cancer. PMID:26211663

  4. Analysis of CpG methylation sites and CGI among human papillomavirus DNA genomes

    PubMed Central

    2011-01-01

    Background The Human Papillomavirus (HPV) genome is divided into early and late coding sequences, including 8 open reading frames (ORFs) and a regulatory region (LCR). Viral gene expression may be regulated through epigenetic mechanisms, including cytosine methylation at CpG dinucleotides. We have analyzed the distribution of CpG sites and CpG islands/clusters (CGI) among 92 different HPV genomes grouped in function of their preferential tropism: cutaneous or mucosal. We calculated the proportion of CpG sites (PCS) for each ORF and calculated the expected CpG values for each viral type. Results CpGs are underrepresented in viral genomes. We found a positive correlation between CpG observed and expected values, with mucosal high-risk (HR) virus types showing the smallest O/E ratios. The ranges of the PCS were similar for most genomic regions except E4, where the majority of CpGs are found within islands/clusters. At least one CGI belongs to each E2/E4 region. We found positive correlations between PCS for each viral ORF when compared with the others, except for the LCR against four ORFs and E6 against three other ORFs. The distribution of CpG islands/clusters among HPV groups is heterogeneous and mucosal HR-HPV types exhibit both lower number and shorter island sizes compared to cutaneous and mucosal Low-risk (LR) HPVs (all of them significantly different). Conclusions There is a difference between viral and cellular CpG underrepresentation. There are significant correlations between complete genome PCS and a lack of correlations between several genomic region pairs, especially those involving LCR and E6. L2 and L1 ORF behavior is opposite to that of oncogenes E6 and E7. The first pair possesses relatively low numbers of CpG sites clustered in CGIs while the oncogenes possess a relatively high number of CpG sites not associated to CGIs. In all HPVs, E2/E4 is the only region with at least one CGI and shows a higher content of CpG sites in every HPV type with an

  5. Multiplex Identification of Human Papillomavirus 16 DNA Integration Sites in Cervical Carcinomas

    PubMed Central

    Xu, Bo; Chotewutmontri, Sasithorn; Wolf, Stephan; Klos, Ursula; Schmitz, Martina; Dürst, Matthias; Schwarz, Elisabeth

    2013-01-01

    Cervical cancer is caused by high-risk human papillomaviruses (HPV), in more than half of the worldwide cases by HPV16. Viral DNA integration into the host genome is a frequent mutation in cervical carcinogenesis. Because integration occurs into different genomic locations, it creates unique viral-cellular DNA junctions in every single case. This singularity complicates the precise identification of HPV integration sites enormously. We report here the development of a novel multiplex strategy for sequence determination of HPV16 DNA integration sites. It includes DNA fragmentation and adapter tagging, PCR enrichment of the HPV16 early region, Illumina next-generation sequencing, data processing, and validation of candidate integration sites by junction-PCR. This strategy was performed with 51 cervical cancer samples (47 primary tumors and 4 cell lines). Altogether 75 HPV16 integration sites (3′-junctions) were identified and assigned to the individual samples. By comparing the DNA junctions with the presence of viral oncogene fusion transcripts, 44 tumors could be classified into four groups: Tumors with one transcriptionally active HPV16 integrate (n = 12), tumors with transcribed and silent DNA junctions (n = 8), tumors carrying episomal HPV16 DNA (n = 10), and tumors with one to six DNA junctions, but without fusion transcripts (n = 14). The 3′-breakpoints of integrated HPV16 DNA show a statistically significant (p<0.05) preferential distribution within the early region segment upstream of the major splice acceptor underscoring the importance of deregulated viral oncogene expression for carcinogenesis. Half of the mapped HPV16 integration sites target cellular genes pointing to a direct influence of HPV integration on host genes (insertional mutagenesis). In summary, the multiplex strategy for HPV16 integration site determination worked very efficiently. It will open new avenues for comprehensive mapping of HPV integration sites and for the

  6. Targeting human papillomavirus genome replication for antiviral drug discovery

    PubMed Central

    Archambault, Jacques; Melendy, Thomas

    2015-01-01

    Human papillomavirus (HPV) infections are a major human health problem; they are the cause of recurrent benign warts and of several cancers of the anogenital tract and head and neck region. Although there are two prophylactic HPV vaccines that could, if used universally, prevent as many as two-thirds of HPV-induced cancers, as well as several cytotoxic and immunomodulatory agents for localized treatment of infections, there are currently no HPV antiviral drugs in our arsenal of therapeutic agents. This review examines the status of past and ongoing research into the development of HPV antivirals, focused primarily upon approaches targeting the replication of the viral genome. The only HPV enzyme, E1, is a DNA helicase that interfaces with the cellular DNA replication machinery to replicate the HPV genome. To date, searches for small molecule inhibitors of E1 for use as antivirals have met with limited success. The lack of other viral enzymes has meant that the search for antivirals has shifted to a large degree to the modulation of protein–protein interactions. There has been some success in identifying small molecule inhibitors targeting interactions between HPV proteins but with activity against a small subset of viral types only. As noted in this review, it is thought that targeting E1 interactions with cellular replication proteins may provide inhibitors with broader activity against multiple HPV types. Herein, we outline the steps in HPV DNA replication and discuss those that appear to provide the most advantageous targets for the development of anti-HPV therapeutics. PMID:23615820

  7. Malignant transformation of diploid human fibroblasts by transfection of oncogenes

    SciTech Connect

    McCormick, J.J.

    1992-01-01

    This document consist of brief reports prepared by postdoctoral students supported by the project, each describing his accomplishments under the grant. Topics include (1) Malignant Transformation of MSU-1. 1 Cells by Gamma Radiation, (2) Correlation between Levels of ras Expression and Presence of Transformed Phenotypes Including Tumorigenicity, Using a Modulatable Promoter, (3) Relation between Specific rad Oncogene Expression, (4) Correlation of Genetic Changes in Fibroblastic Tumors with Malignancies, (5)Transformation of MSU-1.1 Cells by sis Oncogene, (6) Malignant Transformation of MSU-1.0 Cells, (7) Correlation of Urokinase Plasminogen Activation (mu-PA) with Malignant Phenotype, (8)Two Dimensional Gel Electrophoresis Studies of the Proteins of the Major Cell Strains of the MSU-1 Family of Cells, and (9) Correlation between Proteinase Activity Levels and Malignancy.

  8. Oncogenes and human cancer--a surgeon's perspective.

    PubMed Central

    Markham, N. I.

    1985-01-01

    Amongst the most significant of the advances that have occurred in molecular biology in the last decade has been the development of our understanding of oncogenes, genes that would seem to be responsible for causing cancer. Subtle genetic differences between tumour cells and their normal counterparts have now been discovered, and there is much excitement being generated as new light is shed on the very roots of malignant change. Much of the technology is complicated and confusing, yet the subject should be one with which practising surgeons have a background understanding, for clinicians will possibly soon be able to utilise the results of this basic scientific research in everyday practice. This review article attempts to explain the background to the discovery of oncogenes, how they act, and how the technology may be able to be clinically used in the future in the battle to overcome cancer. PMID:4051429

  9. Molecular cloning of an activated human oncogene, homologous to v-raf, from primary stomach cancer.

    PubMed Central

    Shimizu, K; Nakatsu, Y; Sekiguchi, M; Hokamura, K; Tanaka, K; Terada, M; Sugimura, T

    1985-01-01

    Transfection with high molecular weight DNA from a primary stomach cancer induced foci of transformed NIH 3T3 cells, and the transformed cells were tumorigenic in nude mice. By screening with a human Alu-family probe, we isolated the human DNA sequence from the secondary transformant cells. This transforming sequence encompasses about 60 kilobase pairs and is unrelated to known human transforming genes. Examination of homologies between this sequence and retroviral oncogenes revealed that the human transforming sequence is closely related to the v-raf oncogene of murine transforming retrovirus 3611-MSV. Images PMID:3862088

  10. Characterization of a novel human papillomavirus DNA in the cervical carcinoma cell line ME180.

    PubMed Central

    Reuter, S; Delius, H; Kahn, T; Hofmann, B; zur Hausen, H; Schwarz, E

    1991-01-01

    The human cervical carcinoma cell line ME180 was examined for human papillomavirus (HPV) DNA and RNA. The integrated DNA of a presumably new HPV type showing a relationship closer to HPV39 than to HPV18 was cloned and sequenced. HPV sequences from the E6-E7-E1 region are expressed as poly(A)+ RNAs. Images PMID:1716694

  11. Oral Human Papillomavirus in Youth From the Pediatric HIV/AIDS Cohort Study.

    PubMed

    Moscicki, Anna-Barbara; Farhat, Sepideh; Yao, Tzy-Jyun; Ryder, Mark I; Russell, Jonathan S; Van Dyke, Russell B; Hazra, Rohan; Shiboski, Caroline H

    2016-08-01

    In contrast to high rates of oral human papillomavirus (HPV) found in human immunodeficiency virus (HIV)-infected adults, only 2% of 209 perinatally HIV-infected youth had oral HPV. This rate was similar in HIV-exposed but uninfected youth. No association was found with sexual activity; however, low CD4 counts were associated with oral HPV. PMID:27414680

  12. Human papillomavirus in vulvar and vaginal carcinoma cell lines.

    PubMed Central

    Hietanen, S.; Grénman, S.; Syrjänen, K.; Lappalainen, K.; Kauppinen, J.; Carey, T.; Syrjänen, S.

    1995-01-01

    A number of reports associate human papillomavirus (HPV) with cervical cancer and cancer cell lines derived from this tumour type. Considerably fewer reports have focused on the role of HPV in carcinomas from other sites of female anogenital squamous epithelia. In this study we have tested for the presence of HPV in eight low-passage vulvar carcinoma cell lines and one extensively passaged cell line, A431. One cell line from a primary vaginal carcinoma was included. The presence of the HPV was evaluated by the polymerase chain reaction (PCR), by Southern blot analysis and by two-dimensional gel electrophoresis. General primer-mediated PCR was applied by using primers from the L1 region, E1 region and HPV 16 E7 region. Southern blot hybridisation was performed under low-stringency conditions (Tm = -35 degrees C) using a whole genomic HPV 6/16/18 probe mixture and under high stringency conditions (Tm = -18 degrees C) with the whole genomic probes of HPV 16 and 33. HPV 16 E6-E7 mRNA was assessed by ribonuclease protection assay (RPA). HPV was found in only one vulvar carcinoma cell line, UM-SCV-6. The identified type, HPV 16, was integrated in the cell genome and could be amplified with all primers used. Also E6-E7 transcripts were found in these cells. Five original tumour biopsies were available from the HPV-negative cell lines for in situ hybridisation. All these were HPV negative with both the HPV 6/16/18 screening probe mixture under low stringency and the HPV 16 probe under high stringency. The results indicate that vulvar carcinoma cell lines contain HPV less frequently than cervical carcinoma cell lines and suggest that a significant proportion of vulvar carcinomas may evolve by an HPV-independent mechanism. Images Figure 1 Figure 2 Figure 3 Figure 4 Figure 5 Figure 6 PMID:7599042

  13. Quadrivalent Human Papillomavirus Vaccine Effectiveness: A Swedish National Cohort Study

    PubMed Central

    2013-01-01

    Background Incidence of condyloma, or genital warts (GW), is the earliest possible disease outcome to measure when assessing the effectiveness of human papillomavirus (HPV) vaccination strategies. Efficacy trials that follow prespecified inclusion and exclusion criteria may not be fully generalizable to real-life HPV vaccination programs, which target a broader segment of the population. We assessed GW incidence after on-demand vaccination with quadrivalent HPV vaccine using individual-level data from the entire Swedish population. Methods An open cohort of girls and women aged 10 to 44 years living in Sweden between 2006 and 2010 (N > 2.2 million) was linked to multiple population registers to identify incident GW in relation to HPV vaccination. For vaccine effectiveness, incidence rate ratios of GW were estimated using time-to-event analyses with adjustment for attained age and parental education level, stratifying on age at first vaccination. Results A total of 124 000 girls and women were vaccinated between 2006 and 2010. Girls and women with at least one university-educated parent were 15 times more likely to be vaccinated before age 20 years than girls and women whose parents did not complete high school (relative risk ratio = 15.45, 95% confidence interval [CI] = 14.65 to 16.30). Among those aged older than 20 years, GW rates declined among the unvaccinated, suggesting that HPV vaccines were preferentially used by women at high risk of GW. Vaccination effectiveness was 76% (95% CI = 73% to 79%) among those who received three doses of the vaccine with their first dose before age 20 years. Vaccine effectiveness was highest in girls vaccinated before age 14 years (effectiveness = 93%, 95% CI = 73% to 98%). Conclusions Young age at first vaccination is imperative for maximizing quadrivalent HPV vaccine effectiveness. PMID:23486550

  14. Immune therapy for human papillomaviruses-related cancers.

    PubMed

    Rosales, Ricardo; Rosales, Carlos

    2014-12-10

    Human papillomaviruses (HPVs) are a large family of double strand DNA viruses comprising more than 180 types. Infection with HPV is very common and it is associated with benign and malignant proliferation of skin and squamous mucosae. Many HPVs, considered low-risk such as HPV 6 and 11, produce warts; while high-risk viruses, such as HPVs 16, 18, 31, 33, 35, 39, 45, 51, 52, 56, and 58, induce tumors. About 5% of all cancers in men and women are associated with HPV infection. Because there are not antiviral drugs for HPV infection, current therapies for low-risk HPV infections involve physical removal of the lesion by cryotherapy, trichloracetic acid, laser, or surgical removal. Surgical procedures are effective in the treatment of pre-cancerous lesions, however after these procedures, many recurrences appear due to new re-infections, or to failure of the procedure to eliminate the HPV. In addition, HPV can inhibit recognition of malignant cells by the immune system, leading to the development of cancer lesions. When this occurs, radiotherapy and chemotherapy are then used. Unfortunately, about 50% of the HPV-cancer patients still die. In the past decade, a better knowledge of the natural history of the virus-host interaction and of the immune response against this viral infection has brought new therapeutic strategies geared to modulate the immune system to generate an efficient virus-specific cytotoxic response. Novel HPV protein-expressing vaccines have shown some significant clinical efficacy and systemic HPV-specific cytotoxic T cell responses. This review will describe the current status of the several therapeutic strategies used to treat HPV-induced lesions, and discuss the various new therapies now being tested. PMID:25493236

  15. Human Papillomavirus Genotype Distribution in Invasive Cervical Cancer in Pakistan

    PubMed Central

    Loya, Asif; Serrano, Beatriz; Rasheed, Farah; Tous, Sara; Hassan, Mariam; Clavero, Omar; Raza, Muhammad; De Sanjosé, Silvia; Bosch, F. Xavier; Alemany, Laia

    2016-01-01

    Few studies have assessed the burden of human papillomavirus (HPV) infection in Pakistan. We aim to provide specific information on HPV-type distribution in invasive cervical cancer (ICC) in the country. A total of 280 formalin-fixed paraffin-embedded tissue blocks were consecutively selected from Shaukat Khanum Memorial Cancer Hospital and Research Centre (Lahore, Pakistan). HPV-DNA was detected by SPF10 broad-spectrum PCR followed by DNA enzyme immunoassay and genotyping by LiPA25. HPV-DNA prevalence was 87.5% (95%CI: 83.0–91.1), with 96.1% of cases histologically classified as squamous cell carcinoma. Most of the HPV-DNA positive cases presented single infections (95.9%). HPV16 was the most common type followed by HPV18 and 45. Among HPV-DNA positive, a significantly higher contribution of HPV16/18 was detected in Pakistan (78.4%; 72.7–83.3), compared to Asia (71.6%; 69.9–73.4) and worldwide (70.8%; 69.9–71.8) and a lower contribution of HPVs31/33/45/52/58 (11.1%; 7.9–15.7 vs. 19.8%; 18.3–21.3 and 18.5%; 17.7–19.3). HPV18 or HPV45 positive ICC cases were significantly younger than cases infected by HPV16 (mean age: 43.3, 44.4, 50.5 years, respectively). A routine cervical cancer screening and HPV vaccination program does not yet exist in Pakistan; however, the country could benefit from national integrated efforts for cervical cancer prevention and control. Calculated estimations based on our results show that current HPV vaccine could potentially prevent new ICC cases. PMID:27483322

  16. Prevalence of human papillomavirus in oropharyngeal cancer: a systematic review

    PubMed Central

    Stein, Andrew P.; Saha, Sandeep; Kraninger, Jennifer L.; Swick, Adam D.; Yu, Menggang; Lambertg, Paul F.; Kimple, Randall

    2015-01-01

    Purpose The global incidence of oropharyngeal squamous cell carcinoma (OPSCC) has been increasing, and it has been proposed that a rising rate of human papillomavirus (HPV) associated cancers is driving the observed changes in OPSCC incidence. We carried out this systematic review to further examine the prevalence of HPV in OPSCC over time worldwide. Methods A systematic literature search was performed to identify all articles through January 31, 2014 that reported on the prevalence of HPV in OPSCC. Articles that met inclusion criteria were divided into four time frames (pre-1995, 1995—1999, 2000—2004, and 2005—present) based on the median year of the study's sample collection period. Employing a weighted analysis of variance (ANOVA) model, we examined the trends of HPV-positivity over time worldwide, in North America, and in Europe. Results Our literature search identified 699 unique articles. 175 underwent review of the entire study and 105 met inclusion criteria. These 105 articles reported on the HPV prevalence in 9541 OPSCC specimens across 23 nations. We demonstrated significant increases in the percentage change of HPV-positive OPSCCs from pre-1995 to present: 20.6% worldwide (p-value for trend: p<0.001), 21.6% in North America (p=0.013) and 21.5% in Europe (p=0.033). Discussion Interestingly, while in Europe there was a steady increase in HPV prevalence across all time frames, reaching nearly 50% most recently, in North America HPV prevalence appears to have plateaued over the past decade at about 65%. These findings may have important implications regarding predictions for the future incidence of OPSCC. PMID:26049691

  17. Geospatial patterns of human papillomavirus vaccine uptake in Minnesota

    PubMed Central

    Nelson, Erik J; Hughes, John; Oakes, J Michael; Pankow, James S; Kulasingam, Shalini L

    2015-01-01

    Objectives To identify factors associated with human papillomavirus (HPV) vaccination and to determine the geographic distribution of vaccine uptake while accounting for spatial autocorrelation. Design This study is cross-sectional in design using data collected via the Internet from the Survey of Minnesotans About Screening and HPV study. Setting and participants The sample consists of 760 individuals aged 18–30 years nested within 99 ZIP codes surrounding the downtown area of Minneapolis, Minnesota. Results In all, 46.2% of participants had received≥1 dose of HPV vaccine (67.7% of women and 13.0% of men). Prevalence of HPV vaccination was found to exhibit strong spatial dependence () across ZIP codes. Accounting for spatial dependence, age (OR=0.76, 95% CI 0.70 to 0.83) and male gender (OR=0.04, 95% CI 0.03 to 0.07) were negatively associated with vaccination, while liberal political preferences (OR=4.31, 95% CI 2.32 to 8.01), and college education (OR=2.58, 95% CI 1.14 to 5.83) were found to be positively associated with HPV vaccination. Conclusions Strong spatial dependence and heterogeneity of HPV vaccination prevalence were found across ZIP codes, indicating that spatial statistical models are needed to accurately identify and estimate factors associated with vaccine uptake across geographic units. This study also underscores the need for more detailed data collected at local levels (eg, ZIP code), as patterns of HPV vaccine receipt were found to differ significantly from aggregated state and national patterns. Future work is needed to further pinpoint areas with the greatest disparities in HPV vaccination and how to then access these populations to improve vaccine uptake. PMID:26316652

  18. Physicians’ Human Papillomavirus Vaccine Recommendations, 2009 and 2011

    PubMed Central

    Vadaparampil, Susan T.; Malo, Teri L.; Kahn, Jessica A.; Salmon, Daniel A.; Lee, Ji-Hyun; Quinn, Gwendolyn P.; Roetzheim, Richard G.; Bruder, Karen L.; Proveaux, Tina M.; Zhao, Xiuhua; Halsey, Neal A.; Giuliano, Anna R.

    2014-01-01

    Background Physician recommendation is a key predictor of human papillomavirus (HPV) vaccine uptake. Understanding factors associated with recommendation is important for efforts to increase current suboptimal vaccine uptake. Purpose This study aimed to examine physician recommendations to vaccinate female patients aged 11–26 years, in 2009 and 2011, at 3 and 5 years postvaccine licensure, respectively. A second aim was to identify trends in factors associated with vaccine recommendation for ages 11 and 12 years. Methods Nationally representative samples of physicians practicing family medicine, pediatrics, and obstetrics and gynecology were randomly selected from the American Medical Association Physician Masterfile (n=1538 in 2009, n=1541 in 2011). A mailed survey asked physicians about patient and clinical practice characteristics; immunization support; and frequency of HPV vaccine recommendation (“always” = >75% of the time vs other). Analyses were conducted in 2012. Results Completed surveys were received from 1013 eligible physicians (68% response rate) in 2009 and 928 (63%) in 2011. The proportion of physicians who reported “always” recommending HPV vaccine increased significantly from 2009 to 2011 for patients aged 11 or 12 years (35% vs 40%, respectively; p=0.03), but not for patients aged 13–17 years (53% vs 55%; p= 0.28) or 18–26 years (50% vs 52%; p=0.52). Physician specialty, age, and perceived issues/barriers to vaccination were associated with vaccine recommendation for patients aged 11 or 12 in both years. Conclusions Results suggest a modest increase in recommendations for HPV vaccination of girls aged 11 or 12 years over a 2-year period; however, recommendations remain suboptimal for all age groups despite national recommendations for universal immunization. PMID:24355675

  19. The Cell Cycle Timing of Human Papillomavirus DNA Replication

    PubMed Central

    Reinson, Tormi; Henno, Liisi; Toots, Mart; Ustav, Mart; Ustav, Mart

    2015-01-01

    Viruses manipulate the cell cycle of the host cell to optimize conditions for more efficient viral genome replication. One strategy utilized by DNA viruses is to replicate their genomes non-concurrently with the host genome; in this case, the viral genome is amplified outside S phase. This phenomenon has also been described for human papillomavirus (HPV) vegetative genome replication, which occurs in G2-arrested cells; however, the precise timing of viral DNA replication during initial and stable replication phases has not been studied. We developed a new method to quantitate newly synthesized DNA levels and used this method in combination with cell cycle synchronization to show that viral DNA replication is initiated during S phase and is extended to G2 during initial amplification but follows the replication pattern of cellular DNA during S phase in the stable maintenance phase. E1 and E2 protein overexpression changes the replication time from S only to both the S and G2 phases in cells that stably maintain viral episomes. These data demonstrate that the active synthesis and replication of the HPV genome are extended into the G2 phase to amplify its copy number and the duration of HPV genome replication is controlled by the level of the viral replication proteins E1 and E2. Using the G2 phase for genome amplification may be an important adaptation that allows exploitation of changing cellular conditions during cell cycle progression. We also describe a new method to quantify newly synthesized viral DNA levels and discuss its benefits for HPV research. PMID:26132923

  20. Barriers to human papillomavirus vaccine acceptability in Israel.

    PubMed

    Fisher, William A; Laniado, Hila; Shoval, Hila; Hakim, Marwan; Bornstein, Jacob

    2013-11-22

    Barriers to human papillomavirus (HPV) vaccine acceptability in Israel include Israel's relatively low incidence of cervical cancer; the religiously-based 80% circumcision rate in Israel, which is regarded as contributing to the lower incidence of HPV infection in the country; the fact that HPV vaccine provides immunity against only few virus types; the vaccine's high cost; and the perception that HPV transmission is associated with unacceptable sexual relations. A recent survey has demonstrated that, following media two campaigns, Israeli's level of awareness of the vaccine increased but the actual vaccination rate remained low, at approximately 10%. Survey findings also indicated that an enduring barrier to HPV vaccination is the vaccine's high cost. Recent research on a convenience sample of Israeli undergraduate women 21 to 24 years of age showed that intentions to receive HPV vaccination in the coming year were a function of women's attitudes towards getting vaccinated and their perceptions of social support for doing so. Undergraduate women who intended to be vaccinated perceived the prevention of cervical cancer, avoidance of personal health threat, and avoidance of HPV infection per se to be the advantages of undergoing HPV vaccination. Disadvantages of getting vaccinated included fear of vaccine side effects, cost of the vaccine, and newness of the vaccine, doubts about vaccines, time required to undergo multiple vaccinations, and dislike of injections. Friends', mothers' and physicians' recommendations influenced women's intentions to be vaccinated in the coming year as well. This article forms part of a regional report entitled "Comprehensive Control of HPV Infections and Related Diseases in Israel" Vaccine Volume 31, Supplement 8, 2013. Updates of the progress in the field are presented in a separate monograph entitled "Comprehensive Control of HPV Infections and Related Diseases" Vaccine Volume 30, Supplement 5, 2012. PMID:24229720

  1. Therapeutic human papillomavirus vaccines: current clinical trials and future directions

    PubMed Central

    Hung, Chien-Fu; Ma, Barbara; Monie, Archana; Tsen, Shaw-Wei; Wu, T-C

    2011-01-01

    Background Cervical cancer is the second largest cause of cancer deaths in women worldwide. It is now evident that persistent infection with high-risk human papillomavirus (HPV) is necessary for the development and maintenance of cervical cancer. Thus, effective vaccination against HPV represents an opportunity to restrain cervical cancer and other important cancers. The FDA recently approved the HPV vaccine Gardasil for the preventive control of HPV, using HPV virus-like particles (VLP) to generate neutralizing antibodies against major capsid protein, L1. However, prophylactic HPV vaccines do not have therapeutic effects against pre-existing HPV infections and HPV-associated lesions. Furthermore, due to the considerable burden of HPV infections worldwide, it would take decades for preventive vaccines to affect the prevalence of cervical cancer. Thus, in order to speed up the control of cervical cancer and treat current infections, the continued development of therapeutic vaccines against HPV is critical. Therapeutic HPV vaccines can potentially eliminate pre-existing lesions and malignant tumors by generating cellular immunity against HPV-infected cells that express early viral proteins such as E6 and E7. Objective This review discusses the future directions of therapeutic HPV vaccine approaches for the treatment of established HPV-associated malignancies, with emphasis on current progress of HPV vaccine clinical trials. Methods Relevant literature is discussed. Results/conclusion Though their development has been challenging, many therapeutic HPV vaccines have been shown to induce HPV-specific antitumor immune responses in preclinical animal models and several promising strategies have been applied in clinical trials. With continued progress in the field of vaccine development, HPV therapeutic vaccines may provide a potentially promising approach for the control of lethal HPV-associated malignancies. PMID:18352847

  2. Human Papillomavirus Infection in Women from Tlaxcala, Mexico

    PubMed Central

    Velázquez-Márquez, Noé; Jaime Jiménez-Aranda, Lucio; Sánchez-Alonso, Patricia; Santos-López, Gerardo; Reyes-Leyva, Julio; Vallejo-Ruiz, Verónica

    2010-01-01

    Cervical cancer is an important health problem in women living in developing countries. Infection with some genotypes of human papillomavirus (HPV) is the most important risk factor associated with cervical cancer. Little information exists about HPV genotype distribution in rural and suburban regions of Mexico. Thus, we determined the prevalence of HPV genotypes in women from Tlaxcala, one of the poorest states in central Mexico, and we evaluated age infection prevalence and risk factors associated with cervical neoplasm. A cross-sectional study was conducted in 236 women seeking gynecological care at the Mexican Institute for Social Security in Tlaxcala, Mexico. Cervical scrapings were diagnosed as normal, low-grade, and high-grade squamous intraepithelial lesions (LGSIL, HGSIL). Parallel samples were used to detect HPV genotypes by PCR assays using type-specific primers for HPV 6, 11, 16, 18, and 31. An epidemiological questionnaire was applied. Prevalence of HPV infection was 31.3%. From the infected samples, prevalence of HPV 16 was 45.9%; HPV 18, 31.1%; HPV 31, 16.2%; HPV 6, 10.8%; HPV 11, 6.7%. With regard to age, the highest HPV prevalence (43.5%) was found in the 18- to 24-year-old group and the lowest (19%) in the 45- to 54-year-old group. None of the risk factors showed association with cervical neoplasia grade. HPV 16 was the most common in cervical lesions. HPV was present in 22% of normal samples and, of these, 82.6% represented high-risk HPVs. Tlaxcala showed HPV prevalence comparable to that of the largest cities in Mexico, with higher prevalence for HPV 31. PMID:24031552

  3. Commercially available molecular tests for human papillomaviruses (HPV): 2015 update.

    PubMed

    Poljak, Mario; Kocjan, Boštjan J; Oštrbenk, Anja; Seme, Katja

    2016-03-01

    Commercial molecular tests for human papillomaviruses (HPV) are invaluable diagnostic tools in cervical carcinoma screening and management of women with cervical precancerous lesions as well as important research tools for epidemiological studies, vaccine development, and implementation and monitoring of vaccination programs. In this third inventory of commercial HPV tests, we identified 193 distinct commercial HPV tests and at least 127 test variants available on the market in 2015, which represents a 54% and 79% increase in the number of distinct HPV tests and variants, respectively, in comparison to our last inventory performed in 2012. Identified HPV tests were provisionally divided into eight main groups and several subgroups. Among the 193 commercial HPV tests, all but two target alpha-HPV types only. Although the number of commercial HPV tests with at least one published study in peer-reviewed literature has increased significantly in the last three years, several published performance evaluations are still not in line with agreed-upon standards in the HPV community. Manufacturers should invest greater effort into evaluating their products and publishing validation/evaluation results in peer-reviewed journals. To achieve this, more clinically oriented external quality-control panels and initiatives are required. For evaluating the analytical performance of the entire range of HPV tests currently on the market, more diverse and reliable external quality-control programs based on international standards for all important HPV types are indispensable. The performance of a wider range of HPV tests must be promptly evaluated on a variety of alternative clinical specimens. In addition, more complete HPV assays containing validated sample-extraction protocols and appropriate internal controls are urgently needed. Provision of a broader range of automated systems allowing large-scale HPV testing as well as the development of reliable, rapid, and affordable molecular

  4. Human Papillomavirus Genotype Distribution in Invasive Cervical Cancer in Pakistan.

    PubMed

    Loya, Asif; Serrano, Beatriz; Rasheed, Farah; Tous, Sara; Hassan, Mariam; Clavero, Omar; Raza, Muhammad; De Sanjosé, Silvia; Bosch, F Xavier; Alemany, Laia

    2016-01-01

    Few studies have assessed the burden of human papillomavirus (HPV) infection in Pakistan. We aim to provide specific information on HPV-type distribution in invasive cervical cancer (ICC) in the country. A total of 280 formalin-fixed paraffin-embedded tissue blocks were consecutively selected from Shaukat Khanum Memorial Cancer Hospital and Research Centre (Lahore, Pakistan). HPV-DNA was detected by SPF10 broad-spectrum PCR followed by DNA enzyme immunoassay and genotyping by LiPA25. HPV-DNA prevalence was 87.5% (95%CI: 83.0-91.1), with 96.1% of cases histologically classified as squamous cell carcinoma. Most of the HPV-DNA positive cases presented single infections (95.9%). HPV16 was the most common type followed by HPV18 and 45. Among HPV-DNA positive, a significantly higher contribution of HPV16/18 was detected in Pakistan (78.4%; 72.7-83.3), compared to Asia (71.6%; 69.9-73.4) and worldwide (70.8%; 69.9-71.8) and a lower contribution of HPVs31/33/45/52/58 (11.1%; 7.9-15.7 vs. 19.8%; 18.3-21.3 and 18.5%; 17.7-19.3). HPV18 or HPV45 positive ICC cases were significantly younger than cases infected by HPV16 (mean age: 43.3, 44.4, 50.5 years, respectively). A routine cervical cancer screening and HPV vaccination program does not yet exist in Pakistan; however, the country could benefit from national integrated efforts for cervical cancer prevention and control. Calculated estimations based on our results show that current HPV vaccine could potentially prevent new ICC cases. PMID:27483322

  5. Oral human papillomavirus is common in individuals with Fanconi anemia

    PubMed Central

    Sauter, Sharon L.; Wells, Susanne I.; Zhang, Xue; Hoskins, Elizabeth E.; Davies, Stella M.; Myers, Kasiani C.; Mueller, Robin; Panicker, Gitika; Unger, Elizabeth R.; Sivaprasad, Umasundari; Brown, Darron R.; Mehta, Parinda A.; Butsch Kovacic, Melinda

    2015-01-01

    Background Fanconi Anemia (FA) is a rare genetic disorder resulting in a loss of function of the FA-related DNA repair pathway. Individuals with FA are predisposed to some cancers including oropharyngeal and gynecological cancers with known associations with human papillomavirus (HPV) in the general population. Since individuals with FA respond poorly to chemotherapy and radiation, prevention of cancer is critical. Methods To determine if individuals with FA are particularly susceptible to oral HPV infection, we analyzed survey-based risk factor data and tested DNA isolated from oral rinses from 126 individuals with FA and 162 unaffected first-degree family members for 37 HPV types. Results Fourteen individuals (11.1%) with FA tested positive, significantly more (p=0.003) than family members (2.5%). While HPV prevalence was even higher for sexually active individuals with FA (17.7% vs. 2.4% in family; p=0.003), HPV positivity also tended to be higher in the sexually inactive (8.7% in FA vs. 2.9% in siblings). Indeed, having FA increased HPV positivity 4.9 fold (95%CI: 1.6–15.4) considering age and sexual experience, but did not differ by other potential risk factors. Conclusion Our studies suggest that oral HPV is more common in individuals with FA. It will be essential to continue to explore associations between risk factors and immune dysfunction on HPV incidence and persistence over time. Impact HPV vaccination should be emphasized in those with FA as a first step to prevent oropharyngeal cancers, although additional studies are needed to determine if the level of protection it offers in this population is adequate. PMID:25809863

  6. The Cell Cycle Timing of Human Papillomavirus DNA Replication.

    PubMed

    Reinson, Tormi; Henno, Liisi; Toots, Mart; Ustav, Mart; Ustav, Mart

    2015-01-01

    Viruses manipulate the cell cycle of the host cell to optimize conditions for more efficient viral genome replication. One strategy utilized by DNA viruses is to replicate their genomes non-concurrently with the host genome; in this case, the viral genome is amplified outside S phase. This phenomenon has also been described for human papillomavirus (HPV) vegetative genome replication, which occurs in G2-arrested cells; however, the precise timing of viral DNA replication during initial and stable replication phases has not been studied. We developed a new method to quantitate newly synthesized DNA levels and used this method in combination with cell cycle synchronization to show that viral DNA replication is initiated during S phase and is extended to G2 during initial amplification but follows the replication pattern of cellular DNA during S phase in the stable maintenance phase. E1 and E2 protein overexpression changes the replication time from S only to both the S and G2 phases in cells that stably maintain viral episomes. These data demonstrate that the active synthesis and replication of the HPV genome are extended into the G2 phase to amplify its copy number and the duration of HPV genome replication is controlled by the level of the viral replication proteins E1 and E2. Using the G2 phase for genome amplification may be an important adaptation that allows exploitation of changing cellular conditions during cell cycle progression. We also describe a new method to quantify newly synthesized viral DNA levels and discuss its benefits for HPV research. PMID:26132923

  7. Immune therapy for human papillomaviruses-related cancers

    PubMed Central

    Rosales, Ricardo; Rosales, Carlos

    2014-01-01

    Human papillomaviruses (HPVs) are a large family of double strand DNA viruses comprising more than 180 types. Infection with HPV is very common and it is associated with benign and malignant proliferation of skin and squamous mucosae. Many HPVs, considered low-risk such as HPV 6 and 11, produce warts; while high-risk viruses, such as HPVs 16, 18, 31, 33, 35, 39, 45, 51, 52, 56, and 58, induce tumors. About 5% of all cancers in men and women are associated with HPV infection. Because there are not antiviral drugs for HPV infection, current therapies for low-risk HPV infections involve physical removal of the lesion by cryotherapy, trichloracetic acid, laser, or surgical removal. Surgical procedures are effective in the treatment of pre-cancerous lesions, however after these procedures, many recurrences appear due to new re-infections, or to failure of the procedure to eliminate the HPV. In addition, HPV can inhibit recognition of malignant cells by the immune system, leading to the development of cancer lesions. When this occurs, radiotherapy and chemotherapy are then used. Unfortunately, about 50% of the HPV-cancer patients still die. In the past decade, a better knowledge of the natural history of the virus-host interaction and of the immune response against this viral infection has brought new therapeutic strategies geared to modulate the immune system to generate an efficient virus-specific cytotoxic response. Novel HPV protein-expressing vaccines have shown some significant clinical efficacy and systemic HPV-specific cytotoxic T cell responses. This review will describe the current status of the several therapeutic strategies used to treat HPV-induced lesions, and discuss the various new therapies now being tested. PMID:25493236

  8. DNA sequence and genome organization of genital human papillomavirus type 6b.

    PubMed Central

    Schwarz, E; Dürst, M; Demankowski, C; Lattermann, O; Zech, R; Wolfsperger, E; Suhai, S; zur Hausen, H

    1983-01-01

    The complete nucleotide sequence of the circular double-stranded DNA of the genital human papillomavirus type 6b (HPV6b) comprising 7902 bp was determined and compared with the DNA sequences of human papillomavirus type 1a (HPV1a) and bovine papillomavirus type 1 (BPV1). All major open reading frames are located on one DNA strand only. Their arrangement reveals that the genomic organization of HPV6b is similar to that of HPV1a and BPV1. The putative early region includes two large open reading frames E1 and E2 with marked amino acid sequence homologies to HPV1a and BPV1 which are flanked by several smaller frames. The internal part of E2 completely overlaps with another open reading frame E4. The putative late region contains two large open reading frames L1 and L2. The L1 amino acid sequences are highly conserved among analyzed papillomavirus types. By sequence comparison, potential promoter, splicing and polyadenylation signals can be localized in HPV6b DNA suggesting possible mechanisms of genital papillomavirus gene expression. PMID:6321162

  9. Lifelong widespread warts associated with human papillomavirus type 70/85: a new diagnostic entity?

    PubMed

    Giuliodori, Katia; Campanati, Anna; Liberati, Giulia; Ganzetti, Giulia; Giangiacomi, Mirella; Marinelli, Katia; Cataldi, Ivana; Marconi, Barbara; Offidani, Annamaria

    2016-01-01

    We present a patient with HPV 70/85-positive widespread cutaneous warts characterized by clinical and histological features atypical for classic generalized verrucosis or epidermodysplasia verruciformis. The cutaneous HPV infection is characterized by verrucous papules or plaques variable in size, number, and distribution depending on the genotype of HPV involved and the immune status of the patient. Human papillomaviruses comprise five genera (alpha, beta, gamma, mu, and nu papillomavirus) with different life-cycle characteristics, epithelial tropisms, and disease associations. Epidermodysplasia verruciformis (EV) is a rare, lifelong, autosomal recessive skin disease characterized by persistent cutaneous human papillomavirus infection not necessarily associated with immune system defects. The disease results from an unusual genetic susceptibility to infections with various types of HPVs (especially β-HPV), some of which cause malignant transformation. Conversely, generalized verrucosis has been more typically associated with generalized warts, which are associated with immunocompromised conditions. PMID:27014773

  10. High prevalence of high risk human papillomavirus-capsid antibodies in human immunodeficiency virus-seropositive men: a serological study

    PubMed Central

    Höpfl, Reinhard; Petter, Anton; Thaler, Petra; Sarcletti, Mario; Widschwendter, Andreas; Zangerle, Robert

    2003-01-01

    Background Serological study of human papillomavirus (HPV)-antibodies in order to estimate the HPV-prevalence as risk factor for the development of HPV-associated malignancies in human immunodeficiency virus (HIV)-positive men. Methods Sera from 168 HIV-positive men and 330 HIV-negative individuals (including 198 controls) were tested using a direct HPV-ELISA specific to HPV-6, -11, -16, -18, -31 and bovine PV-1 L1-virus-like particles. Serological results were correlated with the presence of HPV-associated lesions, the history of other sexually transmitted diseases (STD) and HIV classification groups. Results In HIV-negative men low risk HPV-antibodies were prevailing and associated with condylomatous warts (25.4%). Strikingly, HIV-positive men were more likely to have antibodies to the high-risk HPV types -16, -18, -31, and low risk antibodies were not increased in a comparable range. Even those HIV-positive heterosexual individuals without any HPV-associated lesions exhibited preferentially antibody responses to the oncogenic HPV-types (cumulative 31.1%). The highest antibody detection rate (88,8%) was observed within the subgroup of nine HIV-positive homosexual men with anogenital warts. Three HIV-positive patients had HPV-associated carcinomas, in all of them HPV-16 antibodies were detected. Drug use and mean CD4-cell counts on the day of serologic testing had no influence on HPV-IgG antibody prevalence, as had prior antiretroviral therapy or clinical category of HIV-disease. Conclusion High risk HPV-antibodies in HIV-infected and homosexual men suggest a continuous exposure to HPV-proteins throughout the course of their HIV infection, reflecting the known increased risk for anogenital malignancies in these populations. The extensive increase of high risk antibodies (compared to low risk antibodies) in HIV-positive patients cannot be explained by differences in exposure history alone, but suggests defects of the immunological control of oncogenic HPV

  11. Updating the Natural History of Human Papillomavirus and Anogenital Cancers

    PubMed Central

    Moscicki, Anna-Barbara; Schiffman, Mark; Burchell, Ann; Albero, Ginesa; Giuliano, Anna; Goodman, Marc T.; Kjaer, Susanne K.; Palefsky, Joel

    2013-01-01

    This chapter addresses the natural history of anogenital human papillomavirus (HPV) infection. Cervical infections are the best understood HPV infection. Cervical HPV persistence is the known necessary event for the development of cervical cancer. New infections appearing at any age are benign unless they persist. Several long-term natural history studies have now shed light on the very low risk of cervical intraepithelial neoplasia (CIN) 3+ in women past the peak of HPV acquisition (e.g., 30 or older) who are HPV-negative or clear their HPV. Although data on transmission of HPV are finally emerging, rates of transmission between heterosexual couples vary widely among studies. Factors that affect the calculations of these rates include a) intervals between testing points, b) rates of concordance or discordance at baseline, and c) difficulty in defining established infections versus contamination. Both cervix to anus and anus to cervix autoinoculation in the same woman appears to be quite common. Whether either site serves as a long-term reservoir is unknown. Studies show that anal infections in women and in men who have sex with men are quite common with cumulative rates up to 70–90%. Similarly, clearance of anal HPV is also common, with few individuals showing persistence unless they are human immunodeficiency virus (HIV)-infected. HIV strongly influences the development of anal intraepithelial neoplasia (AIN). The few studies on the natural history of AIN in HIV-infected men suggest that high-grade AIN is a precursor to invasive anal cancer. Although no natural history studies of AIN are available in women, women with other HPV-associated lesions, including CIN3+ and vulvar cancer, have higher rates of anal cancer. Data on the natural history of HPV of the male genitalia are also emerging, although penile intraepithelial neoplasia is poorly understood. Cumulative rates of HPV are extremely high in men and risks are associated with sexual behavior. Unlike women

  12. Oncogenic rearrangements driving ionizing radiation–associated human cancer

    PubMed Central

    Santoro, Massimo; Carlomagno, Francesca

    2013-01-01

    The Chernobyl nuclear disaster has caused a remarkable increase in radiation-induced papillary thyroid carcinoma in children and young adults. In this issue of the JCI, Ricarte-Filho and colleagues demonstrate that chromosomal rearrangements are the oncogenic “drivers” in most post-Chernobyl carcinomas and that they often lead to unscheduled activation of the MAPK signaling pathway. These findings represent a major step forward in our understanding of radiation-induced carcinogenesis and suggest various hypotheses about the mechanisms underlying the formation and selection of gene rearrangements during cancer cell evolution. PMID:24162670

  13. In vivo transformation of human skin with human papillomavirus type 11 from condylomatot acuminata

    SciTech Connect

    Kreider, J.W.; Howett, M.K.; Lill, N.L.; Bartlett, G.L.; Zaino, R.J.; Sedlacek, T.V.; Mortel, R.

    1986-08-01

    Human papillomaviruses (HPVs) have been implicated in the development of a number of human malignancies, but direct tests of their involvement have not been possible. The authors describe a system in which human skin from various skin from various sites was infected with HPV type 11 (HPV-11) extracted from vulvar condylomata and was grafted beneath the renal capsule of athymic mice. Most of the skin grafts so treated underwent morphological transformation, resulting in the development of condylomata identical to those which occur spontaneously in patients. Foreskins responded with the most vigorous proliferative response to HPV-11. The lesions produced the characteristic intranuclear group-specific antigen of papillomaviruses. Both dot blot and Southern blot analysis of DNA from the lesions revealed the presence of HPV-11 DNA in the transformed grafts. These results demonstrate the first laboratory system for the study of the interaction of human skin with an HPV. The method may be useful in understanding the mechanisms of HPV transformation and replication and is free of the ethical restraints which have impeded study. This system will allow the direct study of factors which permit neoplastic progression of HPV-induced cutaneous lesions in human tissues.

  14. Detection of human papillomavirus types in balanitis xerotica obliterans and other penile conditions.

    PubMed Central

    Lau, P W; Cook, N; Andrews, H; Bracka, A; Myint, S H

    1995-01-01

    OBJECTIVES--To determine the prevalence of human papillomavirus (HPV) types 6, 11, 16 and 18 in foreskin biopsies from patients with balanitis xerotica obliterans (BXO) and other penile conditions. MATERIALS AND METHODS--Foreskin biopsy specimens from 24 patients with penile lesions and 5 control patients were analysed by type-specific polymerase chain reaction (PCR). RESULTS--HPV6 or HPV16 were not detected in patients with BXO. HPV6 was detected in 2 controls. CONCLUSIONS--Genital papillomaviruses do not have a strong association with BXO. Images PMID:7590713

  15. Characterization of human papillomavirus type 13 from focal epithelial hyperplasia Heck lesions.

    PubMed Central

    Pfister, H; Hettich, I; Runne, U; Gissmann, L; Chilf, G N

    1983-01-01

    Focal epithelial hyperplasia Heck lesions of a Turkish patient were shown to contain papillomavirus-specific DNA, which was molecularly cloned into bacteriophage lambda. It proved to be related to human papillomavirus (HPV) type 6 DNA and HPV type 11 DNA. Reassociation kinetics revealed a cross-hybridization of 4 and 3%, respectively. There was no cross-reactivity with HPV type 1, 2, 3, 4, 5, 8, or 10. This papillomavirus type will be referred to as HPV type 13. The DNA was characterized by cleavage with several restriction enzymes, and the cleavage sites were physically mapped. Papules from two additional cases of Morbus Heck contained HPV type 13 DNA as shown by Southern blot hybridization and by the characteristic cleavage patterns. This may indicate that HPV type 13 is more frequently associated with focal epithelial hyperplasia Heck than are other HPV types. Images PMID:6312071

  16. Human papillomavirus infection, vaccination, and cervical cancer communication: the protection dilemma faced by women in southern Appalachia.

    PubMed

    Hutson, Sadie P; Dorgan, Kelly A; Duvall, Kathryn L; Garrett, Linda H

    2011-11-30

    Human papillomavirus is the most frequently occurring sexually transmitted infection and has been recognized as the necessary cause of cervical cancer. Understanding the shift in public awareness caused by recent changes to cervical prevention is critical to addressing cervical cancer disparities in Appalachia. Since the human papillomavirus vaccine was approved for prevention, little data have been collected regarding human papillomavirus risk assessment and vaccine perceptions among Appalachian women. The purpose of the authors in this study was to investigate communication and cultural issues via a social scripting framework that could influence human papillomavirus vaccine uptake among southern Appalachian women; and explore participants' perceptions of human papillomavirus, cervical cancer, and the vaccine. A qualitative, descriptive design was employed to examine these issues in eight counties in northeast Tennessee and southwest Virginia. Thirty-nine women aged 18-49 years participated in a single individual interview or focus group session from October 2007 through August 2008. Interview and focus group data were audio-taped and transcribed verbatim. Two major themes emerged from the data: the human papillomavirus vaccine protection dilemma and spheres of silence surrounding the human papillomavirus vaccine protection dilemma. Study findings suggested areas for future research and may assist healthcare professionals in approaching southern Appalachian women as they make decisions regarding cervical cancer prevention. PMID:22185292

  17. Intracellular Analysis of the Interaction between the Human Papillomavirus Type 16 E6 Oncoprotein and Inhibitory Peptides.

    PubMed

    Stutz, Christina; Reinz, Eileen; Honegger, Anja; Bulkescher, Julia; Schweizer, Johannes; Zanier, Katia; Travé, Gilles; Lohrey, Claudia; Hoppe-Seyler, Karin; Hoppe-Seyler, Felix

    2015-01-01

    Oncogenic types of human papillomaviruses (HPVs) cause cervical cancer and other malignancies in humans. The HPV E6 oncoprotein is considered to be an attractive therapeutic target since its inhibition can lead to the apoptotic cell death of HPV-positive cancer cells. The HPV type 16 (HPV16) E6-binding peptide pep11, and variants thereof, induce cell death specifically in HPV16-positive cancer cells. Although they do not encompass the LxxLL binding motif found in cellular HPV16 E6 interaction partners, such as E6AP, the pep11 variants strongly bind to HPV16 E6 by contacting the recently identified E6AP binding pocket. Thus, these peptides can serve as prototype E6-inhibitory molecules which target the E6AP pocket. We here analyzed their intracellular interaction with HPV16 E6. By comprehensive intracellular binding studies and GST pull-down assays, we show that E6-binding competent pep11 variants induce the formation of a trimeric complex, consisting of pep11, HPV16 E6 and p53. These findings indicate that peptides, which do not contain the LxxLL motif, can reshape E6 to enable its interaction with p53. The formation of the trimeric HPV16 E6 / peptide / p53 complex was associated with an increase of endogenous HPV16 E6 protein amounts. Yet, total cellular p53 amounts were also increased, indicating that the E6 / E6AP-mediated degradation of p53 is blocked. These findings suggest that inhibition of oncogenic activities by targeting the E6AP pocket on HPV16 E6 could be a strategy for therapeutic intervention. PMID:26151636

  18. Comprehensive control of human papillomavirus infections and related diseases.

    PubMed

    Bosch, F Xavier; Broker, Thomas R; Forman, David; Moscicki, Anna-Barbara; Gillison, Maura L; Doorbar, John; Stern, Peter L; Stanley, Margaret; Arbyn, Marc; Poljak, Mario; Cuzick, Jack; Castle, Philip E; Schiller, John T; Markowitz, Lauri E; Fisher, William A; Canfell, Karen; Denny, Lynette A; Franco, Eduardo L; Steben, Marc; Kane, Mark A; Schiffman, Mark; Meijer, Chris J L M; Sankaranarayanan, Rengaswamy; Castellsagué, Xavier; Kim, Jane J; Brotons, Maria; Alemany, Laia; Albero, Ginesa; Diaz, Mireia; de Sanjosé, Silvia

    2013-11-22

    Infection with human papillomavirus (HPV) is recognized as one of the major causes of infection-related cancer worldwide, as well as the causal factor in other diseases. Strong evidence for a causal etiology with HPV has been stated by the International Agency for Research on Cancer for cancers of the cervix uteri, penis, vulva, vagina, anus and oropharynx (including base of the tongue and tonsils). Of the estimated 12.7 million new cancers occurring in 2008 worldwide, 4.8% were attributable to HPV infection, with substantially higher incidence and mortality rates seen in developing versus developed countries. In recent years, we have gained tremendous knowledge about HPVs and their interactions with host cells, tissues and the immune system; have validated and implemented strategies for safe and efficacious prophylactic vaccination against HPV infections; have developed increasingly sensitive and specific molecular diagnostic tools for HPV detection for use in cervical cancer screening; and have substantially increased global awareness of HPV and its many associated diseases in women, men, and children. While these achievements exemplify the success of biomedical research in generating important public health interventions, they also generate new and daunting challenges: costs of HPV prevention and medical care, the implementation of what is technically possible, socio-political resistance to prevention opportunities, and the very wide ranges of national economic capabilities and health care systems. Gains and challenges faced in the quest for comprehensive control of HPV infection and HPV-related cancers and other disease are summarized in this review. The information presented may be viewed in terms of a reframed paradigm of prevention of cervical cancer and other HPV-related diseases that will include strategic combinations of at least four major components: 1) routine introduction of HPV vaccines to women in all countries, 2) extension and simplification of

  19. Comprehensive control of human papillomavirus infections and related diseases.

    PubMed

    Bosch, F Xavier; Broker, Thomas R; Forman, David; Moscicki, Anna-Barbara; Gillison, Maura L; Doorbar, John; Stern, Peter L; Stanley, Margaret; Arbyn, Marc; Poljak, Mario; Cuzick, Jack; Castle, Philip E; Schiller, John T; Markowitz, Lauri E; Fisher, William A; Canfell, Karen; Denny, Lynette A; Franco, Eduardo L; Steben, Marc; Kane, Mark A; Schiffman, Mark; Meijer, Chris J L M; Sankaranarayanan, Rengaswamy; Castellsagué, Xavier; Kim, Jane J; Brotons, Maria; Alemany, Laia; Albero, Ginesa; Diaz, Mireia; de Sanjosé, Silvia

    2013-12-31

    Infection with human papillomavirus (HPV) is recognized as one of the major causes of infection-related cancer worldwide, as well as the causal factor in other diseases. Strong evidence for a causal etiology with HPV has been stated by the International Agency for Research on Cancer for cancers of the cervix uteri, penis, vulva, vagina, anus and oropharynx (including base of the tongue and tonsils). Of the estimated 12.7 million new cancers occurring in 2008 worldwide, 4.8% were attributable to HPV infection, with substantially higher incidence and mortality rates seen in developing versus developed countries. In recent years, we have gained tremendous knowledge about HPVs and their interactions with host cells, tissues and the immune system; have validated and implemented strategies for safe and efficacious prophylactic vaccination against HPV infections; have developed increasingly sensitive and specific molecular diagnostic tools for HPV detection for use in cervical cancer screening; and have substantially increased global awareness of HPV and its many associated diseases in women, men, and children. While these achievements exemplify the success of biomedical research in generating important public health interventions, they also generate new and daunting challenges: costs of HPV prevention and medical care, the implementation of what is technically possible, socio-political resistance to prevention opportunities, and the very wide ranges of national economic capabilities and health care systems. Gains and challenges faced in the quest for comprehensive control of HPV infection and HPV-related cancers and other disease are summarized in this review. The information presented may be viewed in terms of a reframed paradigm of prevention of cervical cancer and other HPV-related diseases that will include strategic combinations of at least four major components: 1) routine introduction of HPV vaccines to women in all countries, 2) extension and simplification of

  20. Comprehensive control of human papillomavirus infections and related diseases.

    PubMed

    Bosch, F Xavier; Broker, Thomas R; Forman, David; Moscicki, Anna-Barbara; Gillison, Maura L; Doorbar, John; Stern, Peter L; Stanley, Margaret; Arbyn, Marc; Poljak, Mario; Cuzick, Jack; Castle, Philip E; Schiller, John T; Markowitz, Lauri E; Fisher, William A; Canfell, Karen; Denny, Lynette A; Franco, Eduardo L; Steben, Marc; Kane, Mark A; Schiffman, Mark; Meijer, Chris J L M; Sankaranarayanan, Rengaswamy; Castellsagué, Xavier; Kim, Jane J; Brotons, Maria; Alemany, Laia; Albero, Ginesa; Diaz, Mireia; de Sanjosé, Silvia

    2013-12-30

    Infection with human papillomavirus (HPV) is recognized as one of the major causes of infection-related cancer worldwide, as well as the causal factor in other diseases. Strong evidence for a causal etiology with HPV has been stated by the International Agency for Research on Cancer for cancers of the cervix uteri, penis, vulva, vagina, anus and oropharynx (including base of the tongue and tonsils). Of the estimated 12.7 million new cancers occurring in 2008 worldwide, 4.8% were attributable to HPV infection, with substantially higher incidence and mortality rates seen in developing versus developed countries. In recent years, we have gained tremendous knowledge about HPVs and their interactions with host cells, tissues and the immune system; have validated and implemented strategies for safe and efficacious prophylactic vaccination against HPV infections; have developed increasingly sensitive and specific molecular diagnostic tools for HPV detection for use in cervical cancer screening; and have substantially increased global awareness of HPV and its many associated diseases in women, men, and children. While these achievements exemplify the success of biomedical research in generating important public health interventions, they also generate new and daunting challenges: costs of HPV prevention and medical care, the implementation of what is technically possible, socio-political resistance to prevention opportunities, and the very wide ranges of national economic capabilities and health care systems. Gains and challenges faced in the quest for comprehensive control of HPV infection and HPV-related cancers and other disease are summarized in this review. The information presented may be viewed in terms of a reframed paradigm of prevention of cervical cancer and other HPV-related diseases that will include strategic combinations of at least four major components: 1) routine introduction of HPV vaccines to women in all countries, 2) extension and simplification of

  1. Human papillomavirus-related carcinomas of the sinonasal tract.

    PubMed

    Bishop, Justin A; Guo, Theresa W; Smith, David F; Wang, Hao; Ogawa, Takenori; Pai, Sara I; Westra, William H

    2013-02-01

    High-risk human papillomavirus (HPV) is an established cause of head and neck carcinomas arising in the oropharynx. The presence of HPV has also been reported in some carcinomas arising in the sinonasal tract, but little is known about their overall incidence or their clinicopathologic profile. The surgical pathology archives of The Johns Hopkins Hospital were searched for all carcinomas arising in the sinonasal tract from 1995 to 2011, and tissue microarrays were constructed. p16 immunohistochemical analysis and DNA in situ hybridization for high-risk types of HPV were performed. Demographic and clinical outcome data were extracted from patient medical records. Of 161 sinonasal carcinomas, 34 (21%) were positive for high-risk HPV DNA, including type 16 (82%), type 31/33 (12%), and type 18 (6%). HPV-positive carcinomas consisted of 28 squamous cell carcinomas and variants (15 nonkeratinizing or partially keratinizing, 4 papillary, 5 adenosquamous, 4 basaloid), 1 small cell carcinoma, 1 sinonasal undifferentiated carcinoma, and 4 carcinomas that were difficult to classify but exhibited adenoid cystic carcinoma-like features. Immunohistochemistry for p16 was positive in 59/161 (37%) cases, and p16 expression strongly correlated with the presence of HPV DNA: 33 of 34 (97%) HPV-positive tumors exhibited high p16 expression, whereas only 26 of 127 (20%) HPV-negative tumors were p16 positive (P<0.0001). The HPV-related carcinomas occurred in 19 men and 15 women ranging in age from 33 to 87 years (mean, 54 y). A trend toward improved survival was observed in the HPV-positive group (hazard ratio=0.58, 95% confidence interval [0.26, 1.28]). The presence of high-risk HPV in 21% of sinonasal carcinomas confirms HPV as an important oncologic agent of carcinomas arising in the sinonasal tract. Although nonkeratinizing squamous cell carcinoma is the most common histologic type, there is a wide morphologic spectrum of HPV-related disease that includes a variant that resembles

  2. Comprehensive Control of Human Papillomavirus Infections and Related Diseases

    PubMed Central

    Bosch, F. Xavier; Broker, Thomas R.; Forman, David; Moscicki, Anna-Barbara; Gillison, Maura L.; Doorbar, John; Stern, Peter L.; Stanley, Margaret; Arbyn, Marc; Poljak, Mario; Cuzick, Jack; Castle, Philip E.; Schiller, John T.; Markowitz, Lauri E.; Fisher, William A.; Canfell, Karen; Denny, Lynette A.; Franco, Eduardo L.; Steben, Marc; Kane, Mark A.; Schiffman, Mark; Meijer, Chris J.L.M.; Sankaranarayanan, Rengaswamy; Castellsagué, Xavier; Kim, Jane J.; Brotons, Maria; Alemany, Laia; Albero, Ginesa; Diaz, Mireia; de Sanjosé, Silvia

    2014-01-01

    Infection with human papillomavirus (HPV) is recognized as one of the major causes of infection-related cancer worldwide, as well as the causal factor in other diseases. Strong evidence for a causal etiology with HPV has been stated by the International Agency for Research on Cancer for cancers of the cervix uteri, penis, vulva, vagina, anus and oropharynx (including base of the tongue and tonsils). Of the estimated 12.7 million new cancers occurring in 2008 worldwide, 4.8% were attributable to HPV infection, with substantially higher incidence and mortality rates seen in developing versus developed countries. In recent years, we have gained tremendous knowledge about HPVs and their interactions with host cells, tissues and the immune system; have validated and implemented strategies for safe and efficacious prophylactic vaccination against HPV infections; have developed increasingly sensitive and specific molecular diagnostic tools for HPV detection for use in cervical cancer screening; and have substantially increased global awareness of HPV and its many associated diseases in women, men, and children. While these achievements exemplify the success of biomedical research in generating important public health interventions, they also generate new and daunting challenges: costs of HPV prevention and medical care, the implementation of what is technically possible, socio-political resistance to prevention opportunities, and the very wide ranges of national economic capabilities and health care systems. Gains and challenges faced in the quest for comprehensive control of HPV infection and HPV-related cancers and other disease are summarized in this review. The information presented may be viewed in terms of a reframed paradigm of prevention of cervical cancer and other HPV-related diseases that will include strategic combinations of at least four major components: 1) routine introduction of HPV vaccines to women in all countries, 2) extension and simplification of

  3. A Review of Clinical Trials of Human Papillomavirus Prophylactic Vaccines

    PubMed Central

    Schiller, John T.; Castellsagué, Xavier; Garland, Suzanne M.

    2015-01-01

    End of study analyses of the phase III trials of prophylactic human papillomavirus (HPV) virus-like particle (VLP) vaccines in young women are now largely completed. Two distinct vaccines were evaluated, Gardasil® (Merck & Co., Whitehouse Station, NJ USA) a quadrivalent vaccine containing VLPs of types 6, 11, 16 and 18 and Cervarix® (GlaxoSmithKline Biologicals, Rixensart, Belgium), a bivalent vaccine containing VLPs of types 16 and 18. Both vaccines exhibited excellent safety and immunogenicity profiles. The vaccines also demonstrated remarkably high and similar efficacy against the vaccine-targeted types for a range of cervical endpoints from persistent infection to cervical intraepithelial neoplasia grade 3 (CIN3) in women naïve to the corresponding type at the time of vaccination. However, protection from incident infection or disease from non-vaccine types was restricted, and the vaccines had no effect on prevalent infection or disease. Gardasil® also demonstrated strong protection against genital warts and vulvar/vaginal neoplasia associated with the vaccine types. In other trials, Gardasil® protected mid-adult women from incident infection and CIN caused by the vaccine types and protected men for incident infection, genital warts and anal intraepithelial neoplasia by the vaccine types. Cervarix® protected against vaccine-targeted anal infections in women in an end of study evaluation. For practical reasons, efficacy studies have not been conducted in the primary target populations of current vaccination programs, adolescent girls and boys. However, immunogenicity bridging studies demonstrating excellent safety and strong immune responses in adolescence, coupled with the documentation of durable antibody responses and protection in young adults, leads to an optimistic projection of the effectiveness of the vaccines in adolescent vaccination programs. Taken together, the excellent clinical trial results strongly support the potential of the vaccines as

  4. Comprehensive control of human papillomavirus infections and related diseases.

    PubMed

    Bosch, F Xavier; Broker, Thomas R; Forman, David; Moscicki, Anna-Barbara; Gillison, Maura L; Doorbar, John; Stern, Peter L; Stanley, Margaret; Arbyn, Marc; Poljak, Mario; Cuzick, Jack; Castle, Philip E; Schiller, John T; Markowitz, Lauri E; Fisher, William A; Canfell, Karen; Denny, Lynette A; Franco, Eduardo L; Steben, Marc; Kane, Mark A; Schiffman, Mark; Meijer, Chris J L M; Sankaranarayanan, Rengaswamy; Castellsagué, Xavier; Kim, Jane J; Brotons, Maria; Alemany, Laia; Albero, Ginesa; Diaz, Mireia; de Sanjosé, Silvia

    2013-12-29

    Infection with human papillomavirus (HPV) is recognized as one of the major causes of infection-related cancer worldwide, as well as the causal factor in other diseases. Strong evidence for a causal etiology with HPV has been stated by the International Agency for Research on Cancer for cancers of the cervix uteri, penis, vulva, vagina, anus and oropharynx (including base of the tongue and tonsils). Of the estimated 12.7 million new cancers occurring in 2008 worldwide, 4.8% were attributable to HPV infection, with substantially higher incidence and mortality rates seen in developing versus developed countries. In recent years, we have gained tremendous knowledge about HPVs and their interactions with host cells, tissues and the immune system; have validated and implemented strategies for safe and efficacious prophylactic vaccination against HPV infections; have developed increasingly sensitive and specific molecular diagnostic tools for HPV detection for use in cervical cancer screening; and have substantially increased global awareness of HPV and its many associated diseases in women, men, and children. While these achievements exemplify the success of biomedical research in generating important public health interventions, they also generate new and daunting challenges: costs of HPV prevention and medical care, the implementation of what is technically possible, socio-political resistance to prevention opportunities, and the very wide ranges of national economic capabilities and health care systems. Gains and challenges faced in the quest for comprehensive control of HPV infection and HPV-related cancers and other disease are summarized in this review. The information presented may be viewed in terms of a reframed paradigm of prevention of cervical cancer and other HPV-related diseases that will include strategic combinations of at least four major components: 1) routine introduction of HPV vaccines to women in all countries, 2) extension and simplification of

  5. Long-term efficacy and safety of human papillomavirus vaccination

    PubMed Central

    De Vincenzo, Rosa; Conte, Carmine; Ricci, Caterina; Scambia, Giovanni; Capelli, Giovanni

    2014-01-01

    In this paper, we review the published evidence about the long-term efficacy of the available human papillomavirus (HPV) vaccines and their safety profile. Two prophylactic HPV vaccines – bivalent (bHPV) and quadrivalent (qHPV) – are now available, and vaccination programs are being widely implemented, primarily targeting adolescent girls. Efficacy has been widely demonstrated for both vaccines. Since the risk of HPV exposure potentially persists throughout a woman’s sexual life, vaccine duration of protection is critical to overall effectiveness. Interpreting the results of long-term efficacy studies for the two HPV vaccines can be puzzling, due to the heterogeneity of studies, different methods used in the assessment of immunogenicity, histopathological and virological end points, and statistical power issues. Moreover, an immunologic correlate of protection has not yet been established, and it is unknown whether higher antibody levels will really result in a longer duration of protection. Disease prevention remains the most important measure of long-term duration of vaccine efficacy. To date, the longest follow-up of an HPV vaccine has been 9.4 years for the bHPV vaccine. Long-term follow-up for qHPV vaccine goes up to 8 years. The vaccine continues to be immunogenic and well tolerated up to 9 years following vaccination. All randomized controlled clinical trials of the bHPV and the qHPV vaccines provide evidence of an excellent safety profile. The most common complaint reported is pain in the injection site, which is self-limiting and spontaneously resolved. The incidence of systemic adverse events (AEs), serious AEs, and discontinuations due to a serious AE reported in clinical studies are similar between the two vaccines and their control groups. In particular, no increased risk of autoimmune disease has been shown among HPV-vaccinated subjects in long-term observation studies. As these are crucial topics in HPV vaccination, it is important to establish

  6. Multivalent Human Papillomavirus L1 DNA Vaccination Utilizing Electroporation

    PubMed Central

    Kwak, Kihyuck; Jiang, Rosie; Jagu, Subhashini; Wang, Joshua W.; Wang, Chenguang; Christensen, Neil D.; Roden, Richard B. S.

    2013-01-01

    Objectives Naked DNA vaccines can be manufactured simply and are stable at ambient temperature, but require improved delivery technologies to boost immunogenicity. Here we explore in vivo electroporation for multivalent codon-optimized human papillomavirus (HPV) L1 and L2 DNA vaccination. Methods Balb/c mice were vaccinated three times at two week intervals with a fusion protein comprising L2 residues ∼11−88 of 8 different HPV types (11−88×8) or its DNA expression vector, DNA constructs expressing L1 only or L1+L2 of a single HPV type, or as a mixture of several high-risk HPV types and administered utilizing electroporation, i.m. injection or gene gun. Serum was collected two weeks and 3 months after the last vaccination. Sera from immunized mice were tested for in-vitro neutralization titer, and protective efficacy upon passive transfer to naive mice and vaginal HPV challenge. Heterotypic interactions between L1 proteins of HPV6, HPV16 and HPV18 in 293TT cells were tested by co-precipitation using type-specific monoclonal antibodies. Results Electroporation with L2 multimer DNA did not elicit detectable antibody titer, whereas DNA expressing L1 or L1+L2 induced L1-specific, type-restricted neutralizing antibodies, with titers approaching those induced by Gardasil. Co-expression of L2 neither augmented L1-specific responses nor induced L2-specific antibodies. Delivery of HPV L1 DNA via in vivo electroporation produces a stronger antibody response compared to i.m. injection or i.d. ballistic delivery via gene gun. Reduced neutralizing antibody titers were observed for certain types when vaccinating with a mixture of L1 (or L1+L2) vectors of multiple HPV types, likely resulting from heterotypic L1 interactions observed in co-immunoprecipitation studies. High titers were restored by vaccinating with individual constructs at different sites, or partially recovered by co-expression of L2, such that durable protective antibody titers were achieved for each type

  7. Characterization of the Human Papillomavirus 16 E8 Promoter

    PubMed Central

    Straub, Elke; Fertey, Jasmin; Dreer, Marcel; Iftner, Thomas

    2015-01-01

    ABSTRACT Persistent infections with certain human papillomaviruses (HPV) such as HPV16 are a necessary risk factor for the development of anogenital and oropharyngeal cancers. HPV16 genomes replicate as low-copy-number plasmids in the nucleus of undifferentiated keratinocytes, which requires the viral E1 and E2 replication proteins. The HPV16 E8^E2C (or E8^E2) protein limits genome replication by repressing both viral transcription and the E1/E2-dependent DNA replication. How E8^E2C expression is regulated is not understood. Previous transcript analyses indicated that the spliced E8^E2C RNA is initiated at a promoter located in the E1 region upstream of the E8 gene. Deletion and mutational analyses of the E8 promoter region identify two conserved elements that are required for basal promoter activity in HPV-negative keratinocytes. In contrast, the transcriptional enhancer in the upstream regulatory region of HPV16 does not modulate basal E8 promoter activity. Cotransfection studies indicate that E8^E2C inhibits, whereas E2 weakly activates, the E8 promoter. Interestingly, the cotransfection of E1 and E2 induces the E8 promoter much more strongly than the major early promoter, and this is partially dependent upon binding of E2 to Brd4. Mutation of E8 promoter elements in the context of HPV16 genomes results in an increased genome copy number and elevated levels of viral early and late transcripts. In summary, the promoter responsible for the expression of E8^E2C is both positively and negatively regulated by viral and cellular factors, and this regulatory circuit may be crucial to maintain a low but constant copy number of HPV16 genomes in undifferentiated cells. IMPORTANCE HPV16 replicates in differentiating epithelia and can cause cancer. How HPV16 maintains its genome in undifferentiated cells at a low but constant level is not well understood but may be relevant for the immunological escape of HPV16 in the basal layers of the infected epithelium. This study

  8. Human Papillomavirus Vaccine Administration Among Medicaid Providers Who Consistently Recommended Vaccination

    PubMed Central

    Malo, Teri L.; Staras, Stephanie A. S.; Bynum, Shalanda A.; Giuliano, Anna R.; Shenkman, Elizabeth A.; Vadaparampil, Susan T.

    2014-01-01

    We examined factors potentially related to providers’ self-reported human papillomavirus vaccine administration to female Medicaid enrollees among providers who consistently recommended vaccination. Some pronounced variability was observed in characteristics among providers who consistently administered vaccination, including provider age, race, and Vaccines for Children enrollment; patient/parent vaccine refusal; patient race/ethnicity; and patient volume. PMID:24335743

  9. Knowledge, Attitudes, and Informational Behaviors of College Students in Regard to the Human Papillomavirus

    ERIC Educational Resources Information Center

    Sandfort, Jessica R.; Pleasant, Andrew

    2009-01-01

    Objective: To assess students' human papillomavirus (HPV) knowledge, attitudes, and behaviors. Participants/ Methods: Students (N = 1,282) at a large, public university in the Northeast United States completed a questionnaire during February 2008 assessing HPV knowledge, prevalence, transmission, cervical cancer risk and stigma; sexual behavior,…

  10. Men's Perceptions and Knowledge of Human Papillomavirus (HPV) Infection and Cervical Cancer

    ERIC Educational Resources Information Center

    McPartland, Tara S.; Weaver, Bethany A.; Lee, Shu-Kuang; Koutsky, Laura A.

    2005-01-01

    The authors assessed young men's knowledge and perceptions of genital human papillomavirus (HPV) infection to identify factors that predict intention to make positive behavioral changes. Male university students aged 18 to 25 years completed a self-report instrument to assess knowledge and perceptions of genital HPV infection. If diagnosed with…

  11. Investigating Stakeholder Attitudes and Opinions on School-Based Human Papillomavirus Vaccination Programs

    ERIC Educational Resources Information Center

    Nodulman, Jessica A.; Starling, Randall; Kong, Alberta S.; Buller, David B.; Wheeler, Cosette M.; Woodall, W. Gill

    2015-01-01

    Background: In several countries worldwide, school-based human papillomavirus (HPV) vaccination programs have been successful; however, little research has explored US stakeholders' acceptance toward school-based HPV vaccination programs. Methods: A total of 13 focus groups and 12 key informant interviews (N?=?117; 85% females; 66% racial/ethnic…

  12. The Acceptability of Human Papillomavirus (HPV) Vaccination among Women with Physical Disabilities

    ERIC Educational Resources Information Center

    Yen, Chia-Feng; Chen, Si-Fan; Lin, Lan-Ping; Hsu, Shang-Wei; Chang, Mao-Jung; Wu, Chia-Ling; Lin, Jin-Ding

    2011-01-01

    The present paper aims to explore awareness and acceptability of human papillomavirus (HPV) vaccination and to identify factors influencing HPV acceptability among women with physical disabilities in Taiwan. The study participants were 438 adult women with physical disabilities, aged 18-69 years. The participants were all officially registered as…

  13. Human Papillomavirus Vaccine Intention among College Men: What's Oral Sex Got to Do with It?

    ERIC Educational Resources Information Center

    Crosby, Richard A.; DiClemente, Ralph J.; Salazar, Laura F.; Nash, Rachel; Younge, Sinead; Head, Sara

    2012-01-01

    Objective: To identify associations between engaging in oral sex and perceived risk of oral cancer among college men. Also, to identify associations, and their moderating factors, between oral sex and human papillomavirus (HPV) vaccine acceptance. Methods: Young men were recruited from 2 university campuses in the South (N = 150). Men completed an…

  14. Knowledge, Beliefs, and Behaviors: Examining Human Papillomavirus-Related Gender Differences among African American College Students

    ERIC Educational Resources Information Center

    Bynum, Shalanda A.; Brandt, Heather M.; Friedman, Daniela B.; Annang, Lucy; Tanner, Andrea

    2011-01-01

    Objective: Given recent approval for administration of a human papillomavirus (HPV) vaccine to men, it is important to assess the HPV-related perspectives of men and women. The purpose of this study was to examine gender differences in HPV knowledge, beliefs, and vaccine acceptance among college students attending 3 historically black…

  15. Print News Coverage of School-Based Human Papillomavirus Vaccine Mandates

    ERIC Educational Resources Information Center

    Casciotti, Dana M.; Smith, Katherine C.; Andon, Lindsay; Vernick, Jon; Tsui, Amy; Klassen, Ann C.

    2014-01-01

    Background: In 2007, legislation was proposed in 24 states and the District of Columbia for school-based human papillomavirus (HPV) vaccine mandates, and mandates were enacted in Texas, Virginia, and the District of Columbia. Media coverage of these events was extensive, and media messages both reflected and contributed to controversy surrounding…

  16. Beliefs and Knowledge about the Human Papillomavirus Vaccine among Undergraduate Men

    ERIC Educational Resources Information Center

    Hunter, Theresa; Weinstein, Melissa

    2016-01-01

    Objective: The objective of this study was to assess male undergraduate students' human papillomavirus (HPV) knowledge and intentions to receive the HPV vaccination. Design: Cross-sectional survey. Method: A sample of 116 male undergraduate students from a university in the Midwestern USA completed a survey questionnaire assessing various aspects…

  17. Human Papillomavirus Vaccine Stages of Change among Male and Female University Students: Ready or Not?

    ERIC Educational Resources Information Center

    Patel, Divya A.; Grunzweig, Katherine A.; Zochowski, Melissa K.; Dempsey, Amanda F.; Carlos, Ruth C.; Dalton, Vanessa K.

    2013-01-01

    Objective: To examine gender differences in human papillomavirus (HPV) vaccine stages of change following the recommendations for permissive use of HPV vaccine in males. Participants: Students aged 18-26 attending a large, public, Midwest university in April 2010. Methods: Participants completed a self-administered, online questionnaire. HPV…

  18. Opportunities for Increasing Human Papillomavirus Vaccine Provision in School Health Centers

    ERIC Educational Resources Information Center

    Moss, Jennifer L.; Feld, Ashley L.; O'Malley, Brittany; Entzel, Pamela; Smith, Jennifer S.; Gilkey, Melissa B.; Brewer, Noel T.

    2014-01-01

    Background: Uptake of human papillomavirus (HPV) vaccine remains low among adolescents in the United States. We sought to assess barriers to HPV vaccine provision in school health centers to inform subsequent interventions. Methods: We conducted structured interviews in the fall of 2010 with staff from all 33 school health centers in North…

  19. Safety of human papillomavirus 6, 11, 16 and 18 (recombinant): systematic review and meta-analysis

    PubMed Central

    Coelho, Pedro Luiz Spinelli; Calestini, Gustavo Lacerda da Silva; Alvo, Fernando Salgueiro; Freitas, Jefferson Michel de Moura; Castro, Paula Marcela Vilela; Konstantyner, Tulio

    2015-01-01

    Objective: To identify and quantify the adverse effects associated with the recombinant human papillomavirus (types 6, 11, 16 and 18) vaccine in adolescents. Data source: Systematic review of randomized clinical trials from PubMed, SciELO and Lilacs databases. Articles investigating the safety of the vaccine in subjects under 18 years and comparing the recombinant human papillomavirus types 6, 11, 16 and 18 vaccine with a control group were included. Meta-analyses were performed for the outcomes of pain, erythema, swelling and fever, using clinical trials with maximum Jadad score. Data synthesis: Fourteen studies were included. The most common adverse effects related to the human papillomavirus vaccine were effects with no severity (pain, erythema, edema, and fever). Five studies were used for the meta-analyses: pain-risk difference (RD)=11% (p<0.001); edema-RD=8% (p<0.001); erythema-RD=5% (p<0.001); fever-RD=2% (p<0.003). Conclusions: The recombinant human papillomavirus types 6, 11, 16 and 18 vaccine was safe and well tolerated. The main adverse effects related to vaccination were pain, erythema, edema and fever. The low frequency of severe adverse effects encourages the administration of the vaccine in the population at risk. PMID:26376359

  20. Human papillomavirus vaccine administration among Medicaid providers who consistently recommended vaccination.

    PubMed

    Malo, Teri L; Staras, Stephanie A S; Bynum, Shalanda A; Giuliano, Anna R; Shenkman, Elizabeth A; Vadaparampil, Susan T

    2014-01-01

    We examined factors potentially related to providers' self-reported human papillomavirus vaccine administration to female Medicaid enrollees among providers who consistently recommended vaccination. Some pronounced variability was observed in characteristics among providers who consistently administered vaccination, including provider age, race, and Vaccines for Children enrollment; patient/parent vaccine refusal; patient race/ethnicity; and patient volume. PMID:24335743

  1. Receipt of the Human Papillomavirus Vaccine among Female College Students in the United States, 2009

    ERIC Educational Resources Information Center

    Lindley, Lisa L.; Elkind, Julia S.; Landi, Suzanne N.; Brandt, Heather M.

    2013-01-01

    Objective: To determine receipt of the human papillomavirus (HPV) vaccine among female college students by demographic/descriptive characteristics and sexual behaviors. Methods: A secondary analysis of the Spring 2009 National College Health Assessment-II was conducted with 40,610 female college students (aged 18 to 24 years) attending 4-year…

  2. Human papillomavirus, anal cancer, and screening considerations among HIV-infected individuals.

    PubMed

    Cachay, Edward R; Mathews, William Christopher

    2013-01-01

    Invasive anal cancer has become an important cause of non AIDS-related cancer among HIV-infected individuals. Human papillomavirus is the main etiological agent. This review explains the pathophysiologic role of human papillomavirus in the development of invasive anal cancer, summarizes recent epidemiological trends of invasive anal cancer, and reviews the evidence to address common clinical questions posed when screening for anal cancer in HIV-infected patients. The effect of highly active antiretroviral therapy on human papillomavirus oncogenesis is still unclear, but given the increased clinical burden of invasive anal cancer among HIV-infected patients, many clinics have implemented screening programs for anal cancer and its precursors. Despite the availability of several modalities for treatment of precursors of anal cancer, evidence that current treatment modalities favorably alter the natural history of human papillomavirus oncogenesis in the anal and perianal regions is still inconclusive. However, there is sufficient evidence to state that the accuracy of anal cancer screening procedures (cytology and high-resolution anoscopy directed biopsy) is comparable to the accuracy of those used in screening for cervical cancer precursors. Studies that systematically assess the efficacy of these anal cancer screening programs in reducing the incidence of and morbidity and mortality from invasive anal cancer among HIV-infected patients are needed. PMID:23681437

  3. Tobacco Smoke Activates Human Papillomavirus 16 p97 Promoter and Cooperates with High-Risk E6/E7 for Oxidative DNA Damage in Lung Cells

    PubMed Central

    Muñoz, Juan P.; Chnaiderman, Jonás; Urzúa, Ulises; León, Oscar; Tornesello, Maria L.; Corvalán, Alejandro H.; Soto-Rifo, Ricardo; Aguayo, Francisco

    2015-01-01

    We have previously shown a functional interaction between human papillomavirus type 16 (HPV-16) E6 and E7 oncoproteins and cigarette smoke condensate (CSC) in lung cells suggesting cooperation during carcinogenesis. The molecular mechanisms of such interaction, however, remain to be elucidated. Here we first present evidence showing that cigarette smoke condensate (CSC) has the ability to activate the HPV-16 p97 promoter by acting on the long control region (LCR) in lung epithelial cells. Interestingly, we observed that CSC-induced p97 promoter activation occurs in a dose-dependent manner in both tumor A-549 (lung adenocarcinoma), H-2170 (bronchial carcinoma), SiHa or Hela (cervical carcinoma) cells but not in non-tumor BEAS-2B (bronchial) or NL-20 (alveolar) lung cells unless they ectopically expressed the HPV-16 E6 and E7 oncogenes. In addition, we also observed a significant increase of primary DNA damage in tumor and non-tumor CSC-treated lung cells expressing HPV-16 E6 and E7 oncogenes suggesting a cooperative effect in this process, even though the contribution of E7 was significantly higher. Taken together, our results strongly suggest that tobacco smoke is able to induce the activation of the HPV-16 p97 promoter in cooperation with HPV-16 E6 and E7 oncogenes that, in turn, sensitize lung cells to tobacco smoke-induced DNA damage. PMID:25830243

  4. Human papillomavirus type 6b DNA required for initiation but not maintenance of transformation of C127 mouse cells.

    PubMed Central

    Morgan, D; Pecoraro, G; Rosenberg, I; Defendi, V

    1990-01-01

    We describe the transformation of C127 mouse fibroblasts with human papillomavirus type 6b (HPV-6b) DNA, which is associated primarily with benign tumors of the human genital tract. The major transformed phenotype of the HPV-6b-transfected cells lines, which had been G418 selected, pooled, and maintained without subsequent selection, was tumorigenicity in nude mice. We found that, unlike that reported for other HPVs or papovaviruses, the transformed phenotype was expressed after a delay, in which the cells had undergone extensive culture passages (about 20 passages or 100 generations). Interestingly, the HPV-6b DNA had become reduced or nondetectable in copy number in the cells by the time the transformed phenotype was expressed and in most of the tumors induced by the cells in nude mice, indicating that high levels of HPV-6b DNA were not required for maintenance of the transformed phenotype. Clonal cell lines gave similar results. When continued G418 selection was used to maintain high-copy-number HPV-6b DNA, the cells were tumorigenic, indicating that high levels of HPV-6b DNA did not suppress tumorigenesis. These studies suggest that HPV-6b DNA initiates transformation of C127 cells but is dispensable for expression or maintenance of the transformed phenotype. Transformation by HPV-6b DNA in vitro may provide insights into the HPV type-specific association with benign versus malignant lesions in vivo and may elucidate some of the oncogenic processes involved in tumor progression. Images PMID:2154622

  5. Oncogenes in human testicular cancer: DNA and RNA studies.

    PubMed Central

    Peltomäki, P.; Alfthan, O.; de la Chapelle, A.

    1991-01-01

    Oncogene dosage and expression were studied in 16 testicular neoplasms, 14 of germ cell and two of non-germ cell origin. In comparison with normal DNA, tumour DNA of a total of eight patients (seven with germ cell neoplasm and one with testicular lymphoma) showed increased dosages of KRAS2, PDGFA, EGFR, MET and PDGFB. The most frequent (occurring in six tumours) and prominent (up to 3-4-fold) increases were detected in the dosages of KRAS2 (on chromosome 12p) and PDGFA (chromosome 7p), relative to a reference locus from chromosome 2. Importantly, there was a similar increase in 12p dosage in general in these tumours, suggesting the presence of the characteristic isochromosome 12p marker. On the contrary, possible 7p polysomy (assessed by molecular methods) did not explain the PDGFA (or EGFR) changes in all cases. NRAS, MYCN, CSFIR, MYB, MYC, ABL, HRASI, TP53, and ERBB2 did not reveal any consistent alterations in tumour DNA. In RNA dot blot assays the expression of KRAS2, PDGFA, EGFR, or MYC was generally not increased in the tumour samples when compared to that in normal testicular tissue of the same patients although there was interindividual variation in mRNA levels. It thus appears that while oncogene dosage changes occur in a proportion of testis cancers, they are often part of changes in large chromosomal regions or whole arms and are seldom accompanied by altered expression. Images Figure 1 Figure 2 Figure 3 Figure 4 Figure 5 Figure 6 PMID:1829952

  6. Delineation of Interfaces on Human Alpha-Defensins Critical for Human Adenovirus and Human Papillomavirus Inhibition

    PubMed Central

    Wiens, Mayim E.; Lu, Wuyuan; Smith, Jason G.

    2014-01-01

    Human α-defensins are potent anti-microbial peptides with the ability to neutralize bacterial and viral targets. Single alanine mutagenesis has been used to identify determinants of anti-bacterial activity and binding to bacterial proteins such as anthrax lethal factor. Similar analyses of α-defensin interactions with non-enveloped viruses are limited. We used a comprehensive set of human α-defensin 5 (HD5) and human neutrophil peptide 1 (HNP1) alanine scan mutants in a combination of binding and neutralization assays with human adenovirus (AdV) and human papillomavirus (HPV). We have identified a core of critical hydrophobic residues that are common determinants for all of the virus-defensin interactions that were analyzed, while specificity in viral recognition is conferred by specific surface-exposed charged residues. The hydrophobic residues serve multiple roles in maintaining the tertiary and quaternary structure of the defensins as well as forming an interface for virus binding. Many of the important solvent-exposed residues of HD5 group together to form a critical surface. However, a single discrete binding face was not identified for HNP1. In lieu of whole AdV, we used a recombinant capsid subunit comprised of penton base and fiber in quantitative binding studies and determined that the anti-viral potency of HD5 was a function of stoichiometry rather than affinity. Our studies support a mechanism in which α-defensins depend on hydrophobic and charge-charge interactions to bind at high copy number to these non-enveloped viruses to neutralize infection and provide insight into properties that guide α-defensin anti-viral activity. PMID:25188351

  7. Genital Tract HIV RNA Levels and Their Associations with Human Papillomavirus Infection and Risk of Cervical Pre-Cancer

    PubMed Central

    GHARTEY, Jeny; KOVACS, Andrea; BURK, Robert D.; MASSAD, L. Stewart; MINKOFF, Howard; XIE, Xianhong; D’SOUZA, Gypsyamber; XUE, Xiaonan; WATTS, D. Heather; LEVINE, Alexandra M.; EINSTEIN, Mark H.; COLIE, Christine; ANASTOS, Kathryn; ELTOUM, Isam-Eldin; HEROLD, Betsy C.; PALEFSKY, Joel M.; STRICKLER, Howard D.

    2014-01-01

    Objective Plasma HIV RNA levels have been associated with risk of human papillomavirus (HPV) and cervical neoplasia in HIV-seropositive women. However, little is known regarding local genital tract HIV RNA levels and their relation with cervical HPV and neoplasia. Design/Methods In an HIV-seropositive women’s cohort with semi-annual follow-up, we conducted a nested case-control study of genital tract HIV RNA levels and their relation with incident high-grade squamous intraepithelial lesions sub-classified as severe (severe HSIL), as provided for under the Bethesda 2001 classification system. Specifically, 66 incident severe HSIL were matched to 130 controls by age, CD4+ count, HAART use, and other factors. We also studied HPV prevalence, incident detection, and persistence in a random sample of 250 subjects. Results Risk of severe HSIL was associated with genital tract HIV RNA levels (odds ratio comparing HIV RNA ≥ the median among women with detectable levels versus undetectable [ORVL] 2.96; 95% CI: 0.99–8.84; Ptrend=0.03). However, this association became non-significant (Ptrend=0.51) following adjustment for plasma HIV RNA levels. There was also no association between genital tract HIV RNA levels and the prevalence of any HPV or oncogenic HPV. However, the incident detection of any HPV (Ptrend=0.02) and persistence of oncogenic HPV (Ptrend=0.04) were associated with genital tract HIV RNA levels, after controlling plasma HIV RNA levels. Conclusion These prospective data suggest that genital tract HIV RNA levels are not a significant independent risk factor for cervical pre-cancer in HIV-seropositive women, but leave open the possibility that they may modestly influence HPV infection, an early stage of cervical tumoriogenesis. PMID:24694931

  8. Oncogenically active MYD88 mutations in human lymphoma

    PubMed Central

    Ngo, Vu N.; Young, Ryan M.; Schmitz, Roland; Jhavar, Sameer; Xiao, Wenming; Lim, Kian-Huat; Kohlhammer, Holger; Xu, Weihong; Yang, Yandan; Zhao, Hong; Shaffer, Arthur L.; Romesser, Paul; Wright, George; Powell, John; Rosenwald, Andreas; Muller-Hermelink, Hans Konrad; Ott, German; Gascoyne, Randy D.; Connors, Joseph M.; Rimsza, Lisa M.; Campo, Elias; Jaffe, Elaine S.; Delabie, Jan; Smeland, Erlend B.; Fisher, Richard I.; Braziel, Rita M.; Tubbs, Raymond R.; Cook, J. R.; Weisenburger, Denny D.; Chan, Wing C.; Staudt, Louis M.

    2016-01-01

    The activated B-cell-like (ABC) subtype of diffuse large B-cell lymphoma (DLBCL) remains the least curable form of this malignancy despite recent advances in therapy1. Constitutive nuclear factor (NF)-κB and JAK kinase signalling promotes malignant cell survival in these lymphomas, but the genetic basis for this signalling is incompletely understood. Here we describe the dependence of ABC DLBCLs on MYD88, an adaptor protein that mediates toll and interleukin (IL)-1 receptor signalling2,3, and the discovery of highly recurrent oncogenic mutations affecting MYD88 in ABC DLBCL tumours. RNA interference screening revealed that MYD88 and the associated kinases IRAK1 and IRAK4 are essential for ABC DLBCL survival. High-throughput RNA resequencing uncovered MYD88 mutations in ABC DLBCL lines. Notably, 29% of ABC DLBCL tumours harboured the same amino acid substitution, L265P, in the MYD88 Toll/IL-1 receptor (TIR) domain at an evolutionarily invariant residue in its hydrophobic core. This mutation was rare or absent in other DLBCL subtypes and Burkitt’s lymphoma, but was observed in 9% of mucosa-associated lymphoid tissue lymphomas. At a lower frequency, additional mutations were observed in the MYD88 TIR domain, occurring in both the ABC and germinal centre B-cell-like (GCB) DLBCL subtypes. Survival of ABC DLBCL cells bearing the L265P mutation was sustained by the mutant but not the wild-type MYD88 isoform, demonstrating that L265P is a gain-of-function driver mutation. The L265P mutant promoted cell survival by spontaneously assembling a protein complex containing IRAK1 and IRAK4, leading to IRAK4 kinase activity, IRAK1 phosphorylation, NF-κB signalling, JAK kinase activation of STAT3, and secretion of IL-6, IL-10 and interferon-β. Hence, theMYD88 signalling pathway is integral to the pathogenesis of ABC DLBCL, supporting the development of inhibitors of IRAK4 kinase and other components of this pathway for the treatment of tumours bearing oncogenic MYD88 mutations

  9. [Prostate cancer: papillomaviruses as a possible cause].

    PubMed

    Volgareva, G M

    2015-01-01

    Prostate cancer (PC) incidence and mortality are steadily increasing. Causation of PC is not clearly understood; in particular, role of human papillomaviruses (HPV) is still disputable. The review contains analysis of literature data on possible participation of HPV powerful biological carcinogens, in PC genesis. PC incidence increase in persons with immunodeficiency indicates involvement of some infectious agent in the disease etiology. Several research groups communicated HPV DNA finding including that of oncogenic types in PC specimens (transrectal biopsies). There are limited data on the occurrence of oncogenic HPV 16 oncoprotein E7 in such specimens and on its unfavorable effect on disease prognosis. The successful attempt is known to transfect normal human prostate cells with oncogenic HPVDNA in vitro. Epidemiological data on associations of PC with HPV are controversial. It may result from the considered in the present review certain technical peculiarities of these studies. Controlfor serum antibodies to HPV E6 and E7 oncoproteins recognized to indicate HPV-positive tumor growth in an organism has not been performed yet in PC patients. DNA of oncogenic HPV is rather commonly found in organs adjacent to prostate--urethra, rectum, urinary bladder. In the study held in Russia on a group of healthy men examined for sexually transmitted diseases genitourinary HPVinfection was found in every second person; 42% of them harbored oncogenic HPV. Possible participation of oncogenic HPV in PC genesis deserves close attention and further study. PMID:26027277

  10. Human Papillomaviruses; Epithelial Tropisms, and the Development of Neoplasia.

    PubMed

    Egawa, Nagayasu; Egawa, Kiyofumi; Griffin, Heather; Doorbar, John

    2015-07-01

    Papillomaviruses have evolved over many millions of years to propagate themselves at specific epithelial niches in a range of different host species. This has led to the great diversity of papillomaviruses that now exist, and to the appearance of distinct strategies for epithelial persistence. Many papillomaviruses minimise the risk of immune clearance by causing chronic asymptomatic infections, accompanied by long-term virion-production with only limited viral gene expression. Such lesions are typical of those caused by Beta HPV types in the general population, with viral activity being suppressed by host immunity. A second strategy requires the evolution of sophisticated immune evasion mechanisms, and allows some HPV types to cause prominent and persistent papillomas, even in immune competent individuals. Some Alphapapillomavirus types have evolved this strategy, including those that cause genital warts in young adults or common warts in children. These strategies reflect broad differences in virus protein function as well as differences in patterns of viral gene expression, with genotype-specific associations underlying the recent introduction of DNA testing, and also the introduction of vaccines to protect against cervical cancer. Interestingly, it appears that cellular environment and the site of infection affect viral pathogenicity by modulating viral gene expression. With the high-risk HPV gene products, changes in E6 and E7 expression are thought to account for the development of neoplasias at the endocervix, the anal and cervical transformation zones, and the tonsilar crypts and other oropharyngeal sites. A detailed analysis of site-specific patterns of gene expression and gene function is now prompted. PMID:26193301

  11. Human Papillomaviruses; Epithelial Tropisms, and the Development of Neoplasia

    PubMed Central

    Egawa, Nagayasu; Egawa, Kiyofumi; Griffin, Heather; Doorbar, John

    2015-01-01

    Papillomaviruses have evolved over many millions of years to propagate themselves at specific epithelial niches in a range of different host species. This has led to the great diversity of papillomaviruses that now exist, and to the appearance of distinct strategies for epithelial persistence. Many papillomaviruses minimise the risk of immune clearance by causing chronic asymptomatic infections, accompanied by long-term virion-production with only limited viral gene expression. Such lesions are typical of those caused by Beta HPV types in the general population, with viral activity being suppressed by host immunity. A second strategy requires the evolution of sophisticated immune evasion mechanisms, and allows some HPV types to cause prominent and persistent papillomas, even in immune competent individuals. Some Alphapapillomavirus types have evolved this strategy, including those that cause genital warts in young adults or common warts in children. These strategies reflect broad differences in virus protein function as well as differences in patterns of viral gene expression, with genotype-specific associations underlying the recent introduction of DNA testing, and also the introduction of vaccines to protect against cervical cancer. Interestingly, it appears that cellular environment and the site of infection affect viral pathogenicity by modulating viral gene expression. With the high-risk HPV gene products, changes in E6 and E7 expression are thought to account for the development of neoplasias at the endocervix, the anal and cervical transformation zones, and the tonsilar crypts and other oropharyngeal sites. A detailed analysis of site-specific patterns of gene expression and gene function is now prompted. PMID:26193301

  12. The Asian-American E6 Variant Protein of Human Papillomavirus 16 Alone Is Sufficient To Promote Immortalization, Transformation, and Migration of Primary Human Foreskin Keratinocytes

    PubMed Central

    Niccoli, Sarah; Abraham, Suraj; Richard, Christina

    2012-01-01

    We examined how well the human papillomavirus (HPV) E6 oncogene can function in the absence of the E7 oncogene during the carcinogenic process in human keratinocytes using a common HPV variant strongly associated with cervical cancer: the Asian-American E6 variant (AAE6). This E6 variant is 20 times more frequently detected in cervical cancer than the prototype European E6 variant, as evidenced by independent epidemiological data. Using cell culture and cell-based functional assays, we assessed how this variant can perform crucial carcinogenesis steps compared to the prototype E6 variant. The ability to immortalize and transform primary human foreskin keratinocytes (PHFKs) to acquire resilient phenotypes and the ability to promote cell migration were evaluated. The immortalization capability was assayed based on population doublings, number of passages, surpassing mortality stages 1 and 2, human telomerase reverse transcriptase (hTERT) expression, and the ability to overcome G1 arrest via p53 degradation. Transformation and migration efficiency were analyzed using a combination of functional cell-based assays. We observed that either AAE6 or prototype E6 proteins alone were sufficient to immortalize PHFKs, although AAE6 was more potent in doing so. The AAE6 variant protein alone pushed PHFKs through transformation and significantly increased their migration ability over that of the E6 prototype. Our findings are in line with epidemiological data that the AA variant of HPV16 confers an increased risk over the European prototype for cervical cancer, as evidenced by a superior immortalization, transformation, and metastatic potential. PMID:22951839

  13. [Study of Her-2/neu oncogene in relation to prognosis of human breast cancer].

    PubMed

    Chen, R S

    1993-10-01

    A follow-up study of 143 cases of human breast cancer for over 5 years proved that Her-2/neu oncogene overexpression is much more common in the high risk group (patients died within 5 years) in comparison with the low risk group (patients survived over 5 years). The difference between these 2 groups was statistically significant. The Her-2/neu oncogene positive rate in infiltrative ductal carcinoma was 33.3%, the lower the differentiation, the higher the positive rate. Histological typing is also related to the positive rate, comedocarcinoma (intraductal carcinoma) expresses the highest positive rate while lobular carcinoma the lowest. Selection of fixation fluid and the mastering of diagnostic criteria are also important. In the author's opinion, only membrane staining in monoclonal antibody C-erbB-2 can be recognized as truly positive. In conclusion, Her-2/neu oncogene expression can be used as a supplemental marker when considering prognosis in breast cancer. PMID:7909501

  14. Pre-clinical immunogenicity of human papillomavirus alpha-7 and alpha-9 major capsid proteins

    PubMed Central

    Bissett, Sara L.; Mattiuzzo, Giada; Draper, Eve; Godi, Anna; Wilkinson, Dianna E.; Minor, Philip; Page, Mark; Beddows, Simon

    2014-01-01

    Human papillomavirus (HPV) vaccines confer protection against the oncogenic genotypes HPV16 and HPV18 through the generation of type-specific neutralizing antibodies raised against the constituent virus-like particles (VLP) based upon the major capsid proteins (L1) of these genotypes. The vaccines also confer a degree of cross-protection against some genetically related types from the Alpha-9 (HPV16-like: HPV31, HPV33, HPV35, HPV52, HPV58) and Alpha-7 (HPV18-like: HPV39, HPV45, HPV59, HPV68) species groups. The mechanism of cross-protection is unclear but may involve antibodies capable of recognizing shared inter-genotype epitopes. The relationship(s) between the genetic and antigenic diversity of the L1 protein, particularly for non-vaccine genotypes, is poorly understood. We carried out a comprehensive evaluation of the immunogenicity of L1 VLP derived from genotypes within the Alpha-7 and Alpha-9 species groups in New Zealand White rabbits and used L1L2 pseudoviruses as the target antigens in neutralization assays. The majority antibody response against L1 VLP was type-specific, as expected, but several instances of robust cross-neutralization were nevertheless observed including between HPV33 and HPV58 within the Alpha-9 species and between HPV39, HPV59 and HPV68 in the Alpha-7 species. Immunization with an experimental tetravalent preparation comprising VLP based upon HPV16, HPV18, HPV39 and HPV58 was capable of generating neutralizing antibodies against all the Alpha-7 and Alpha-9 genotypes. Competition of HPV31 and HPV33 cross-neutralizing antibodies in the tetravalent sera confirmed that these antibodies originated from HPV16 and HPV58 VLP, respectively, and suggested that they represent minority specificities within the antibody repertoire generated by the immunizing antigen. These data improve our understanding of the antigenic diversity of the L1 protein per se and may inform the rational design of a next generation vaccine formulation based upon

  15. Anal Human Papillomavirus Infection among HIV-Infected Men in Korea

    PubMed Central

    Lee, Chang Hun; Lee, Sun Hee; Lee, Shinwon; Cho, Heerim; Kim, Kye-Hyung; Lee, Jung Eun; Jung, Eun ju; Lee, Su jin; Kim, Eun Jung; Kim, Ki Hyung; Moon, Eunsoo; Cho, Hong Je

    2016-01-01

    Background Little is known about the epidemiology on human papillomavirus (HPV) infection among HIV-infected men in Korea. The objective of this study was to determine the prevalence, genotype distribution and risk factors associated with anal HPV infection among HIV-infected men in Korea. Methods A single-center cross-sectional study was conducted with HIV-infected men in Korea. Participants completed a detailed sexual behavior risk factor questionnaire. Anal samples were collected for cytology and HPV genotyping. Factors associated with anal HPV infection were assessed using multivariable logistic regression, stratifying by sexual behaviour. Results A total of 201 HIV-infected men were included in the study: 133 were from men who have sex with men (MSM) and 68 from men who have sex with women (MSW). Any anal HPV infection was detected in 82.7% of HIV-infected MSM and in 51.5% of HIV- infected MSW (P < 0.001). High-risk HPV (HR-HPV) prevalence was higher among MSM (47.4%) than MSW (25.0%; P = 0.002). The HR-HPV types identified most frequently were HPV 16 (11%), HPV 18 (9.9%), and HPV 58 (5%) in MSM, and HPV 58(11%) and HPV 16 (8.9%) in MSW. Prevalence of any HPV types in 9-valent vaccine types was higher among MSM than MSW (47.4% vs 22.1%. P = 0.001). Abnormal anal cytology was more commonly detected in MSM than MSW (42.9% vs.19.1%, P < 0.001). In HIV-infected MSM, higher number of lifetime male sex partners was significantly associated with any anal HPV infection, but age was a significant risk factor associated with anal HR-HPV infection. Conclusion Anal HPV infection was highly prevalent in HIV-infected MSM in Korea, and also commonly found in HIV-infected MSW. In HIV-infected MSM, the significant risk factor for being infected with any HPV infection was lifetime number of male sexual partners, and with anal oncogenic HPV infection was age. PMID:27548632

  16. Human papillomavirus DNA positivity and seropositivity in rural Chinese men and women: a population-based cross-sectional study.

    PubMed

    Liu, Fangfang; Deng, Qiuju; Zhang, Chanyuan; Pan, Yaqi; Liu, Ying; He, Zhonghu; Sun, Min; Liu, Mengfei; Li, Jingjing; Li, Xiang; Zhang, Chaoting; Hang, Dong; Ning, Tao; Guo, Chuanhai; Liang, Yongmei; Xu, Ruiping; Zhang, Lixin; Cai, Hong; Ke, Yang

    2016-01-01

    Data on simultaneous analysis of human papillomavirus (HPV) DNA and serology and the correlations within a single general population are limited. Among 1603 men and 2187 women enrolled from rural China, serum antibodies against bacterially derived GST-L1 fusion proteins of HPV were assessed with multiplexed serology and HPV DNA was evaluated with PCR-based sequencing. Few subjects were dually positive to HPV DNA and serum antibodies for any HPV (6.6% of men and 3.1% of women). The proportion of men ever having been infected with any HPV (DNA and/or antibody positive) was higher than that of women (71.0% vs. 65.2%, P < 0.001). Type-specific association was observed for genital HPV infection and HPV seropositivity among women but not among men. A positive correlation between the number of lifetime sexual partners and positivity for oncogenic HPV DNA and/or antibodies was found in men but was absent in women. Among 762 couples, the presence of HPV DNA and/or antibodies in one partner was positively associated with the identical HPV type in the other partner. These findings may reflect a site-specific natural course of HPV infection and further understanding of the epidemiology of HPV. PMID:27211017

  17. DNA Damage Reduces the Quality, but Not the Quantity of Human Papillomavirus 16 E1 and E2 DNA Replication

    PubMed Central

    Bristol, Molly L.; Wang, Xu; Smith, Nathan W.; Son, Minkyeong P.; Evans, Michael R.; Morgan, Iain M.

    2016-01-01

    Human papillomaviruses (HPVs) are causative agents in almost all cervical carcinomas. HPVs are also causative agents in head and neck cancer, the cases of which are increasing rapidly. Viral replication activates the DNA damage response (DDR) pathway; associated proteins are recruited to replication foci, and this pathway may serve to allow for viral genome amplification. Likewise, HPV genome double-strand breaks (DSBs) could be produced during replication and could lead to linearization and viral integration. Many studies have shown that viral integration into the host genome results in unregulated expression of the viral oncogenes, E6 and E7, promoting HPV-induced carcinogenesis. Previously, we have demonstrated that DNA-damaging agents, such as etoposide, or knocking down viral replication partner proteins, such as topoisomerase II β binding protein I (TopBP1), does not reduce the level of DNA replication. Here, we investigated whether these treatments alter the quality of DNA replication by HPV16 E1 and E2. We confirm that knockdown of TopBP1 or treatment with etoposide does not reduce total levels of E1/E2-mediated DNA replication; however, the quality of replication is significantly reduced. The results demonstrate that E1 and E2 continue to replicate under genomically-stressed conditions and that this replication is mutagenic. This mutagenesis would promote the formation of substrates for integration of the viral genome into that of the host, a hallmark of cervical cancer. PMID:27338449

  18. DNA Damage Reduces the Quality, but Not the Quantity of Human Papillomavirus 16 E1 and E2 DNA Replication.

    PubMed

    Bristol, Molly L; Wang, Xu; Smith, Nathan W; Son, Minkyeong P; Evans, Michael R; Morgan, Iain M

    2016-01-01

    Human papillomaviruses (HPVs) are causative agents in almost all cervical carcinomas. HPVs are also causative agents in head and neck cancer, the cases of which are increasing rapidly. Viral replication activates the DNA damage response (DDR) pathway; associated proteins are recruited to replication foci, and this pathway may serve to allow for viral genome amplification. Likewise, HPV genome double-strand breaks (DSBs) could be produced during replication and could lead to linearization and viral integration. Many studies have shown that viral integration into the host genome results in unregulated expression of the viral oncogenes, E6 and E7, promoting HPV-induced carcinogenesis. Previously, we have demonstrated that DNA-damaging agents, such as etoposide, or knocking down viral replication partner proteins, such as topoisomerase II β binding protein I (TopBP1), does not reduce the level of DNA replication. Here, we investigated whether these treatments alter the quality of DNA replication by HPV16 E1 and E2. We confirm that knockdown of TopBP1 or treatment with etoposide does not reduce total levels of E1/E2-mediated DNA replication; however, the quality of replication is significantly reduced. The results demonstrate that E1 and E2 continue to replicate under genomically-stressed conditions and that this replication is mutagenic. This mutagenesis would promote the formation of substrates for integration of the viral genome into that of the host, a hallmark of cervical cancer. PMID:27338449

  19. Human papillomavirus DNA positivity and seropositivity in rural Chinese men and women: a population-based cross-sectional study

    PubMed Central

    Liu, Fangfang; Deng, Qiuju; Zhang, Chanyuan; Pan, Yaqi; Liu, Ying; He, Zhonghu; Sun, Min; Liu, Mengfei; Li, Jingjing; Li, Xiang; Zhang, Chaoting; Hang, Dong; Ning, Tao; Guo, Chuanhai; Liang, Yongmei; Xu, Ruiping; Zhang, Lixin; Cai, Hong; Ke, Yang

    2016-01-01

    Data on simultaneous analysis of human papillomavirus (HPV) DNA and serology and the correlations within a single general population are limited. Among 1603 men and 2187 women enrolled from rural China, serum antibodies against bacterially derived GST-L1 fusion proteins of HPV were assessed with multiplexed serology and HPV DNA was evaluated with PCR-based sequencing. Few subjects were dually positive to HPV DNA and serum antibodies for any HPV (6.6% of men and 3.1% of women). The proportion of men ever having been infected with any HPV (DNA and/or antibody positive) was higher than that of women (71.0% vs. 65.2%, P < 0.001). Type-specific association was observed for genital HPV infection and HPV seropositivity among women but not among men. A positive correlation between the number of lifetime sexual partners and positivity for oncogenic HPV DNA and/or antibodies was found in men but was absent in women. Among 762 couples, the presence of HPV DNA and/or antibodies in one partner was positively associated with the identical HPV type in the other partner. These findings may reflect a site-specific natural course of HPV infection and further understanding of the epidemiology of HPV. PMID:27211017

  20. Human papillomavirus infection and P53 codon 72 genotypes in a Hispanic population at high-risk for cervical cancer.

    PubMed

    Haws, Andrea L Fuessel; Woeber, Sabine; Gomez, Miroslava; Garza, Noe; Gomez, Yvonne; Rady, Peter; He, Qin; Zhang, Lifang; Grady, James J; McCormick, Joseph B; Fisher-Hoch, Susan P; Tyring, Stephen K

    2005-10-01

    Cervical cancer mortality is high in Texas, especially among Hispanic women living in south Texas and adjacent Mexico. Though human papillomavirus (HPV) infection has a causal role in the development of cervical cancer, there are no published data on the prevalence of HPV genotypes in this underscreened region. We studied 398 Hispanic women on both sides of the border along the lower Rio Grande River to determine the prevalence of HPV genotypes and risk factors for cervical cancer. Using a nested PCR system HPV was detected in 62% of cervical specimens, including all the known high-risk HPV genotypes, with HPV16 and HPV18 the most frequent (30.6% and 23.0%, respectively). Multiple infections were common (29.4% of the infected specimens), and where this occurred we were more likely to find high-risk HPV genotypes. We examined host p53 codon 72 genotype frequencies and found that patients with cervical abnormalities and women with HPV16 and HPV18 infections had a lower genotype frequency of the homozygous (AA) previously reported to be associated with cervical cancer, than uninfected women with no abnormalities. In this US/Mexico border population high rates of potentially oncogenic HPV viruses and multiple infections are consistent with observed elevated cervical cancer rates. These data are further evidence that in this underserved population HPV infections are associated with high rates of malignancy, but that host p53 genotypic variations are unlikely to be primary factors in oncogenesis. PMID:16121365

  1. Human Papillomavirus Biology, Pathogenesis, and Potential for Drug Discovery: A Literature Review for HIV Nurse Clinical Scientists.

    PubMed

    Walhart, Tara

    2015-01-01

    Persistent oncogenic human papillomavirus (HPV) infection increases the probability that precancerous anal high-grade squamous intraepithelial lesions will progress to invasive anal cancer. Anal neoplasia associated with HPV disproportionately affects HIV-infected individuals, especially men who have sex with men. Prevention is limited to HPV vaccine recommendations, highlighting the need for new treatments. The purpose of this review is to provide HIV information to nurse clinical scientists about HPV-related cancer to highlight the connection between: (a) HPV biology and pathogenesis and (b) the development of drugs and novel therapeutic methods using high-throughput screening. PubMed and CINAHL were used to search the literature to determine HPV-related epidemiology, biology, and use of high-throughput screening for drug discovery. Several events in the HPV life cycle have the potential to be developed into biologic targets for drug discovery using the high-throughput screening technique, which has been successfully used to identify compounds to inhibit HPV infections. PMID:26277046

  2. Abrogation of growth arrest signals by human papillomavirus type 16 E7 is mediated by sequences required for transformation.

    PubMed Central

    Demers, G W; Espling, E; Harry, J B; Etscheid, B G; Galloway, D A

    1996-01-01

    Cells arrest in the G1 or G0 phase of the cell cycle in response to a variety of negative growth signals that induce arrest by different molecular pathways. The ability of human papillomavirus (HPV) oncogenes to bypass these signals and allow cells to progress into the S phase probably contributes to the neoplastic potential of the virus. The E7 protein of HPV-16 was able to disrupt the response of epithelial cells to three different negative growth arrest signals: quiescence imposed upon suprabasal epithelial cells, G1 arrest induced by DNA damage, and inhibition of DNA synthesis caused by treatment with transforming growth factor beta. The same set of mutated E7 proteins was able to abrogate all three growth arrest signals. Mutant proteins that failed to abrogate growth arrest signals were transformation deficient and included E7 proteins that bound retinoblastoma protein in vitro. In contrast, HPV-16 E6 was able to bypass only DNA damage-induced G1 arrest, not suprabasal quiescence or transforming growth factor beta-induced arrest. The E6 and E7 proteins from the low-risk virus HPV-6 were not able to bypass any of the growth arrest signals. PMID:8794328

  3. cobas 4800 HPV Test, a real-time polymerase chain reaction assay for the detection of human papillomavirus in cervical specimens.

    PubMed

    Isidean, Sandra D; Coutlée, François; Franco, Eduardo L

    2014-01-01

    Cervical cancer screening incorporating high-risk human papillomavirus (HPV) detection has become the preferred screening strategy in some countries and is increasingly more widespread in other countries with organized or opportunistic screening programs. Given knowledge that high-risk HPV genotypes differ in their oncogenic potential, commercial HPV assays with genotyping capabilities have been developed and have garnered attention in the recent literature. The cobas 4800 HPV Test is a qualitative multiplex assay that provides specific genotyping information for HPV types 16 and 18, while concurrently detecting 12 other high-risk HPV genotypes as a pooled result. It is currently the only clinically validated, US FDA-approved assay with this capability. Since HPV types 16 and 18 have been designated as conferring the greatest risk for cervical disease, their detection may prove useful in guiding patient management. PMID:24308341

  4. Prevalence of various Human Papillomavirus (HPV) genotypes among women who subjected to routine Pap smear test in Bushehr city (South west of Iran)2008-2009

    PubMed Central

    2010-01-01

    Background Some genotypes of human papillomaviruses can infect the genital tract and they are important infectious agents which their oncogenicity is regardable. Thus the aim of this study was to determine the prevalence of various genital human papillomaviruses (HPV) among women being subjected to routine pap smear test in Bushehr city of Iran. Results Based on the collected data, 11(5.5%) samples were detected positive for HPV DNA and 189(94.5%) samples out of 200 samples were detected negative for HPV DNA. Meanwhile 4(2%) samples detected positive for HPV DNA by PCR were detected positive for HPV by pap smear test as well. On the other hand 5 samples which were detected positive for HPV by pap smear test didn't have HPV DNA after being tested by PCR method. Among the 11 positive samples 7 samples were identified as HPV-16, 3 samples were HPV-18 and one was HPV-53. Conclusion Regarding the prevalence of highly carcinogen genotypes of HPV in our study determination of genital HPV prevalence among the normal population of women of Bushehr city is recommended. PMID:20302680

  5. Branchiogenic carcinoma with high-risk-type human papillomavirus infection: A case report

    PubMed Central

    Maeda, Hiroyuki; Deng, Zeyi; Ikegami, Taro; Matayoshi, Sen; Agena, Shinya; Kiyuna, Asanori; Yamashita, Yukashi; Uehara, Takayuki; Ganaha, Akira; Suzuki, Mikio

    2016-01-01

    Branchiogenic carcinoma (BC) usually appears as a mass lesion with a predominant cystic component. Since lymph node metastasis from oropharyngeal carcinoma (OPC) has a cystic appearance, it is occasionally difficult to distinguish between BC and nodal metastases from clinically silent OPC. Factors associated with the malignant transformation process in BC remain obscure. The present study reports the case of a 56-year-old man with a right cystic cervical mass that was diagnosed as squamous cell carcinoma based on examination by fine-needle aspiration biopsy. The primary tumor could not be detected despite several imaging examinations, a pan-endoscopy of the head and neck, esophagus and stomach, biopsies of the head and neck regions, and bilateral tonsillectomies. The pathological findings of the surgical specimens from a radical neck dissection were consistent with the histological characteristics of BC, with evidence of transition from dysplasia through intraepithelial carcinoma to invasive carcinoma. Normal squamous epithelium and dysplastic and cancerous portions in the BC showed strong p16INK4a immunoreactivity. The expression of p16INK4a was also observed in all 9 nodal metastases in the neck dissection specimens. The cystic formation observed in the BC was not observed in the nodal metastases. As the presence of human papillomavirus-16 in the tumor was confirmed by polymerase chain reaction, quantitative polymerase chain reaction was employed for the measurement of human papillomavirus-16 viral load and integration. The results showed that the viral load of human papillomavirus-16 was 3.01×107/50 ng genomic DNA, and the E2/E6 ratio was 0.13, so the integration state was judged to be the mixed type. To the best of our knowledge, this is the first report of BC associated with high-risk-type human papillomavirus infection. The study indicates that a human papillomavirus-positive neck mass may not necessarily be OPC, but that it could be BC with a poor prognosis

  6. Competitive binding of viral E2 protein and mammalian core-binding factor to transcriptional control sequences of human papillomavirus type 8 and bovine papillomavirus type 1.

    PubMed Central

    Schmidt, H M; Steger, G; Pfister, H

    1997-01-01

    The promoter P7535 of human papillomavirus type 8 and the promoter P7185 of bovine papillomavirus type 1 are negatively regulated by viral E2 proteins via the promoter proximal binding sites P2 and BS1, respectively. Mutations of these E2 binding sites can reduce basal promoter activity. This suggests binding of a transcription-stimulating factor and may indicate that repression by E2 is due to competitive binding of viral and cellular proteins. A computer search revealed putative binding sites for core-binding factor (CBF; also referred to as PEA2, PEBP2, or AML), overlapping with P2 and BS1. Binding of recombinant CBF proteins to these sites was confirmed by band shift analysis. Competition of CBF and E2 protein for DNA binding was shown for both human papillomavirus type 8 and bovine papillomavirus type 1. The importance of CBF-E2 competition in E2-mediated repression could be demonstrated by comparing the E2 effect on P7185 activity in two cell lines containing different amounts of endogenous CBF. In cells with large amounts of CBF, E2 repressed P7185 wild-type constructs to the basal promoter activity of a mutant (50%) that could not bind this protein any more. In contrast, in a cell line containing small amounts of CBF, the promoter activities of constructs with wild-type and mutated CBF binding sites hardly differed and specific repression by E2 was not detectable. PMID:9311900

  7. Association of Chlamydia trachomatis infection and herpes simplex virus type 2 serostatus with genital human papillomavirus infection in men: the HIM Study

    PubMed Central

    Alberts, Catharina Johanna; Schim van der Loeff, Maarten F.; Papenfuss, Mary R.; da Silva, Roberto José Carvalho; Villa, Luisa Lina; Lazcano-Ponce, Eduardo; Nyitray, Alan G.; Giuliano, Anna R.

    2013-01-01

    Background Studies in women indicate that some sexually transmitted infections promote human papillomavirus (HPV) persistence and carcinogenesis. Little is known about this association in men, therefore we assessed whether Chlamydia trachomatis (CT) infection and herpes simplex virus type 2 (HSV-2) serostatus are associated with genital HPV prevalence, an early event in HPV related pathogenesis. Methods Genital exfoliated cells, first-void urine and blood from 3,971 men recruited in the USA, Mexico, and Brazil, were tested for HPV, CT, and HSV-2 antibodies, respectively. Multivariable logistic regression was used to assess the association of CT infection and HSV-2 serostatus with four HPV outcomes (any, oncogenic, non-oncogenic only, and multiple infections). Results A total of 64 (1.6%) men were CT positive and 811 (20.4%) men were HSV-2 seropositive. After adjustment for potential confounders, CT was associated with any HPV (aOR 2.19, 95%CI: 1.13–4.24), oncogenic HPV (aOR 3.10, 95%CI: 1.53–6.28), and multiple HPV (aOR 3.43, 95%CI: 1.69-6.95) prevalence. HSV-2 serostatus was associated with any HPV (aOR 1.25, 95%CI: 1.02-1.52), non-oncogenic HPV only (aOR 1.38, 95%CI: 1.08-1.75), and multiple HPV (aOR 1.33, 95%CI: 1.06-1.68) prevalence. In analyses stratified by sexual behaviour, CT infection was significantly associated with HPV detection among men reporting ≥2 recent sexual partners, while HSV-2 serostatus was significantly associated with HPV detection in men reporting 0-5 lifetime sexual partners. Conclusion In this population, CT infection and HSV-2 serostatus were associated with prevalent genital HPV infection. Future prospective studies should investigate whether these infections influence HPV acquisition and/or persistence. PMID:23680908

  8. Human lung epithelial cells progressed to malignancy through specific oncogenic manipulations

    PubMed Central

    Sato, Mitsuo; Larsen, Jill E.; Lee, Woochang; Sun, Han; Shames, David S.; Dalvi, Maithili P.; Ramirez, Ruben D.; Tang, Hao; DiMaio, J. Michael; Gao, Boning; Xie, Yang; Wistuba, Ignacio I.; Gazdar, Adi F.; Shay, Jerry W.; Minna, John D.

    2013-01-01

    We used CDK4/hTERT-immortalized normal human bronchial epithelial cells (HBECs) from several individuals to study lung cancer pathogenesis by introducing combinations of common lung cancer oncogenic changes (p53, KRAS, MYC) and followed the stepwise transformation of HBECs to full malignancy. This model demonstrated that: 1) the combination of five genetic alterations (CDK4, hTERT, sh-p53, KRASV12, and c-MYC) is sufficient for full tumorigenic conversion of HBECs; 2) genetically-identical clones of transformed HBECs exhibit pronounced differences in tumor growth, histology, and differentiation; 3) HBECs from different individuals vary in their sensitivity to transformation by these oncogenic manipulations; 4) high levels of KRASV12 are required for full malignant transformation of HBECs, however prior loss of p53 function is required to prevent oncogene-induced senescence; 5) over-expression of c-MYC greatly enhances malignancy but only in the context of sh-p53+KRASV12; 6) growth of parental HBECs in serum-containing medium induces differentiation while growth of oncogenically manipulated HBECs in serum increases in vivo tumorigenicity, decreases tumor latency, produces more undifferentiated tumors, and induces epithelial-to-mesenchymal transition (EMT); 7) oncogenic transformation of HBECs leads to increased sensitivity to standard chemotherapy doublets; 8) an mRNA signature derived by comparing tumorigenic vs. non-tumorigenic clones was predictive of outcome in lung cancer patients. Collectively, our findings demonstrate this HBEC model system can be used to study the effect of oncogenic mutations, their expression levels, and serum-derived environmental effects in malignant transformation, while also providing clinically translatable applications such as development of prognostic signatures and drug response phenotypes. PMID:23449933

  9. Activation of proto-oncogenes in human and mouse lung tumors

    SciTech Connect

    Reynolds, S.H.; Anderson, M.W. )

    1991-06-01

    Lung cancer is a leading cause of cancer-related deaths in several nations. Epidemiological studies have indicated that 85% of all lung cancer deaths and 30% of all cancer deaths in the US are associated with tobacco smoking. Various chemicals in tobacco smoke are thought to react with DNA and to ultimately yield heritable mutations. In an effort to understand the molecular mechanisms involved in lung tumorigenesis, the authors have analyzed proto-oncogene activation in a series of human lung tumors from smokers and spontaneously occurring and chemically induced lung tumors in mice. Approximately 86% of the human lung tumors and > 90% of the mouse lung tumors were found to contain activated oncogenes. ras Oncogenes activated by point mutations were detected in many of the human lung adenocarcinomas and virtually all of the mouse lung adenomas and adenocarcinomas. The mutation profiles of the activated K-ras genes detected in the chemically induced mouse lung tumors suggest that the observed mutations result from genotoxic effects of the chemicals. Comparison of the K-ras mutations observed in the human lung adenocarcinomas with mutation profiles observed in the mouse lung tumors suggest that bulky hydrophobic DNA adducts may be responsible for the majority of the mutations observed in the activated human K-ras genes. Other data indicate that approximately 20% of human lung tumors contain potentially novel transforming genes that may also be targets for mutagens in cigarette smoke.

  10. Proteomic analysis of human papillomavirus-related oral squamous cell carcinoma: identification of thioredoxin and epidermal-fatty acid binding protein as upregulated protein markers in microdissected tumor tissue.

    PubMed

    Melle, Christian; Ernst, Günther; Winkler, Robert; Schimmel, Bettina; Klussmann, Jens Peter; Wittekindt, Claus; Guntinas-Lichius, Orlando; von Eggeling, Ferdinand

    2009-04-01

    Human papillomavirus (HPV) infection has been identified as an etiologic agent for a subset of oral squamous cell carcinoma (OSCC) with increasing incidence. HPV DNA-positivity may confer better prognosis but the related oncogenic mechanisms are unknown. For the identification of HPV relevant proteins, we analyzed microdissected cells from HPV DNA-positive (n = 17) and HPV DNA-negative (n = 7) OSCC tissue samples. We identified 18 proteins from tumor tissues by peptide fingerprint mapping and SELDI MS that were separated using 2-DE. Among a number of signals that were detected as significantly different in the protein profiling analysis, we identified thioredoxin (TRX) and epidermal-fatty acid binding protein as upregulated in HPV related tumor tissue. This study, investigating for the first time proteomic changes in microdissected HPV infected tumor tissue, provides an indication on the oncogenic potential of viruses. PMID:19337991

  11. The levels of epithelial anchor proteins β-catenin and zona occludens-1 are altered by E7 of human papillomaviruses 5 and 8.

    PubMed

    Heuser, Sandra; Hufbauer, Martin; Marx, Benjamin; Tok, Ali; Majewski, Slawomir; Pfister, Herbert; Akgül, Baki

    2016-02-01

    Infection with viruses of the genus Betapapillomavirus, β-human papillomaviruses (β-HPV), is implicated in the development of non-melanoma skin cancer. This was first evidenced for HPV5 and HPV8 in patients with the skin disease epidermodysplasia verruciformis (EV). The relocalization of the junctional bridging proteins β-catenin and zona occludens-1 (ZO-1) from the adherens and tight junctions are common processes of the epithelial-mesenchymal transition (EMT) associated with tumour invasion. Here, we report that β-catenin and ZO-1 are strongly upregulated by the E7 oncoproteins of HPV5 and HPV8 in keratinocytes grown in organotypic skin cultures. Although the membrane-tethered form of β-catenin was elevated, no signs of β-catenin activity within the canonical Wnt signalling pathway could be detected. The upregulation of β-catenin and ZO-1 could also be confirmed in the skin of HPV8 transgenic mice as well as in cutaneous squamous cell carcinomas of EV patients. These data provide the first evidence that β-catenin and ZO-1 are direct targets of E7 of the oncogenic β-HPV types 5 and 8. The ability to deregulate these epithelial junction proteins may contribute to the oncogenic potential of these viruses in human skin. PMID:26645068

  12. Repurposing a Prokaryotic Toxin-Antitoxin System for the Selective Killing of Oncogenically Stressed Human Cells.

    PubMed

    Preston, Mark A; Pimentel, Belén; Bermejo-Rodríguez, Camino; Dionne, Isabelle; Turnbull, Alice; de la Cueva-Méndez, Guillermo

    2016-07-15

    Prokaryotes express intracellular toxins that pass unnoticed to carrying cells until coexpressed antitoxin partners are degraded in response to stress. Although not evolved to function in eukaryotes, one of these toxins, Kid, induces apoptosis in mammalian cells, an effect that is neutralized by its cognate antitoxin, Kis. Here we engineered this toxin-antitoxin pair to create a synthetic system that becomes active in human cells suffering a specific oncogenic stress. Inspired by the way Kid becomes active in bacterial cells, we produced a Kis variant that is selectively degraded in human cells expressing oncoprotein E6. The resulting toxin-antitoxin system functions autonomously in human cells, distinguishing those that suffer the oncogenic insult, which are killed by Kid, from those that do not, which remain protected by Kis. Our results provide a framework for developing personalized anticancer strategies avoiding off-target effects, a challenge that has been hardly tractable by other means thus far. PMID:26230535

  13. Initiation of oncogenic transformation in human mammary epithelial cells by charged particles

    NASA Technical Reports Server (NTRS)

    Yang, T. C.; Georgy, K. A.; Craise, L. M.; Durante, M.

    1997-01-01

    Experimental studies have shown that high linear-energy transfer (LET) charged particles can be more effective than x-rays and gamma-rays in inducing oncogenic transformation in cultured cells and tumors in animals. Based on these results, experiments were designed and performed with an immortal human mammary epithelial cell line (H184B5), and several clones transformed by heavy ions were obtained. Cell fusion experiments were subsequently done, and results indicate that the transforming gene(s) is recessive. Chromosome analysis with fluorescence in situ hybridization (FISH) techniques also showed additional translocations in transformed human mammary epithelial cells. In addition, studies with these cell lines indicate that heavy ions can effectively induce deletion, break, and dicentrics. Deletion of tumor suppressor gene(s) and/or formation of translocation through DNA double strand breaks is a likely mechanism for the initiation of oncogenic transformation in human mammary epithelial cells.

  14. [Human papillomavirus and cervical cancer in México: a constant struggle].

    PubMed

    Torres-Poveda, Kirvis; Madrid-Marina, Vicente

    2015-01-01

    Given that human papillomavirus and cervical cancer are a health problem in México, since they affect women of reproductive age and have a negative impact on our society, it is crucial to prevent those diseases and to raise awareness among physicians who deal with their clinical and therapeutic management. That is the reason why we show three Original contributions and 13 Current themes in this supplement of the Revista Médica del Instituto Mexicano del Seguro Social. PMID:26462506

  15. Increased cycling cell numbers and stem cell associated proteins as potential biomarkers for high grade human papillomavirus+ve pre-neoplastic cervical disease.

    PubMed

    Canham, Maurice; Charsou, Chara; Stewart, June; Moncur, Sharon; Hoodless, Laura; Bhatia, Ramya; Cong, Duanduan; Cubie, Heather; Busby-Earle, Camille; Williams, Alistair; McLoughlin, Victoria; Campbell, John D M; Cuschieri, Kate; Howie, Sarah

    2014-01-01

    High risk (oncogenic) human papillomavirus (HPV) infection causes cervical cancer. Infections are common but most clear naturally. Persistent infection can progress to cancer. Pre-neoplastic disease (cervical intraepithelial neoplasia/CIN) is classified by histology (CIN1-3) according to severity. Cervical abnormalities are screened for by cytology and/or detection of high risk HPV but both methods are imperfect for prediction of which women need treatment. There is a need to understand the host virus interactions that lead to different disease outcomes and to develop biomarker tests for accurate triage of infected women. As cancer is increasingly presumed to develop from proliferative, tumour initiating, cancer stem cells (CSCs), and as other oncogenic viruses induce stem cell associated gene expression, we evaluated whether presence of mRNA (detected by qRT-PCR) or proteins (detected by flow cytometry and antibody based proteomic microarray) from stem cell associated genes and/or increased cell proliferation (detected by flow cytometry) could be detected in well-characterised, routinely collected cervical samples from high risk HPV+ve women. Both cytology and histology results were available for most samples with moderate to high grade abnormality. We found that stem cell associated proteins including human chorionic gonadotropin, the oncogene TP63 and the transcription factor SOX2 were upregulated in samples from women with CIN3 and that the stem cell related, cell surface, protein podocalyxin was detectable on cells in samples from a subset of women with CIN3. SOX2, TP63 and human gonadotrophin mRNAs were upregulated in high grade disease. Immunohistochemistry showed that SOX2 and TP63 proteins clearly delineated tumour cells in invasive squamous cervical cancer. Samples from women with CIN3 showed increased proliferating cells. We believe that these markers may be of use to develop triage tests for women with high grade cervical abnormality to distinguish

  16. Oncogenic RAS-induced senescence in human primary thyrocytes: molecular effectors and inflammatory secretome involved

    PubMed Central

    Vizioli, Maria Grazia; Santos, Joana; Pilotti, Silvana; Mazzoni, Mara; Anania, Maria Chiara; Miranda, Claudia; Pagliardini, Sonia; Pierotti, Marco A.

    2014-01-01

    Oncogene-induced senescence (OIS) is a robust and sustained antiproliferative response to oncogenic stress and constitutes an efficient barrier to tumour progression. We have recently proposed that OIS may be involved in the pathogenesis of thyroid carcinoma by restraining tumour progression as well as the transition of well differentiated to more aggressive variants. Here, an OIS inducible model was established and used for dissecting the molecular mechanisms and players regulating senescence in human primary thyrocytes. We show that oncogenic RAS induces senescence in thyrocytes as judged by changes in cell morphology, activation of p16INK4a and p53/p21CIP1 tumour suppressor pathways, senescence-associated β-galactosidase (SA-β-Gal) activity, and induction of proinflammatory components including IL-8 and its receptor CXCR2. Using RNA interference (RNAi) we demonstrate that p16INK4a is necessary for the onset of senescence in primary thyrocytes as its depletion rescues RAS-induced senescence. Furthermore, we found that IL-8/CXCR2 network reinforces the growth arrest triggered by oncogenic RAS, as its abrogation is enough to resume proliferation. Importantly, we observed that CXCR2 expression coexists with OIS markers in thyroid tumour samples, suggesting that CXCR2 contributes to senescence, thus limiting thyroid tumour progression. PMID:25268744

  17. Oncogene transcription in normal human IMR-90 fibroblasts: induction by serum and tetradecanoyl phorbol acetate

    SciTech Connect

    Bower, E.A.; Kaji, H.

    1988-01-01

    The authors report studies of oncogene transcription induced by the addition of serum to quiescent cultures of human IMR-90 fibroblasts. Oncogene messenger RNAs for c-myc, c-erbB and c-ras were increased in a specific temporal sequence after the addition of serum. Compounds that are proposed to exert their actions by the stimulation of cell growth were tested for their effect on oncogene transcription in IMR-90 fibroblasts. The tumor promoter tetradecanoyl phorbol acetate (TPA) was found to selectively induce the transcription of c-myc without observable effect on the transcription of the other oncogenes studied, and without inducing cell division. The inactive analog, phorbol didecanoate (PDD), and two complete carcinogens dimethylbenzanthracene (DMBA) and 4-nitro quinoline-1-oxide (4NQO) were without effect on the transcription of the genes studied. These results suggest that the complete ordered sequence of gene transcription is necessary to achieve the physiologic response of cell division, and that classical promoters and complete carcinogens achieve their effects through different pathways.

  18. High Frequency of Human Papillomavirus Genotype 16 Among Patients With Anogenital Warts

    PubMed Central

    Yaghoobi, Reza; Makvandi, Manoochehr; Afshar, Nasim; Pazyar, Nader; Hamidifard, Mojtaba; Sharifpour, Chia

    2015-01-01

    Background: Human Papillomavirus (HPV) infection is considered the most prevalent sexually transmitted virus infection. Human Papillomavirus 16 and 18 have been documented as high-risk HPV infections and responsible for 70% of all cervical cancers. Objectives: The aim of this study was to determine HPV genotypes in patients with anogenital warts. Patients and Methods: In this study lesion samples were collected from 54 patients with an age ranged of 19 to 44 years. Initially, DNA extraction was carried out for all samples followed by detection of HPV DNA by the polymerase chain reaction. The positive PCR products were sequenced and the results were blasted to determine HPV genotypes. Results: Out of 54 samples, 46 (85.18%) cases showed positive results for HPV DNA. A total of 26 (56.6%) samples were males and 20 (43.4%) females while eight (14.81%) showed HPV negative results. Overall, 37 (80%) patients had multiple sexual partners, and nine (20%) had one sexual partner. The frequency of anogenital warts was higher in married patients. The results of sequencing revealed that frequency of HPV16, HPV11 and HPV6 was 58.69%, 26.08% and 15.21%, respectively. Conclusions: Human Papillomavirus 16 as a high risk HPV was found to have the highest frequency among patients with anogenital warts. PMID:26862384

  19. Vaccinating HIV patients: focus on human papillomavirus and herpes zoster vaccines.

    PubMed

    Koenig, Helen C; Garland, Joseph M; Weissman, Drew; Mounzer, Karam

    2013-01-01

    Vaccination has been one of our most powerful tools to decrease morbidity and mortality from infectious diseases in the last century. It is critical to understand the evolving safety and efficacy data for vaccines in HIV-infected individuals as the number of people living with HIV in the United States and globally continues to increase. The quadrivalent human papillomavirus vaccine and the herpes zoster vaccine are newly licensed in the general population, and several studies have recently been published on the safety and efficacy of these vaccines in HIV populations. This manuscript reviews recent data for the vaccines most commonly administered in HIV patients and incorporates these data into our body of knowledge about the safety and efficacy of vaccines in this population. In addition, patient factors that predict response for each vaccine are discussed. Given the great burden of human papillomavirus and herpes zoster in HIV patients, we discuss the benefits and the challenges of vaccinating HIV patients with the human papillomavirus and herpes zoster vaccines. This review provides information that clinicians need to make real-time decisions in the absence of large-scale trials in the HIV population. PMID:23681435

  20. Prevalence of human papillomavirus infection, distribution of viral types and risk factors in cervical samples from human immunodeficiency virus-positive women attending three human immunodeficiency virus-acquired immune deficiency syndrome reference centres in northeastern Brazil

    PubMed Central

    Martins, Albert Eduardo Silva; Lucena-Silva, Norma; Garcia, Renan Gomes; Welkovic, Stefan; Barboza, Aureliana; Menezes, Maria Luiza Bezerra; Maruza, Magda; Tenório, Terezinha; Ximenes, Ricardo AA

    2014-01-01

    Human immunodeficiency virus (HIV)-positive patients have a greater prevalence of coinfection with human papillomavirus (HPV) is of high oncogenic risk. Indeed, the presence of the virus favours intraepithelial squamous cell lesion progression and may induce cancer. The aim of this study was to evaluate the prevalence of HPV infection, distribution of HPV types and risk factors among HIV-positive patients. Cervical samples from 450 HIV-positive patients were analysed with regard to oncotic cytology, colposcopy and HPV presence and type by means of polymerase chain reaction and sequencing. The results were analysed by comparing demographic data and data relating to HPV and HIV infection. The prevalence of HPV was 47.5%. Among the HPV-positive samples, 59% included viral types of high oncogenic risk. Multivariate analysis showed an association between HPV infection and the presence of cytological alterations (p = 0.003), age greater than or equal to 35 years (p = 0.002), number of partners greater than three (p = 0.002), CD4+ lymphocyte count < 200/mm3 (p = 0.041) and alcohol abuse (p = 0.004). Although high-risk HPV was present in the majority of the lesions studied, the low frequency of HPV 16 (3.3%), low occurrence of cervical lesions and preserved immunological state in most of the HIV-positive patients were factors that may explain the low occurrence of precancerous cervical lesions in this population. PMID:25317701

  1. Detection of human papillomavirus type 10 DNA in eccrine syringofibroadenomatosis occurring in Clouston's syndrome.

    PubMed

    Carlson, J A; Rohwedder, A; Daulat, S; Schwartz, J; Schaller, J

    1999-02-01

    Syringofibroadenomatosis is often associated with an underlying condition such as diabetes mellitus or hidrotic ectodermal dysplasia. By reason of these associations, a reactive or hamartomatous cause is suspected. We report a case of a 71-year-old woman with Clouston's syndrome in whom progressive multiple palmoplantar syringofibroadenomas developed over a 10-year period. The syringofibroadenomas formed flat-topped papules simulating verruca plana; the widespread distribution and chronic progressive course resembled epidermodysplasia verruciformis. Contiguous with the syringofibroadenoma's characteristic epithelial-stromal proliferation were epidermal changes of verruca plana. Evidence of human papillomavirus (HPV) infection was verified by immunolabeling with antibodies to bovine papillomavirus type 1 and detection of HPV 10 viral DNA by means of polymerase chain reaction. Rather than a hamartomatous process, these findings suggest that syringofibroadenomas occurring in the setting of Clouston's syndrome could represent an HPV-induced epithelial proliferation. PMID:10025758

  2. Human papillomavirus type 16 DNA-induced malignant transformation of NIH 3T3 cells

    SciTech Connect

    Yasumoto, S.; Burkhardt, A.L.; Doniger, J.; DiPaolo, J.A.

    1986-02-01

    A biological function for human papillomavirus 16 (HPV 16) DNA was demonstrated by transformation of NIH 3T3 cells. HPV 16 DNA has been found frequently in genital cancer and has been classified as a papillomavirus on the basis of DNA homology. A recombinant HPV 16 DNA (pSHPV16d), which contains a head-to-tail dimer of the full-length HPV 16 genome, induced morphologic transformation; the transformed cells were tumorigenic in nude mice. Expression of transforming activity was unique because of the long latency period (more than 4 weeks) required for induction of morphologic transformation and because the transfected DNA existed primarily in a multimeric form with some rearrangement. Furthermore, virus-specific RNAs were expressed in the transformants. The transformation of NIH 3T3 cells provides a model for analyzing the functions of HPV 16, which is associated with cervical carcinomas.

  3. Opposing oncogenic activities of small DNA tumor virus transforming proteins

    PubMed Central

    Chinnadurai, G.

    2011-01-01

    The E1A gene of species C human adenovirus is an intensely investigated model viral oncogene that immortalizes primary cells and mediates oncogenic cell transformation in cooperation with other viral or cellular oncogenes. Investigations using E1A proteins have illuminated important paradigms in cell proliferation and the functions of cellular proteins such as the retinoblastoma protein. Studies with E1A have led to the surprising discovery that E1A also suppresses cell transformation and oncogenesis. Here, I review our current understanding of the transforming and tumor suppressive functions of E1A, and how E1A studies led to the discovery of a related tumor suppressive function in benign human papillomaviruses. The potential role of these opposing functions in viral replication in epithelial cells is also discussed. PMID:21330137

  4. Loss of oncogenic ras expression does not correlate with loss of tumorigenicity in human cells.

    PubMed Central

    Plattner, R; Anderson, M J; Sato, K Y; Fasching, C L; Der, C J; Stanbridge, E J

    1996-01-01

    ras oncogenes are mutated in at variety of human tumors, which suggests that they play an important role in human carcinogenesis. To determine whether continued oncogenic ras expression is necessary to maintain the malignant phenotype, we studied the human fibrosarcoma cell line, HT1080, which contains one mutated and one wild-type N-ras allele. We isolated a variant of this cell line that no longer contained the mutated copy of the N-ras gene. Loss of mutant N-ras resulted in cells that displayed a less transformed phenotype characterized by a flat morphology, decreased growth rate, organized actin stress fibers, and loss of anchorage-independent growth. The transformed phenotype was restored following reintroduction of mutant N-ras. Although loss of the oncogenic N-ras drastically affected in vitro growth parameters, the variant remained tumorigenic in nude mice indicating that mutated N-ras expression is not necessary for maintenance of the tumorigenic phenotype. We confirmed this latter observation in colon carcinoma cell lines that have lost activated K-ras expression via targeted knockout of the mutant K-ras gene. Images Fig. 1 Fig. 2 Fig. 3 Fig. 5 PMID:8692875

  5. The Subcellular Localisation of the Human Papillomavirus (HPV) 16 E7 Protein in Cervical Cancer Cells and Its Perturbation by RNA Aptamers

    PubMed Central

    Cesur, Özlem; Nicol, Clare; Groves, Helen; Mankouri, Jamel; Blair, George Eric; Stonehouse, Nicola J.

    2015-01-01

    Human papillomavirus (HPV) is the most common viral infection of the reproductive tract, affecting both men and women. High-risk oncogenic types are responsible for almost 90% of anogenital and oropharyngeal cancers including cervical cancer. Some of the HPV “early” genes, particularly E6 and E7, are known to act as oncogenes that promote tumour growth and malignant transformation. Most notably, HPV-16 E7 interacts with the tumour suppressor protein pRb, promoting its degradation, leading to cell cycle dysregulation in infected cells. We have previously shown that an RNA aptamer (termed A2) selectively binds to HPV16 E7 and is able to induce apoptosis in HPV16-transformed cervical carcinoma cell lines (SiHa) through reduction of E7 levels. In this study, we investigated the effects of the A2 aptamer on E7 localisation in order to define its effects on E7 activity. We demonstrate for the first time that E7 localised to the plasma membrane. In addition, we show that A2 enhanced E7 localisation in the ER and that the A2-mediated reduction of E7 was not associated with proteasomal degradation. These data suggest that A2 perturbs normal E7 trafficking through promoting E7 ER retention. PMID:26131956

  6. Alpha-Defensin HD5 Inhibits Furin Cleavage of Human Papillomavirus 16 L2 To Block Infection

    PubMed Central

    Wiens, Mayim E.

    2014-01-01

    ABSTRACT Human papillomavirus (HPV) is a significant oncogenic virus, but the innate immune response to HPV is poorly understood. Human α-defensin 5 (HD5) is an innate immune effector peptide secreted by epithelial cells in the genitourinary tract. HD5 is broadly antimicrobial, exhibiting potent antiviral activity against HPV at physiologic concentrations; however, the specific mechanism of HD5-mediated inhibition against HPV is unknown. During infection, the HPV capsid undergoes several critical cell-mediated viral protein processing steps, including unfolding and cleavage of the minor capsid protein L2 by host cyclophilin B and furin. Using HPV16 pseudovirus, we show that HD5 interacts directly with the virus and inhibits the furin-mediated cleavage of L2 at the cell surface during infection at a step downstream of the cyclophilin B-mediated unfolding of L2. Importantly, HD5 does not affect the enzymatic activity of furin directly. Thus, our data support a model in which HD5 prevents furin from accessing L2 by occluding the furin cleavage site via direct binding to the viral capsid. IMPORTANCE Our study elucidates a new antiviral action for α-defensins against nonenveloped viruses in which HD5 directly interferes with a critical host-mediated viral processing step, furin cleavage of L2, at the cell surface. Blocking this key event has deleterious effects on the intracellular steps of virus infection. Thus, in addition to informing the antiviral mechanisms of α-defensins, our studies highlight the critical role of furin cleavage in HPV entry. Innate immune control, mediated in part by α-defensins expressed in the genital mucosa, may influence susceptibility to HPV infections that lead to cervical cancer. Moreover, understanding the mechanism of these natural antivirals may inform the design of therapeutics to limit HPV infection. PMID:25540379

  7. Utilising proteomic approaches to understand oncogenic human herpesviruses (Review)

    PubMed Central

    OWEN, CHRISTOPHER B.; HUGHES, DAVID J.; BAQUERO-PEREZ, BELINDA; BERNDT, ANJA; SCHUMANN, SOPHIE; JACKSON, BRIAN R.; WHITEHOUSE, ADRIAN

    2014-01-01

    The γ-herpesviruses Epstein-Barr virus and Kaposi’s sarcoma-associated herpesvirus are successful pathogens, each infecting a large proportion of the human population. These viruses persist for the life of the host and may each contribute to a number of malignancies, for which there are currently no cures. Large-scale proteomic-based approaches provide an excellent means of increasing the collective understanding of the proteomes of these complex viruses and elucidating their numerous interactions within the infected host cell. These large-scale studies are important for the identification of the intricacies of viral infection and the development of novel therapeutics against these two important pathogens. PMID:25279171

  8. The Oncogenic Potential of Human Cytomegalovirus and Breast Cancer

    PubMed Central

    Herbein, Georges; Kumar, Amit

    2014-01-01

    Breast cancer is the leading causes of cancer-related death among women. The vast majority of breast cancers are carcinomas that originate from cells lining the milk-forming ducts of the mammary gland. Numerous articles indicate that breast tumors exhibit diverse phenotypes depending on their distinct physiopathological signatures, clinical courses, and therapeutic possibilities. The human cytomegalovirus (HCMV) is a multifaceted highly host specific betaherpesvirus that is regarded as asymptomatic or mildly pathogenic virus in immunocompetent host. HCMV may cause serious in utero infections as well as acute and chronic complications in immunocompromised individual. The involvement of HCMV in late inflammatory complications underscores its possible role in inflammatory diseases and cancer. HCMV targets a variety of cell types in vivo, including macrophages, epithelial cells, endothelial cells, fibroblasts, stromal cells, neuronal cells, smooth muscle cells, and hepatocytes. HCMV can be detected in the milk after delivery and thereby HCMV could spread to adjacent mammary epithelial cells. HCMV also infects macrophages and induces an atypical M1/M2 phenotype, close to the tumor-associated macrophage phenotype, which is associated with the release of cytokines involved in cancer initiation or promotion and breast cancer of poor prognosis. HCMV antigens and DNA have been detected in tissue biopsies of breast cancers and elevation in serum HCMV IgG antibody levels has been reported to precede the development of breast cancer in some women. In this review, we will discuss the potential role of HCMV in the initiation and progression of breast cancer. PMID:25202681

  9. E6 and E7 oncoproteins from human papillomavirus type 16 induce activation of human transforming growth factor beta1 promoter throughout Sp1 recognition sequence.

    PubMed

    Peralta-Zaragoza, Oscar; Bermúdez-Morales, Víctor; Gutiérrez-Xicotencatl, Lourdes; Alcocer-González, Juan; Recillas-Targa, Félix; Madrid-Marina, Vicente

    2006-01-01

    Human Papillomavirus (HPV) infection is the main etiologic agent of cervical cancer and HPV E6 and E7 oncogenes trans-regulate many cellular genes. An association between TGF-beta1 gene expression and cervical cancer development has been suggested; however, the mechanisms by which HPV influences TGF-beta1 expression remain unclear. In the present study we analyzed the mechanism through which HPV-16 E6 and E7 oncoproteins regulate the TGF-beta1 promoter in cervical tumor cells. Our results showed that E6 and E7 increased TGF-beta1 promoter activity. Furthermore, we identified a specific DNA sequence motif in the TGF-beta1 core promoter that is responsible for trans-activation and that corresponds to the Sp1e-binding site associated with HPV-16 E6 and E7 oncoproteins. Mutational analysis showed that the Sp1e recognition site abolished the trans-activation caused by E6 and E7. These results suggest a physical interaction and functional cooperation between viral oncoproteins and cellular regulatory elements of the TGF-beta1 promoter, and may explain the contribution of HPV-16 to TGF-beta1 gene expression in cervical cancer. PMID:16987065

  10. The E5 oncoprotein of human papillomavirus type 16 inhibits the acidification of endosomes in human keratinocytes.

    PubMed Central

    Straight, S W; Herman, B; McCance, D J

    1995-01-01

    The human papillomavirus type 16 E5 oncoprotein possesses mitogenic activity that acts synergistically with epidermal growth factor (EGF) in human keratinocytes and inhibits the degradation of the EGF receptor in endosomal compartments after ligand-stimulated endocytosis. One potential explanation for these observations is that E5 inhibits the acidification of endosomes. This may be mediated through the 16-kDa component of the vacuolar proton-ATPase, since animal and human papillomavirus E5 proteins bind this subunit protein. Using a ratio-imaging technique to determine endosomal pH, we found that the acidification of endosomes in E5-expressing keratinocytes was delayed at least fourfold compared with normal human keratinocytes and endosomes in some cells never completely acidified. Furthermore, E5 expression increased the resistance of keratinocytes to protein synthesis inhibition by diphtheria toxin, a process dependent on efficient endosomal acidification. Finally, artificially inhibiting endosomal acidification with chloroquine during the endocytosis of EGF receptors in keratinocytes demonstrated many of the same effects as the expression of human papillomavirus type 16 E5, including prolonged retention of undegraded EGF receptors in intracellular vesicles. PMID:7707548

  11. Gallic acid induces apoptosis in human cervical epithelial cells containing human papillomavirus type 16 episomes.

    PubMed

    Shi, Lin; Lei, Yanjun; Srivastava, Ranjana; Qin, Weihua; Chen, Jason J

    2016-01-01

    The high-risk human papillomaviruses (HPV) that infect the anogenital tract are strongly associated with the development of cervical carcinoma, which is the second most common cancer in women worldwide. Therapeutic drugs specifically targeting HPV are not available. Polyphenolic compounds have gained considerable attention because of their cytotoxic effects against a variety of cancers and certain viruses. In this study, we examined the effects of several polyphenols on cellular proliferation and death of the human cervical cancer cells and human cervical epithelial cells containing stable HPV type 16 episomes (HPVep). Our results show that three polyphenols inhibited proliferation of HeLa cells dose-dependently. Furthermore, one of the examined polyphenols, gallic acid (GA), also inhibited the proliferation of HPVep cells and exhibited significant specificity towards HPV-positive cells. The anti-proliferative effect of GA on HPVep and HeLa cells was associated with apoptosis and upregulation of p53. These results suggest that GA can be a potential candidate for the development of anti-HPV agents. PMID:26059022

  12. Characterization of primary human keratinocytes transformed by human papillomavirus type 18

    SciTech Connect

    Kaur, P.; McDougall, J.K. )

    1988-06-01

    Primary human epithelial cells were cotransfected with pHPV-18 and pSV2neo, and cell strains were generated by selecting in G418. Southern blot analysis revealed the presence of at least one intact, integrated viral genome in these cells. FE-A cells showed altered growth properties, characterized by a change in morphology, and clonal density. Differentiation markers analyzed by Western blotting (immunoblotting), such as cytokeratins and involucrin, indicated that the cells resembled a partially differentiated epithelial population. Increased expression of the 40-kilodalton cytokeratin was observed in FE-A cells, similar to that observed in simian virus 40-immortalized human keratinocytes. Calcium and 12-O-tetradecanoyl-phorbol-13-acetate treatment induced normal epithelial cells to differentiate, whereas the human papillomavirus 18 (HPV-18)-containing keratinocytes were resistant to these signals, indicating their partially transformed nature. These cells were not able to induce tumors in nude mice over a period of up to 8 months. A second cell strain, FE-H18L, also generated by transfecting HPV-18, also exhibited an extended life span and similar alterations in morphology. Viral RNA transcribed from the early region of HPV-18 was detected in both cell strains by Northern (RNA) blot analysis. These cell strains should provide a useful model for determining the role of HPV in carcinogenesis.

  13. A large spectrum of alpha and beta papillomaviruses are detected in human stool samples.

    PubMed

    Di Bonito, Paola; Della Libera, Simonetta; Petricca, Sabrina; Iaconelli, Marcello; Sanguinetti, Maurizio; Graffeo, Rosalia; Accardi, Luisa; La Rosa, Giuseppina

    2015-03-01

    Human papillomaviruses (HPVs) have been detected in urban wastewaters, demonstrating that epitheliotropic viruses can find their way into sewage through the washing of skin and mucous membranes. Papillomavirus shedding through faeces is still an unexplored issue. The objective of the present study was to investigate the presence of HPVs in stool samples. We analysed 103 faecal specimens collected from hospitalized patients with diarrhoea using validated primers able to detect α, β and γ HPVs. PCR products underwent sequencing analysis and sequences were aligned to reference genomes from the Papillomavirus Episteme database. A total of 15 sequences were characterized from the faecal samples. Thirteen samples (12.6 %) were positive for nine genotypes belonging to the α and β genera: HPV32 (LR, α1), HPV39 (HR, α7), HPV44 (LR, α10), HPV8 (β1), HPV9, HPV23, HPV37, HPV38 and HPV120 (β2). Two putative novel genotypes of the β genus, species 1 and 2, were also detected. The tissue(s) of origin is unknown, since faeces can collect HPVs originating from or passing through the entire digestive system. To our knowledge, this is the first investigation on the occurrence and diversity of HPVs in faecal samples. Results from this study demonstrate that HPVs can find their way into sewage as a consequence of shedding in the faeces. This highlights the need for further studies aimed at understanding the prevalence of HPV in different water environments and the potential for waterborne transmission. PMID:25398789

  14. NF-κB signalling is attenuated by the E7 protein from cutaneous human papillomaviruses.

    PubMed

    Byg, Luise M; Vidlund, Jessica; Vasiljevic, Natasa; Clausen, Dorte; Forslund, Ola; Norrild, Bodil

    2012-10-01

    The high-risk Alpha-types of human papillomavirus (HPV) are the causative agent of cervical cancer, which is the second major cause of death among women worldwide. Recent investigations have shown that E7 from the Alpha-papillomavirus HPV-16 interacts with IKKα and IKKβ of the IKK complex in the NF-κB pathway leading to an attenuation of the activity. There is a possible link between development of non-melanoma skin cancer and cutaneous Beta-papillomavirus but if these HPV types attenuate the NF-κB pathway is unclear. Seven different E7 proteins, representing four out of the five different species of the Beta genus (HPV-20, -37, -38, -92, -93 and -96) and one from the Gamma genus (HPV-4) were investigated for potential modulation of the NF-κB pathway in U2OS cells. Our results demonstrate that E7 from all the cutaneous HPV types were capable of inhibiting the NF-κB activity as well as E7 from HPV-16. In addition, E7 proteins from the cutaneous HPV types demonstrated interaction with IKKα but not with IKKβ. The deregulation of the NF-κB pathway by cutaneous HPVs might contribute to the pathogenesis of non-melanoma skin cancers and its precursors. PMID:22776252

  15. Regression of Human Papillomavirus Intraepithelial Lesions Is Induced by MVA E2 Therapeutic Vaccine

    PubMed Central

    López-Contreras, Mario; Rosales, Carlos; Magallanes-Molina, Jose-Roberto; Gonzalez-Vergara, Roberto; Arroyo-Cazarez, Jose Martin; Ricardez-Arenas, Antonio; del Follo-Valencia, Armando; Padilla-Arriaga, Santiago; Guerrero, Miriam Veronica; Pirez, Miguel Angel; Arellano-Fiore, Claudia; Villarreal, Freddy

    2014-01-01

    Abstract Human papilloma viruses can induce warts, condylomas, and other intraepithelial cervical lesions that can progress to cancer. Cervical cancer is a serious problem in developing countries because early detection is difficult, and thus proper early treatment is many times missing. In this phase III clinical trial, we evaluated the potential use of MVA E2 recombinant vaccinia virus to treat intraepithelial lesions associated with papillomavirus infection. A total of 1176 female and 180 male patients with intraepithelial lesions were studied. They were injected with 107 MVA E2 virus particles directly into their uterus, urethra, vulva, or anus. Patients were monitored by colposcopy and cytology. Immune response was determined by measuring the antibody titer against MVA E2 virus and by analyzing the cytotoxic activity against cancer cells bearing papillomavirus DNA. Papillomavirus was determined by the Hybrid Capture method or by polymerase chain reaction analysis. By histology, 1051 (89.3%) female patients showed complete elimination of lesions after treatment with MVA E2. In 28 (2.4%) female patients, the lesion was reduced to CIN 1. Another 97 (8.3%) female patients presented isolated koilocytes after treatment. In men, all lesions were completely eliminated. All MVA E2–treated patients developed antibodies against the MVA E2 vaccine and generated a specific cytotoxic response against papilloma-transformed cells. Papillomavirus DNA was not detected after treatment in 83% of total patients treated. MVA E2 did not generate any apparent side effects. These data suggest that therapeutic vaccination with MVA E2 vaccine is an excellent candidate to stimulate the immune system and generate regression in intraepithelial lesions when applied locally. PMID:25275724

  16. Oncogene-induced telomere dysfunction enforces cellular senescence in human cancer precursor lesions

    PubMed Central

    Suram, Anitha; Kaplunov, Jessica; Patel, Priyanka L; Ruan, Haihe; Cerutti, Aurora; Boccardi, Virginia; Fumagalli, Marzia; Di Micco, Raffaella; Mirani, Neena; Gurung, Resham Lal; Hande, Manoor Prakash; d'Adda di Fagagna, Fabrizio; Herbig, Utz

    2012-01-01

    In normal human somatic cells, telomere dysfunction causes cellular senescence, a stable proliferative arrest with tumour suppressing properties. Whether telomere dysfunction-induced senescence (TDIS) suppresses cancer growth in humans, however, is unknown. Here, we demonstrate that multiple and distinct human cancer precursor lesions, but not corresponding malignant cancers, are comprised of cells that display hallmarks of TDIS. Furthermore, we demonstrate that oncogenic signalling, frequently associated with initiating cancer growth in humans, dramatically affected telomere structure and function by causing telomeric replication stress, rapid and stochastic telomere attrition, and consequently telomere dysfunction in cells that lack hTERT activity. DNA replication stress induced by drugs also resulted in telomere dysfunction and cellular senescence in normal human cells, demonstrating that telomeric repeats indeed are hypersensitive to DNA replication stress. Our data reveal that TDIS, accelerated by oncogene-induced DNA replication stress, is a biological response of cells in human cancer precursor lesions and provide strong evidence that TDIS is a critical tumour suppressing mechanism in humans. PMID:22569128

  17. Virus activated filopodia promote human papillomavirus type 31 uptake from the extracellular matrix

    PubMed Central

    Smith, Jessica L.; Lidke, Diane S.; Ozbun, Michelle A.

    2011-01-01

    Human papillomaviruses (HPVs), etiological agents of epithelial tumors and cancers, initiate infection of basal human keratinocytes (HKs) facilitated by wounding. Virions bind to HKs and their secreted extracellular matrix (ECM), but molecular roles for wounding or ECM binding during infection are unclear. Herein we demonstrate HPV31 activates signals promoting cytoskeletal rearrangements and virion transport required for internalization and infection. Activation of tyrosine and PI3 kinases precedes induction of filopodia whereon virions are transported toward the cell body. Coupled with loss of ECM bound virions this supports a model whereby virus activated filopodial transport contributes to increased and protracted virion uptake into susceptible cells. PMID:18834609

  18. Revising ecological assumptions about Human papillomavirus interactions and type replacement.

    PubMed

    Murall, Carmen Lía; McCann, Kevin S; Bauch, Chris T

    2014-06-01

    The controversy over whether vaccine-targeted HPV types will be replaced by other oncogenic, non-vaccine-targeted types remains unresolved. This is in part because little is known about the ecology of HPV types. Patient data has been interpreted to suggest independence or facilitative interactions between types and therefore replacement is believed to be unlikely. With a novel mathematical model, we investigated which HPV type interactions and their immune responses gave qualitatively similar patterns frequently observed in patients. To assess the possibility of type replacement, vaccination was added to see if non-vaccine-targeted types increased their 'niche'. Our model predicts that independence and facilitation are not necessary for the coexistence of types inside hosts, especially given the patchy nature of HPV infection. In fact, independence and facilitation inadequately represented co-infected patients. We found that some form of competition is likely in natural co-infections. Hence, non-vaccine-targeted types that are not cross-reactive with the vaccine could spread to more patches and can increase their viral load in vaccinated hosts. The degree to which this happens will depend on replication and patch colonization rates. Our results suggest that independence between types could be a fallacy, and so without conclusively untangling HPV within-host ecology, type replacement remains theoretically viable. More ecological thinking is needed in future studies. PMID:24412334

  19. Liquid Biopsy for Detection of Actionable Oncogenic Mutations in Human Cancers and Electric Field Induced Release and Measurement Liquid Biopsy (eLB)

    PubMed Central

    Tu, Michael; Chia, David; Wei, Fang; Wong, David

    2015-01-01

    Oncogenic activations by mutations in key cancer genes such as EGFR and KRAS are frequently associated with human cancers. Molecular targeting of specific oncogenic mutations in human cancer is a major therapeutic inroad for anti-cancer drug therapy. In addition, progressive developments of oncogene mutations lead to drug resistance. Therefore, the ability to detect and continuously monitor key actionable oncogenic mutations is important to guide the use of targeted molecular therapies to improve long-term clinical outcomes in cancer patients. Current oncogenic mutation detection is based on direct sampling of cancer tissue by surgical resection or biopsy. Oncogenic mutations were recently shown to be detectable in circulating bodily fluids of cancer patients. This field of investigation, termed liquid biopsy, permits a less invasive means of assessing the oncogenic mutation profile of a patient. This paper will review the analytical strategies used to assess oncogenic mutations from biofluid samples. Clinical applications will also be discussed. PMID:26645892

  20. The Interaction between Human Immunodeficiency Virus and Human Papillomaviruses in Heterosexuals in Africa

    PubMed Central

    Williamson, Anna-Lise

    2015-01-01

    Sub-Saharan Africa has the highest incidence of human papillomavirus (HPV) and cervical cancer in the world, which is further aggravated by the burden of human immunodeficiency virus/acquired immunodeficiency syndrome (HIV/AIDS) disease with invasive cervical cancer being an AIDS-defining cancer. The prevalence of HPV infection and associated disease is very high in HIV-infected people and continues to be a problem even after anti-retroviral therapy. In the genital tract, the interaction between HPV and HIV is complex, with infection with multiple HPV types reported to make both women and men more susceptible to HIV infection. Besides the national programmes to vaccinate girls against HPV and screen women for cervical cancer, there should be targeted cervical cancer screening, treatment and prevention programmes introduced into HIV treatment centres. There is evidence that in high HIV prevalence areas, HIV-positive women could cause increases in the prevalence of genital HPV infection in HIV-negative men and so increase the HPV circulating in the community. Condom use and circumcision reduce the acquisition of HIV-1, and also to some extent of HPV. This review will highlight what is known about the interaction of HIV and HPV, with an emphasis on research in Africa. PMID:26239348

  1. Regulation of human genome expression and RNA splicing by human papillomavirus 16 E2 protein.

    PubMed

    Gauson, Elaine J; Windle, Brad; Donaldson, Mary M; Caffarel, Maria M; Dornan, Edward S; Coleman, Nicholas; Herzyk, Pawel; Henderson, Scott C; Wang, Xu; Morgan, Iain M

    2014-11-01

    Human papillomavirus 16 (HPV16) is causative in human cancer. The E2 protein regulates transcription from and replication of the viral genome; the role of E2 in regulating the host genome has been less well studied. We have expressed HPV16 E2 (E2) stably in U2OS cells; these cells tolerate E2 expression well and gene expression analysis identified 74 genes showing differential expression specific to E2. Analysis of published gene expression data sets during cervical cancer progression identified 20 of the genes as being altered in a similar direction as the E2 specific genes. In addition, E2 altered the splicing of many genes implicated in cancer and cell motility. The E2 expressing cells showed no alteration in cell growth but were altered in cell motility, consistent with the E2 induced altered splicing predicted to affect this cellular function. The results present a model system for investigating E2 regulation of the host genome. PMID:25129434

  2. Genome-wide analysis of high risk human papillomavirus E2 proteins in human primary keratinocytes.

    PubMed

    Sunthamala, Nuchsupha; Pang, Chai Ling; Thierry, Francoise; Teissier, Sebastien; Pientong, Chamsai; Ekalaksananan, Tipaya

    2014-12-01

    The E2 protein is expressed in the early stage of human papillomavirus (HPV) infection that is associated with cervical lesions. This protein plays important roles in regulation of viral replication and transcription. To characterize the role of E2 protein in modulation of cellular gene expression in HPV infected cells, genome-wide expression profiling of human primary keratinocytes (HPK) harboring HPV16 E2 and HPV18 E2 was investigated using microarray. The Principle Components Analysis (PCA) revealed that the expression data of HPV16 E2 and HPV18 E2-transduced HPKs were rather closely clustered. The Venn diagram of modulated genes showed an overlap of 10 common genes in HPV16 E2 expressing HPK and HPV18 E2 expressing HPK. These genes were expressed with significant difference by comparison with control cells. In addition, the distinct sets of modulated genes were detected 14 and 34 genes in HPV16 E2 and HPV18 E2 expressing HPKs, respectively. PMID:26484085

  3. Interleukin-12-secreting human papillomavirus type 16-transformed cells provide a potent cancer vaccine that generates E7-directed immunity.

    PubMed

    Hallez, S; Detremmerie, O; Giannouli, C; Thielemans, K; Gajewski, T F; Burny, A; Leo, O

    1999-05-01

    The development of a vaccine that would be capable of preventing or curing the (pre)cancerous lesions induced by genital oncogenic human papillomaviruses (HPVs) is the focus of much research. Many studies are presently evaluating vaccines based on the viral E6 and E7 oncoproteins, both of which are continually expressed by tumor cells. The success of a cancer vaccine relies, in large part, on the induction of a tumor-specific Th1-type immunity. In this study, we have evaluated the ability of B7-related and/or interleukin-12 (IL-12)-expressing, non-immunogenic murine HPV16-transformed BMK-16/myc cells, to achieve this goal. BMK-16/myc cells engineered to express surface B7-1 or B7-2 molecules remain tumorigenic in syngeneic BALB/c mice, suggesting that expression of these molecules alone is not sufficient to induce tumor regression. In contrast, mice injected with tumor cells engineered to secrete IL-12 remained tumor-free, demonstrating that IL-12 expression is sufficient to induce tumor rejection. IL-12-secreting BMK-16/myc cells were further shown to induce potent and specific long-term tumor resistance, even after irradiation. B7-1 was found to slightly but systematically improve anti-tumor immunity elicited by IL-12-secreting BMK-16/myc cells. Injection of irradiated B7-1/IL-12+ BMK-16/myc cells generates long-lasting, Th1-type, BMK-16/myc-directed immunity in tumor-resistant mice. These mice display a memory-type, E7-specific, cell-mediated immune response, which is potentially significant for clinical applications. PMID:10209958

  4. Phylogenetic and functional analysis of sequence variation of human papillomavirus type 31 E6 and E7 oncoproteins.

    PubMed

    Ferenczi, Annamária; Gyöngyösi, Eszter; Szalmás, Anita; László, Brigitta; Kónya, József; Veress, György

    2016-09-01

    High-risk human papillomaviruses (HPV) are the causative agents of cervical and other anogenital cancers as well as a subset of head and neck cancers. The E6 and E7 oncoproteins of HPV contribute to oncogenesis by associating with the tumour suppressor protein p53 and pRb, respectively. For HPV types 16 and 18, intratypic sequence variation was shown to have biological and clinical significance. The functional significance of sequence variation among HPV 31 variants was studied less intensively. HPV 31 variants belonging to different variant lineages were found to have differences in persistence and in the ability to cause high grade cervical intraepithelial neoplasia. In the present study, we started to explore the functional effects of natural sequence variation of HPV 31 E6 and E7 oncoproteins. The E6 variants were tested for their effects on p53 protein stability and transcriptional activity, while the E7 variants were tested for their effects on pRb protein level and also on the transcriptional activity of E2F transcription factors. HPV 31 E7 variants displayed uniform effects on pRb stability and also on the activity of E2F transcription factors. HPV 31 E6 variants had remarkable differences in the ability to inhibit the trans-activation function of p53 but not in the ability to induce the in vivo degradation of p53. Our results indicate that natural sequence variation of the HPV 31 E6 protein may be involved in the observed differences in the oncogenic potential between HPV 31 variants. PMID:27197052

  5. Anal human papillomavirus and HIV: An exploratory study among men who have sex with men in Moscow, Russia

    PubMed Central

    Wirtz, AL; Zelaya, CE; Peryshkina, A; McGowan, I; Cranston, RD; Latkin, C; D’Souza, G; Galai, N; Mogilniy, V; Dzhigun, P; Kostetskaya, I; Beyrer, C

    2016-01-01

    Anal human papillomavirus (HPV) is prevalent among men who have sex with men (MSM), but has not been studied in the Russian Federation. HIV seropositive (N=58) and seronegative MSM (N=65) were enrolled in a cross-sectional study in Moscow, Russia, surveyed, and underwent anal cytology and anal HPV genotyping. Multivariable logistic regression was performed to identify correlates of infection with oncogenic HPV genotypes 16 and/or 18 (HPV 16/18). Some 39.5% of all MSM were infected with at least one anal HPV genotype, 31.7% with HPV16/18, and 11.7% had high grade squamous intraepithelial lesion (HSIL). HPV 16/18 was more prevalent among HIV seropositive than seronegative men (41.4% vs. 23.1%; p=0.03). In the final multivariable model, HIV infection was independently associated with HPV 16/18 (AOR:5.08; 95%CI:1.49–17.34), as were migration to/within Russia (AOR:3.18; 95%CI:1.00–10.09) and having 2–4 steady male sex partners in the last year (vs. ≤1 partner; AOR:6.99; 95%CI:1.94–25.24). History of jail/prison and use of incompatible lubricants were marginally associated with HPV 16/18 (p<0.10). Anal HPV 16/18 was prevalent among this sample of Moscow-based MSM and strongly associated with HIV infection. Correlations with mobility and detention in prison/jail, likely reflect behavioural risk and low healthcare access among marginalized populations that limits access to HIV/STI prevention options. Comprehensive prevention options are needed for MSM in Russia and may benefit from inclusion of young men in piloted HPV vaccination programs. PMID:25953132

  6. Prevalence, concordance and determinants of human papillomavirus infection among heterosexual partners in a rural region in central Mexico

    PubMed Central

    2010-01-01

    Background Although human papillomavirus (HPV) infection in heterosexual couples has been sparsely studied, it is relevant to understand disease burden and transmission mechanisms. The present study determined the prevalence and concordance of type-specific HPV infection as well as the determinants of infection in heterosexual couples in a rural area of Mexico. Methods A cross-sectional study was conducted in 504 clinically healthy heterosexual couples from four municipalities in the State of Mexico, Mexico. HPV testing was performed using biotinylated L1 consensus primers and reverse line blot in cervical samples from women and in genital samples from men. Thirty-seven HPV types were detected, including high-risk oncogenic types and low-risk types. Multivariate logistic regression models were utilized to evaluate factors associated with HPV. Results The prevalence of HPV infection was 20.5% in external male genitals and 13.7% in cervical samples. In 504 sexual couples participating in the study, concordance of HPV status was 79%; 34 partners (6.7%) were concurrently infected, and 21 out of 34 partners where both were HPV positive (61.8%) showed concordance for one or more HPV types. The principal risk factor associated with HPV DNA detection in men as well as women was the presence of HPV DNA in the respective regular sexual partner (OR = 5.15, 95%CI 3.01-8.82). In men, having a history of 10 or more sexual partners over their lifetime (OR 2.5, 95%CI 1.3 - 4.8) and having had sexual relations with prostitutes (OR 1.7, 95%CI 1.01 - 2.8) increased the likelihood of detecting HPV DNA. Conclusions In heterosexual couples in rural regions in Mexico, the prevalence of HPV infection and type-specific concordance is high. High-risk sexual behaviors are strong determinants of HPV infection in men. PMID:20667085

  7. Human papillomavirus infection among sexual partners attending a Sexually Transmitted Disease Clinic in Rio de Janeiro, Brazil.

    PubMed

    Afonso, L A; Rocha, W M; Carestiato, F N; Dobao, E A; Pesca, L F; Passos, M R L; Cavalcanti, S M B

    2013-06-01

    Cervical cancer is a major source of illness and death among women worldwide and genital infection with oncogenic human papillomavirus (HPV) its principal cause. There is evidence of the influence of the male factor in the development of cervical neoplasia. Nevertheless, the pathogenic processes of HPV in men are still poorly understood. It has been observed that different HPV types can be found among couples. The objective of the present study was to investigate HPV infections in female patients (n = 60 females/group) as well as in their sexual partners and to identify the concordance of HPV genotypes among them. By using the polymerase chain reaction, we detected a 95% prevalence of HPV DNA in women with cervical intraepithelial neoplasia (CIN) compared to 18.3% in women with normal cervical epithelium, with a statistically significant difference (P < 0.001). The HPV DNA prevalence was 50% in male partners of women with CIN and 16.6% in partners of healthy women. In the control group (healthy women), only 9 couples were simultaneously infected with HPV, and only 22.2% of them had the same virus type, showing a weak agreement rate (kappa index = 0.2). Finally, we observed that HPV DNA was present in both partners in 30 couples if the women had CIN, and among them, 53.3% shared the same HPV type, showing moderate agreement, with a kappa index of 0.5. This finding supports the idea of circulation and recirculation of HPV among couples, perpetuating HPV in the sexually active population, rather than true recurrences of latent infections. PMID:23739745

  8. Prevention of Anal Condyloma with Quadrivalent Human Papillomavirus Vaccination of Older Men Who Have Sex with Men

    PubMed Central

    Swedish, Kristin A.; Goldstone, Stephen E.

    2014-01-01

    Background The quadrivalent human papillomavirus vaccine (qHPV) is FDA-approved for use in males 9 to 26 years old to prevent anogenital condyloma. The objective of this study is to determine if qHPV is effective at preventing anal condyloma among men who have sex with men (MSM) aged 26 years and older. Methods This post-hoc analysis of a nonconcurrent cohort study evaluated 210 patients without history of anal condyloma and 103 patients with previously-treated anal condyloma recurrence-free for at least 12 months prior to vaccination/time zero. We determined the rate of anal condyloma development in vaccinated versus unvaccinated patients. Results 313 patients with mean age 42 years were followed for median 981 days. During 773.6 person-years follow-up, condyloma developed in 10 (8.6%) vaccinated patients (incidence of 3.7 per 100 person-years) and 37 (18.8%) unvaccinated patients (incidence 7.3 per 100 person-years; p = 0.05). Multivariable hazards ratio showed that qHPV was associated with decreased risk of anal condyloma development (HR 0.45; 95% CI 0.22–0.92; p = 0.03). History of anal condyloma was associated with increased risk of anal condyloma development (HR 2.28; 95% CI 1.28–4.05; p = 0.005), as was infection with oncogenic HPV (HR 3.87; 95% CI 1.66–9.03; p = 0.002). Conclusions Among MSM 26 years of age and older with and without history of anal condyloma, qHPV reduces the risk of anal condyloma development. A randomized controlled trial is needed to confirm these findings in this age group. PMID:24714693

  9. Synthetic lethal interaction between oncogenic KRAS dependency and STK33 suppression in human cancer cells.

    PubMed

    Scholl, Claudia; Fröhling, Stefan; Dunn, Ian F; Schinzel, Anna C; Barbie, David A; Kim, So Young; Silver, Serena J; Tamayo, Pablo; Wadlow, Raymond C; Ramaswamy, Sridhar; Döhner, Konstanze; Bullinger, Lars; Sandy, Peter; Boehm, Jesse S; Root, David E; Jacks, Tyler; Hahn, William C; Gilliland, D Gary

    2009-05-29

    An alternative to therapeutic targeting of oncogenes is to perform "synthetic lethality" screens for genes that are essential only in the context of specific cancer-causing mutations. We used high-throughput RNA interference (RNAi) to identify synthetic lethal interactions in cancer cells harboring mutant KRAS, the most commonly mutated human oncogene. We find that cells that are dependent on mutant KRAS exhibit sensitivity to suppression of the serine/threonine kinase STK33 irrespective of tissue origin, whereas STK33 is not required by KRAS-independent cells. STK33 promotes cancer cell viability in a kinase activity-dependent manner by regulating the suppression of mitochondrial apoptosis mediated through S6K1-induced inactivation of the death agonist BAD selectively in mutant KRAS-dependent cells. These observations identify STK33 as a target for treatment of mutant KRAS-driven cancers and demonstrate the potential of RNAi screens for discovering functional dependencies created by oncogenic mutations that may enable therapeutic intervention for cancers with "undruggable" genetic alterations. PMID:19490892

  10. Analysis of cis-elements that facilitate extrachromosomal persistence of human papillomavirus genomes

    SciTech Connect

    Pittayakhajonwut, Daraporn; Angeletti, Peter C.

    2008-05-10

    Human papillomaviruses (HPVs) are maintained latently in dividing epithelial cells as nuclear plasmids. Two virally encoded proteins, E1, a helicase, and E2, a transcription factor, are important players in replication and stable plasmid maintenance in host cells. Recent experiments in yeast have demonstrated that viral genomes retain replication and maintenance function independently of E1 and E2 [Angeletti, P.C., Kim, K., Fernandes, F.J., and Lambert, P.F. (2002). Stable replication of papillomavirus genomes in Saccharomyces cerevisiae. J. Virol. 76(7), 3350-8; Kim, K., Angeletti, P.C., Hassebroek, E.C., and Lambert, P.F. (2005). Identification of cis-acting elements that mediate the replication and maintenance of human papillomavirus type 16 genomes in Saccharomyces cerevisiae. J. Virol. 79(10), 5933-42]. Flow cytometry studies of EGFP-reporter vectors containing subgenomic HPV fragments with or without a human ARS (hARS), revealed that six fragments located in E6-E7, E1-E2, L1, and L2 regions showed a capacity for plasmid stabilization in the absence of E1 and E2 proteins. Interestingly, four fragments within E7, the 3' end of L2, and the 5' end of L1 exhibited stability in plasmids that lacked an hARS, indicating that they possess both replication and maintenance functions. Two fragments lying in E1-E2 and the 3' region of L1 were stable only in the presence of hARS, that they contained only maintenance function. Mutational analyses of HPV16-GFP reporter constructs provided evidence that genomes lacking E1 and E2 could replicate to an extent similar to wild type HPV16. Together these results support the concept that cellular factors influence HPV replication and maintenance, independently, and perhaps in conjunction with E1 and E2, suggesting a role in the persistent phase of the viral lifecycle.

  11. Equilibrium dissociation and unfolding of human papillomavirus E2 transactivation domain.

    PubMed

    Singh, Nitu; Kanthaje, Shruthi; Bose, Kakoli

    2015-08-01

    Papillomavirus E2 protein that performs essential functions such as viral oncogene expression and replication represents specific target for therapeutic intervention. DNA-binding activity is associated with its C-terminal DNA-binding domain (DBD), while the N-terminal transactivation domain (TAD) is responsible for replication and transactivation functions. Although both demonstrate large dependence on dimerization for mediating their functions, KD for N-terminal dimerization is significantly high suggesting more dynamic role of this domain. However, unlike DBD, very little information is available on TAD dimerization, its folding and stability. Therefore, with an aim at delineating the regulatory switch of its dimerization, we have characterized high-risk HPV18 E2 TAD. Our studies demonstrate that E2 TAD is a weak but thermodynamically stable dimer (KD ∼ 1.8 μM, [Formula: see text]  = 18.8 kcal mol(-1)) with α2-α3 helices forming the interface. It follows a three-state folding pathway, in which unfolding involves dissociation of a dimeric intermediate. Interestingly, 90% of the conformational free energy is associated with dimer dissociation (16.9 of 18.8 kcal mol(-1)) suggesting dimerization significantly contributes to its overall thermodynamic stability. These revelations might be important toward designing inhibitors for targeting dimerization or folding intermediates and hence multiple functions that E2 performs. PMID:26091566

  12. Vaccinations and secondary immune thrombocytopenia with antiphospholipid antibodies by human papillomavirus vaccine.

    PubMed

    Bizjak, Mojca; Bruck, Or; Kanduc, Darja; Praprotnik, Sonja; Shoenfeld, Yehuda

    2016-04-01

    A 13-year-old girl developed immune thrombocytopenic purpura (ITP) and concomitant positive antiphospholipid antibodies (aPL) following vaccination with a quadrivalent human papillomavirus (HPV) vaccine. During the course of a disease, she developed clinical manifestation with bleeding and she was treated with intravenous immunoglobulins. Consequently, the number of her platelets remained critically low and she was put on corticosteroids and rituximab. Since then, her platelet count remain within the normal range, but her aPL are still present. PMID:27312165

  13. Human papillomavirus-associated neoplasms of the sinonasal tract and nasopharynx.

    PubMed

    Thavaraj, Selvam

    2016-03-01

    It is now well established that human papillomavirus (HPV) is an important causative factor in a subgroup of head and neck cancer. In the head and neck, while HPV is strongly associated with squamous cell carcinoma arising in the oropharynx, there is a growing interest in HPV-associated neoplasms of non-oropharyngeal origin including those which arise within sinonasal and nasopharyngeal mucosa. This article reviews current literature on the association of HPV with Scheiderian papillomas, sinonasal squamous cell carcinoma, sinonasal undifferentiated carcinoma, carcinoma with adenoid cystic-like features, and nasopharyngeal carcinoma. Several clinical implications of HPV detection in sinonasal and nasopharyngeal carcinomas are briefly discussed. PMID:26482046

  14. Human papillomavirus-induced carcinogenesis and the ubiquitin-proteasome system.

    PubMed

    Scheffner, Martin; Whitaker, Noel J

    2003-02-01

    Certain types of human papillomaviruses have been etiologically associated with malignant lesions, most notably with cervical cancer. The major oncoproteins of these cancer-associated viruses are encoded by the viral E6 and E7 genes. Thorough characterization of these oncoproteins and their interaction with cellular proteins has shown that both E6 and E7 exploit the ubiquitin-proteasome system to degrade and, thus, to functionally inactivate negative cell-regulatory proteins including members of the p110(RB) family and p53. This act of piracy is assumed to contribute to both the efficient propagation of HPVs and HPV-induced carcinogenesis. PMID:12507557

  15. The diagnosis and treatment of human papillomavirus-mediated genital lesions.

    PubMed

    Brodell, Lindsey Ann; Mercurio, Mary Gail; Brodell, Robert T

    2007-04-01

    Genital warts (condyloma acuminatum, venereal warts) are common highly contagious benign epithelial lesions occurring on the genitals, perianal area, and inguinal folds, and are caused by human papillomavirus (HPV). Diagnosis is based largely on the clinical appearance of lesions. New home-based treatments, including podofilox and imiquimod, have revolutionized the therapeutic management of genital warts, empowering patients to participate in their own treatment with products that primarily have local side effects. This article reviews the diagnosis and treatment (office based and home based) of genital warts. PMID:17508490

  16. Human Papillomavirus Infection in Men Who Have Sex with Men in Lima, Peru

    PubMed Central

    Quinn, Roswell; Salvatierra, Javier; Solari, Vicky; Calderon, Martha; Ton, Thanh G.N.

    2012-01-01

    Abstract Human papillomavirus (HPV) infection among men who have sex with men (MSM) is the primary risk factor for anal cancer. Of 105 Peruvian MSM examined, 77.1% were infected with HPV; of these 79.0% were coinfected with two or more types and 47.3% were infected by a carcinogenic type. HPV types 53, 6, 16, and 58 were the most frequent HPV infections detected. High-risk HPV type infection was associated with sex work, HIV status, and having rectal chlamydial or gonorrheal infection. These findings support broadening HPV vaccine coverage and increasing surveillance for the development of cancer in MSM infected with HPV. PMID:22519744

  17. Amplification and expression of the c-myc oncogene in human lung cancer cell lines.

    PubMed

    Little, C D; Nau, M M; Carney, D N; Gazdar, A F; Minna, J D

    Genetic changes involving the c-myc oncogene have been observed in human tumours. In particular, the c-myc gene is translocated in Burkitt's lymphoma and is amplified in the human promyelocytic leukaemia cell line, HL-60, which contains double minute chromosomes (DMs). More recently, an amplified c-myc gene has been positioned on a chromosomal homogeneous staining region (HSR) in a human colon cancer cell line, COLO 320, with neuroendocrine properties. Furthermore, c-myc is expressed in increased amounts in some human tumour lines, and in some cases, human small cell lung cancers (SCLC) contain DMs and HSRs. These findings prompted us to study the c-myc gene and its RNA expression in a series of human lung cancer cell lines. We now report amplification and expression of the c-myc oncogene in a system other than B-cell lymphomas, namely human lung cancer. Of 18 human lung cancer cell lines tested, 8 showed an amplified 12.5-kilobase (kb) EcoRI c-myc DNA band. Of particular interest are five SCLC lines with a high degree of c-myc DNA amplification (20-76-fold) and greatly increased levels of c-myc RNA. All five lines reside in the variant class of SCLC (SCLC-V) characterized by altered morphology, lack of expression of some SCLC-differentiated functions and more malignant behaviour than pure SCLC. Three of the five lines which have been karyotyped also contain DMs or HSRs. The finding of a greatly amplified c-myc gene in all cell lines of the SCLC-V class examined strongly suggests a role for the c-myc gene in the phenotypic conversion and malignant behaviour of human lung cancer. PMID:6646201

  18. [Human papillomavirus and carcinoma of the cervix vaccines against the human papillomavirus-promise of an efficacious prevention].

    PubMed

    Kohl, Igor

    2006-06-01

    The persistent infection with high-risk (oncogenic) HPV types is the necessary cause of cervical cancer. HPV types 16 and 18 are the most important of the high-risk types all around the world. The low risk HPV types, include type 6, 11 and next, cause either benign genital warts or low-grade intraepithelial lesions. Cervical cancer is the third most important cause of cancer deaths in women worldwide, after, first, breast cancer and, second, lung cancer, and the leading cause of cancer deaths in women in the developing world. Every year, half a million women around the world are diagnosed as new cases, and more than 270,000 die from this disease. The majority of deaths, around 80 %, occur in developing countries (in Latin America and Sub-Saharan Africa). The main reason for these variations in incidence is probably the availability of screening programmes in many developed countries but not in poorer developing countries. Pap smear testing forms the basis of cervical cancer screening programmes round the world. A well-implemented screening programme can reduce the incidence of cervical cancer in a country by approximately 80 %. Although useful is fully implemented, a cytology-based screening programme does have limitations. It cannot prevent infection with high-risk HPV or the subsequent development of pre-cancerous lesions. It is also a very expensive and demanding system to set up and maintain. Knowledge that cervical cancer is caused by viral infection provided the exceptional way to use a vaccination as the next tool of cervical cancer prevention. There are the only two realistic approaches for the prevention of cervical cancer--cervical screening and vaccination. Vaccination of a healthy individual to protect them against a disease is an excellent example of primary prevention. Two pharmaceutical companies--GlaxoSmithKline (GSK) and Merck--developed a prophylactic vaccines which are already in the pre-licence phase. The results published up to now showed a

  19. Increased alpha-9 human papillomavirus species viral load in human immunodeficiency virus positive women

    PubMed Central

    2014-01-01

    Background Persistent high-risk (HR) human papillomavirus (HPV) infection and increased HR-HPV viral load are associated with the development of cancer. This study investigated the effect of human immunodeficiency virus (HIV) co-infection, HIV viral load and CD4 count on the HR-HPV viral load; and also investigated the predictors of cervical abnormalities. Methods Participants were 292 HIV-negative and 258 HIV-positive women. HR-HPV viral loads in cervical cells were determined by the real-time polymerase chain reaction. Results HIV-positive women had a significantly higher viral load for combined alpha-9 HPV species compared to HIV-negative women (median 3.9 copies per cell compared to 0.63 copies per cell, P = 0.022). This was not observed for individual HPV types. HIV-positive women with CD4 counts >350/μl had significantly lower viral loads for alpha-7 HPV species (median 0.12 copies per cell) than HIV-positive women with CD4 ≤350/μl (median 1.52 copies per cell, P = 0.008), but low CD4 count was not significantly associated with increased viral load for other HPV species. High viral loads for alpha-6, alpha-7 and alpha-9 HPV species were significant predictors of abnormal cytology in women. Conclusion HIV co-infection significantly increased the combined alpha-9 HPV viral load in women but not viral loads for individual HPV types. High HR-HPV viral load was associated with cervical abnormal cytology. PMID:24484380

  20. Colposcopy of vaginal and vulvar human papillomavirus and adjacent sites.

    PubMed

    Hatch, K

    1993-03-01

    Human papillomaviral infections can affect the entire lower female genital tract as multifocal or multicentric disease as well as the surrounding anatomic and adjacent sites. The traditional colposcopic methods are necessary to assist in the diagnosis and help differentiate these infections from other disease mimics. PMID:8392676

  1. Molecular Characterization of High-Risk Human Papillomavirus in Women in Bobo-Dioulasso, Burkina Faso

    PubMed Central

    Traore, Ina Marie Angèle; Dembele, Adama; Obiri-Yeboah, Dorcas; Traore, Germain; Bambara, Moussa; Ouedraogo, Charlemagne; Traore, Yves

    2016-01-01

    High-risk human papillomavirus (HPV) is found in over 99% of cervical cancers. The aim of this study was to determine the prevalence of HPV in a population of women in Bobo-Dioulasso and to identify the high-risk types present in these women. From May to June, 2015, 181 women who came for consultation at the Souro Sanou University Hospital of Bobo-Dioulasso have been included in this study. Uterine endocervical swabs have been taken in these women. DNA obtained by extraction from the samples thus collected was used to determine the prevalence of high-risk human papillomavirus genotypes through real-time PCR. The age of the women ranged from 20 to 56 years with a mean of 35.3 ± 8.1 years. The prevalence of infection by high-risk HPV types was 25.4% (46/181). The most common high-risk HPV genotypes were HPV 39 (18.5%), HPV 52 (16.7%), HPV 18 (14.8%), and HPV 35 (13.0%). HPV 16 which is included in the HPV vaccines was not found in the population studied. This type of study which is the first one in Bobo-Dioulasso has showed a high prevalence of genotypes HPV 39, HPV 52, and HPV 35 which are not yet covered by a vaccine. PMID:27525275

  2. Selective suppression of human papillomavirus transcription in non-tumorigenic cells by 5-azacytidine.

    PubMed Central

    Rösl, F; Dürst, M; zur Hausen, H

    1988-01-01

    The transcription of human papillomavirus type 18 (HPV 18) is selectively suppressed in non-tumorigenic HeLa x fibroblast or HeLa x keratinocyte cell hybrids by 5-azacytidine. In contrast, viral gene expression is not influenced by 5-azacytidine in both tumorigenic hybrid segregants and in the parental HeLa cells. The suppression mechanism seems to operate at the level of initiation of transcription since nuclear run-on experiments show the absence of elongated nascent viral RNA, whereas the transcription of cellular reference genes remains unaffected. Down-regulation of HPV 18 mRNA correlates directly with cessation of cellular growth and can be abolished using the protein synthesis inhibitor cycloheximide. Furthermore human keratinocytes immortalized by HPV 16 but still retaining the non-tumorigenic phenotype reveal the same inhibitory effect on viral transcription after treatment with 5-azacytidine. These results support a model of a postulated intracellular control mechanism, directed against papillomavirus transcription, which can be induced by 5-azacytidine and appears to correlate with the presence of specific chromosomes in non-tumorigenic cells. Images PMID:2457495

  3. Transmission dynamic modelling of the impact of human papillomavirus vaccination in the United Kingdom.

    PubMed

    Choi, Yoon Hong; Jit, Mark; Gay, Nigel; Cox, Andrew; Garnett, Geoff P; Edmunds, William John

    2010-05-28

    Many countries are considering vaccination against human papillomavirus (HPV). However, the long-term impact of vaccination is difficult to predict due to uncertainty about the prevalence of HPV infection, pattern of sexual partnerships, progression of cervical neoplasias, accuracy of screening as well as the duration of infectiousness and immunity. Dynamic models of human papillomavirus (HPV) transmission were developed to describe the infection spread and development of cervical neoplasia, cervical cancer (squamous cell and adenocarcinoma) and anogenital warts. Using different combinations of assumptions, 9900 scenarios were created. Each scenario was then fitted to epidemiological data and the best-fitting scenarios used to predict the impact of vaccination. Results suggest that vaccinating 12-year-old girls at 80% coverage will result in a 38-82% reduction in cervical cancer incidence and 44-100% reduction in anogenital warts incidence after 60 years of an ongoing vaccination programme if vaccine protection lasts 20 years on average. The marginal benefit of vaccinating boys depends on the degree of protection achieved by vaccinating girls. PMID:19909831

  4. The absence of human papillomavirus in esophageal squamous cell carcinoma in East China

    PubMed Central

    Teng, Haohua; Li, Xiaojing; Liu, Xiuping; Wu, Jie; Zhang, Jie

    2014-01-01

    Esophageal squamous cell carcinoma (ESCC) is one of the most common types of tumors worldwide, particularly in China, and human papillomavirus (HPV) is thought to be a potential risk factor for this cancer. To determine whether this is true, we collected 177 formalin-fixed and paraffin-embedded ESCC samples from two hospitals. We screened for 23 different HPV genotypes using a human papillomavirus genotyping kit, which allowed us to amplify the L1 gene by polymerase chain reaction (PCR) and test for 23 HPV subtypes by reverse dot blot (RDB) on a single membrane. We also used immunohistochemistry (IHC) to detect the P16INK4a protein, the expression of which is linked to HPV E7 activity and which is used to diagnose cervical intraepithelial neoplasia. The genotyping results showed that only six samples were weakly positive for HPV: two for HPV16, two for HPV11 and two for HPV35, with no samples showing strong positive signals. The IHC results showed only five samples with diffuse positive staining, with the other samples being completely negative or having only focal positive signals, which were considered as negative. This study demonstrates that the HPV infection rate in ESCC samples is very low, suggesting that HPV is not the etiological cause of ESCC. PMID:25120798

  5. Molecular Characterization of High-Risk Human Papillomavirus in Women in Bobo-Dioulasso, Burkina Faso.

    PubMed

    Traore, Ina Marie Angèle; Zohoncon, Théodora Mahoukèdè; Dembele, Adama; Djigma, Florencia W; Obiri-Yeboah, Dorcas; Traore, Germain; Bambara, Moussa; Ouedraogo, Charlemagne; Traore, Yves; Simpore, Jacques

    2016-01-01

    High-risk human papillomavirus (HPV) is found in over 99% of cervical cancers. The aim of this study was to determine the prevalence of HPV in a population of women in Bobo-Dioulasso and to identify the high-risk types present in these women. From May to June, 2015, 181 women who came for consultation at the Souro Sanou University Hospital of Bobo-Dioulasso have been included in this study. Uterine endocervical swabs have been taken in these women. DNA obtained by extraction from the samples thus collected was used to determine the prevalence of high-risk human papillomavirus genotypes through real-time PCR. The age of the women ranged from 20 to 56 years with a mean of 35.3 ± 8.1 years. The prevalence of infection by high-risk HPV types was 25.4% (46/181). The most common high-risk HPV genotypes were HPV 39 (18.5%), HPV 52 (16.7%), HPV 18 (14.8%), and HPV 35 (13.0%). HPV 16 which is included in the HPV vaccines was not found in the population studied. This type of study which is the first one in Bobo-Dioulasso has showed a high prevalence of genotypes HPV 39, HPV 52, and HPV 35 which are not yet covered by a vaccine. PMID:27525275

  6. The regulation of MDM2 oncogene and its impact on human cancers

    PubMed Central

    Zhao, Yuhan; Yu, Haiyang; Hu, Wenwei

    2014-01-01

    Tumor suppressor p53 plays a central role in preventing tumor formation. The levels and activity of p53 is under tight regulation to ensure its proper function. Murine double minute 2 (MDM2), a p53 target gene, is an E3 ubiquitin ligase. MDM2 is a key negative regulator of p53 protein, and forms an auto-regulatory feedback loop with p53. MDM2 is an oncogene with both p53-dependent and p53-independent oncogenic activities, and often has increased expression levels in a variety of human cancers. MDM2 is highly regulated; the levels and function of MDM2 are regulated at the transcriptional, translational and post-translational levels. This review provides an overview of the regulation of MDM2. Dysregulation of MDM2 impacts significantly upon the p53 functions, and in turn the tumorigenesis. Considering the key role that MDM2 plays in human cancers, a better understanding of the regulation of MDM2 will help us to develop novel and more effective cancer therapeutic strategies to target MDM2 and activate p53 in cells. PMID:24389645

  7. PPM1D exerts its oncogenic properties in human pancreatic cancer through multiple mechanisms.

    PubMed

    Wu, Bo; Guo, Bo-Min; Kang, Jie; Deng, Xian-Zhao; Fan, You-Ben; Zhang, Xiao-Ping; Ai, Kai-Xing

    2016-03-01

    Protein phosphatase, Mg(2+)/Mn(2+) dependent, 1D (PPM1D) is emerging as an oncogene by virtue of its negative control on several tumor suppressor pathways. However, the clinical significance of PPM1D in pancreatic cancer (PC) has not been defined. In this study, we determined PPM1D expression in human PC tissues and cell lines and their irrespective noncancerous controls. We subsequently investigated the functional role of PPM1D in the migration, invasion, and apoptosis of MIA PaCa-2 and PANC-1 PC cells in vitro and explored the signaling pathways involved. Furthermore, we examined the role of PPM1D in PC tumorigenesis in vivo. Our results showed that PPM1D is overexpressed in human PC tissues and cell lines and significantly correlated with tumor growth and metastasis. PPM1D promotes PC cell migration and invasion via potentiation of the Wnt/β-catenin pathway through downregulation of apoptosis-stimulating of p53 protein 2 (ASPP2). In contrast to PPM1D, our results showed that ASPP2 is downregulated in PC tissues. Additionally, PPM1D suppresses PC cell apoptosis via inhibition of the p38 MAPK/p53 pathway through both dephosphorylation of p38 MAPK and downregulation of ASPP2. Furthermore, PPM1D promotes PC tumor growth in vivo. Our results demonstrated that PPM1D is an oncogene in PC. PMID:26714478

  8. Premature polyadenylation of MAGI3 produces a dominantly-acting oncogene in human breast cancer

    PubMed Central

    Ni, Thomas K; Kuperwasser, Charlotte

    2016-01-01

    Genetic mutation, chromosomal rearrangement and copy number amplification are common mechanisms responsible for generating gain-of-function, cancer-causing alterations. Here we report a new mechanism by which premature cleavage and polyadenylation (pPA) of RNA can produce an oncogenic protein. We identify a pPA event at a cryptic intronic poly(A) signal in MAGI3, occurring in the absence of local exonic and intronic mutations. The altered mRNA isoform, called MAGI3pPA, produces a truncated protein that acts in a dominant-negative manner to prevent full-length MAGI3 from interacting with the YAP oncoprotein, thereby relieving YAP inhibition and promoting malignant transformation of human mammary epithelial cells. We additionally find evidence for recurrent expression of MAGI3pPAin primary human breast tumors but not in tumor-adjacent normal tissues. Our results provide an example of how pPA contributes to cancer by generating a truncated mRNA isoform that encodes an oncogenic, gain-of-function protein. DOI: http://dx.doi.org/10.7554/eLife.14730.001 PMID:27205883

  9. Circumcision and penile human papillomavirus prevalence in human immunodeficiency virus-infected men: heterosexual and men who have sex with men.

    PubMed

    Canadas, M P; Darwich, L; Videla, S; Sirera, G; Coll, J; Rafael, M-L A; Clotet, B

    2013-07-01

    Male circumcision is associated with a lower risk of penile human papillomavirus (HPV) infection in human immunodeficiency virus (HIV) uninfected men. Few studies have evaluated the role of male circumcision in penile HPV infection in HIV-infected men. The aim of this cross-sectional study was to examine the association between male circumcision and the prevalence of penile HPV infection among HIV-infected men-both men who have sex with men (MSM) and heterosexual men. Samples from 706 consecutive men included in the CARH-MEN cohort (overall 24% circumcised: 26% of MSM, 18% of heterosexual men) were examined by Multiplex-PCR. In the overall group (all HIV-infected men included), the prevalence of any penile HPV infection was 22% in circumcised men and 27% in uncircumcised men (OR = 1.0, 95% CI 0.6-1.6, adjusted analysis). In the circumcised group the overall prevalence of HPV infection was 22% in MSM and 24% in the heterosexual men, whereas in the uncircumcised group the prevalence was 26% and 28%, respectively. The prevalence of high-risk HPV types tended to be lower in the circumcised MSM (14% vs 21%, OR = 0.6, 95% CI 0.3-1.1, p 0.088), but it was similar in the heterosexual men (18% in circumcised vs 20% in uncircumcised). These results suggest that male circumcision may be associated with a lower prevalence of oncogenic high-risk penile HPV infection in HIV-infected MSM. PMID:22676057

  10. Characterization of human papillomavirus type 120: a novel betapapillomavirus with tropism for multiple anatomical niches.

    PubMed

    Bottalico, Danielle; Chen, Zigui; Kocjan, Bostjan J; Seme, Katja; Poljak, Mario; Burk, Robert D

    2012-08-01

    Recent studies indicate that human papillomaviruses (HPVs) from the genera Betapapillomavirus and Gammapapillomavirus are abundant in the human oral cavity. We report the cloning and characterization of a 7304 bp HPV120 genome from the oral cavity that is related most closely to HPV23 (L1 ORF, 83.7 % similarity), clustering it in the genus Betapapillomavirus (β-PV). HPV120 contains five early and two late genes, but no E5 ORF. HPV120 was detected from heterogeneous human biological niches, including the oral cavity, eyebrow hairs, anal canal and penile, vulvar and perianal warts. Characterization of the clinical spectrum of HPV120 infections indicates a broader spectrum of epithelial tropism than appreciated previously for HPV types from the genus β-PV. PMID:22552941

  11. Impact of viral E2-gene status on outcome after radiotherapy for patients with human papillomavirus 16-positive cancer of the uterine cervix

    SciTech Connect

    Lindel, Katja . E-mail: Katja_Lindel@med.uni-heidelberg.de; Villiers, Ethel-Michele de; Burri, Philipp; Studer, Ueli; Altermatt, Hans J.; Greiner, Richard H.; Gruber, Guenther

    2006-07-01

    Purpose: Integration of high-risk papillomavirus DNA has been considered an important step in oncogenic progression to cervical carcinoma. Disruption of the human papillomavirus (HPV) genome within the E2 gene is frequently a consequence. This study investigated the influence of episomal viral DNA on outcome in patients with advanced cervical cancer treated with primary radiotherapy. Methods and Materials: Paraffin-embedded biopsies of 82 women with locally advanced cervical cancer could be analyzed for HPV infection by multiplex polymerase chain reaction (PCR) by use of SPF1/2 primers. E2-gene intactness of HPV-16-positive samples was analyzed in 3 separate amplification reactions by use of the E2A, E2B, E2C primers. Statistical analyses (Kaplan-Meier method; log-rank test) were performed for overall survival (OS), disease-free survival (DFS), local progression-free survival (LPFS), and distant metastases-free survival (DMFS). Results: Sixty-one (75%) of 82 carcinomas were HPV positive, 44 of them for HPV-16 (72%). Seventeen of the 44 HPV-16-positive tumors (39%) had an intact E2 gene. Patients with a HPV-16-positive tumor and an intact E2 gene showed a trend for a better DFS (58% vs. 38%, p = 0.06) compared with those with a disrupted E2 gene. A nonsignificant difference occurred regarding OS (87% vs. 66%, p = 0.16) and DMFS (57% vs. 48%, p = 0.15). Conclusion: E2-gene status may be a promising new target, but more studies are required to elucidate the effect of the viral E2 gene on outcome after radiotherapy in HPV-positive tumors.

  12. Human papillomavirus knowledge, vaccine acceptance, and vaccine series completion among female entertainment and sex workers in Phnom Penh, Cambodia: the Young Women's Health Study.

    PubMed

    Wadhera, Priya; Evans, Jennifer L; Stein, Ellen; Gandhi, Monica; Couture, Marie-Claude; Sansothy, Neth; Sichan, Keo; Maher, Lisa; Kaldor, John; Page, Kimberly; Kien

    2015-10-01

    Human papillomavirus is a common sexually transmitted infection and the causative agent for cervical cancer, a frequently occurring malignant disease among women in developing countries. We assessed human papillomavirus awareness prior to the delivery of a brief information and education intervention, and human papillomavirus vaccine provision to female entertainment and sex workers (N = 220). At baseline, only 23.6% of women had heard of human papillomavirus. Following the educational intervention, 90% answered all the human papillomavirus knowledge questions correctly. Of 192 participants attending the first quarterly cohort visit where vaccine was offered, 149 (78%) were eligible for vaccination; HIV-positive (n = 32) and pregnant (n = 11) women were excluded. Acceptance of vaccine among eligible women was universal, and 79.2% completed the three-dose vaccination series. Women who reported use of amphetamine-type stimulants had significantly and independently lower odds of vaccine completion (adjusted odds ratio [AOR] 0.24; 95% confidence interval [CI] 0.08, 0.69). New pregnancies also had an impact on vaccine completion: 5.4% (8/149 5.4%) who started the series had to stop due to new pregnancy. Results demonstrate the effectiveness of a simple education intervention designed to increase human papillomavirus knowledge and the feasibility of successful human papillomavirus vaccine in a population that is often difficult to engage in preventive health care. PMID:25505042

  13. Knowledge of Human Papillomavirus and Perceived Barriers to Vaccination in a Sample of US Female College Students

    ERIC Educational Resources Information Center

    Dillard, James Price; Spear, Margaret E.

    2010-01-01

    Objective: To assess knowledge of human papillomavirus (HPV) and perceived barriers to being vaccinated against the virus. Participants: Three hundred ninety-six undergraduate women enrolled at Penn State University in Fall 2008. Methods: A random sample of students were invited to participate in a Web-based survey. Results: Awareness of HPV and…

  14. How to Inform: Comparing Written and Video Education Interventions to Increase Human Papillomavirus Knowledge and Vaccination Intentions in Young Adults

    ERIC Educational Resources Information Center

    Krawczyk, Andrea; Lau, Elsa; Perez, Samara; Delisle, Vanessa; Amsel, Rhonda; Rosberger, Zeev

    2012-01-01

    Objective: To compare the efficacy of 2 human papillomavirus (HPV) educational interventions on increasing HPV knowledge and vaccination intentions in college students. Participants: Male (n = 60) and female (n = 140) undergraduates (M[subscript age] = 20.4, SD = 2.3) recruited from a university in Montreal, Quebec, Canada, from October 2009 to…

  15. Deconstructing Human Papillomavirus (HPV) Knowledge: Objective and Perceived Knowledge in Males' Intentions to Receive the HPV Vaccine

    ERIC Educational Resources Information Center

    Krawczyk, Andrea; Stephenson, Ellen; Perez, Samara; Lau, Elsa; Rosberger, Zeev

    2013-01-01

    Background: The human papillomavirus (HPV) vaccine was recently approved for men. To effectively tailor HPV education efforts toward men, it is important to understand what men know about HPV and how this knowledge relates to their decision to receive the vaccine. This study examines how objective HPV knowledge, objective HPV vaccine knowledge,…

  16. Relative Persuasiveness of Gain- versus Loss-Framed Human Papillomavirus Vaccination Messages for the Present- and Future-Minded

    ERIC Educational Resources Information Center

    Nan, Xiaoli

    2012-01-01

    This research examines how young adults' attitudes toward human papillomavirus (HPV) vaccination and their intentions to get the vaccine are influenced by the framing of health messages (gain vs. loss) and time orientation (i.e., the extent to which people value immediate vs. distant consequences of their decisions). Results of an experiment…

  17. A Randomized Intervention Study to Evaluate Whether Electronic Messaging Can Increase Human Papillomavirus Vaccine Completion and Knowledge among College Students

    ERIC Educational Resources Information Center

    Richman, Alice R.; Maddy, LaDonna; Torres, Essie; Goldberg, Ellen J.

    2016-01-01

    Objective: To evaluate an intervention aimed at increasing human papillomavirus (HPV) vaccine completion of the 3-dose series and knowledge. Participants: Two hundred sixty-four male and female US college students 18-26 years old who were receiving HPV vaccine dose 1. Methods: Students were randomly assigned to the intervention or control group.…

  18. Human Papillomavirus (HPV) Risk Factors, Vaccination Patterns, and Vaccine Perceptions among a Sample of Male College Students

    ERIC Educational Resources Information Center

    Fontenot, Holly B.; Collins Fantasia, Heidi; Charyk, Anna; Sutherland, Melissa A.

    2014-01-01

    Objective: To examine human papillomavirus (HPV) vaccination rates, including initiation and completion of the vaccine series, and barriers to vaccination in a sample of male college students. Participants: Male students between the ages of 18 and 25 who reported being currently or previously sexually active (N = 735). Methods: A cross-sectional…

  19. College Students' Perceptions of and Experiences with Human Papillomavirus and Herpes: Implications for College Sexual Health Education

    ERIC Educational Resources Information Center

    Hirschler, Christopher; Hope, Andrea; Myers, Jaime L.

    2015-01-01

    Sexually transmitted infections spread through skin-to-skin contact represent unique prevention challenges. This study examines how college students perceive safer sex practices with respect to human papillomavirus (HPV) and herpes. Qualitative and quantitative data (n = 275) were collected using an online questionnaire. College students'…

  20. Does Mother Know Best? An Actor-Partner Model of College-Age Women's Human Papillomavirus Vaccination Behavior

    ERIC Educational Resources Information Center

    Krieger, Janice L.; Kam, Jennifer A.; Katz, Mira L.; Roberto, Anthony J.

    2011-01-01

    This study examined the associations of perceived threat, perceived efficacy, and parent-child communication with the extent to which college-age women received the human papillomavirus (HPV) vaccine. Daughters and their mothers completed a survey about the HPV vaccine (N = 182 dyads). The results showed that mothers' perceived self-efficacy to…

  1. Predicting Human Papillomavirus Vaccine Intentions of College-Aged Males: An Examination of Parents' and Son's Perceptions

    ERIC Educational Resources Information Center

    Katz, Mira L.; Kam, Jennifer A.; Krieger, Janice L.; Roberto, Anthony J.

    2012-01-01

    Objective: To examine male students' and their parents' human papillomavirus (HPV) vaccine communication in relation to males' willingness to discuss the vaccine with their health care provider and the likelihood of being vaccinated. Participants: Dyads (n = 111) of students and parents. Methods: Participants completed a HPV vaccine survey based…

  2. The Uptake of Human Papillomavirus (HPV) Vaccine among Adolescent Females in the United States: A Review of the Literature

    ERIC Educational Resources Information Center

    Bartlett, Jacqueline A.; Peterson, Jane Anthony

    2011-01-01

    A comprehensive review of literature was conducted to identify the barriers and facilitators, from the parents'/guardians' and primary care providers' (PCPs) perspective, that are associated with the uptake of Human Papillomavirus (HPV) vaccine among adolescent females. Findings from 14 peer-reviewed articles indicate that 37% of adolescent…

  3. Understanding Human Papillomavirus: An Internet Survey of Knowledge, Risk, and Experience among Female and Male College Students in Hawaii

    ERIC Educational Resources Information Center

    Bertram, Cathy C.; Niederhauser, Victoria P.

    2008-01-01

    Background: Persistent Human Papillomavirus (HPV) is an etiologic agent in the development of cervical cancer. Despite the increasingly high prevalence of HPV, people at risk of exposure lack knowledge about the virus, its relationship to cervical cancer, and a realistic perspective regarding HPV consequences. Purpose: To describe knowledge about…

  4. Disparities in Human Papillomavirus Vaccine Literacy and Vaccine Completion among Asian American Pacific Islander Undergraduates: Implications for Cancer Health Equity

    ERIC Educational Resources Information Center

    Lee, Hee Yun; Kwon, Melissa; Vang, Suzanne; DeWolfe, Jessica; Kim, Nam Keol; Lee, Do Kyung; Yeung, Miriam

    2015-01-01

    Purpose: Low rates of human papillomavirus (HPV) vaccination among young Asian American and Pacific Islander (AAPI) women need to be addressed, particularly given the high incidence of cervical cancer in this population. The current study aims to investigate predictors of HPV vaccination in young AAPI and non-Latina white (NLW) women. Methods: A…

  5. Correlates to Human Papillomavirus Vaccination Status and Willingness to Vaccinate in Low-Income Philadelphia High School Students

    ERIC Educational Resources Information Center

    Bass, Sarah B.; Leader, Amy; Shwarz, Michelle; Greener, Judith; Patterson, Freda

    2015-01-01

    Background: Little is known about the correlates of human papillomavirus (HPV) vaccination or willingness to be vaccinated in urban, minority adolescents. Methods: Using responses to the 2013 Youth Risk Behavior Survey in Philadelphia, a random sample of high schools provided weighted data representing 20,941 9th to 12th graders. Stratified by…

  6. A prospective study of the relationship between prediagnostic human papillomavirus seropositivity and HPV DNA in subsequent cervical carcinomas.

    PubMed

    Sigstad, E; Lie, A K; Luostarinen, T; Dillner, J; Jellum, E; Lehtinen, M; Thoresen, S; Abeler, V

    2002-07-15

    Several prospective studies with invasive carcinoma as endpoint have supported Human Papillomavirus as a cause of cervical carcinoma. However, the largest study used seroepidemiology and did not analyse presence of Human Papillomavirus DNA in the subsequent tumour. Linkage of serum bank registries and cancer registries had identified 196 women with a registered cervical carcinoma after donation of a serum sample. For the present study, biopsies for 127 cases could be located, verified to contain invasive carcinoma and be amplified by PCR. Three control women who had remained alive and without cervical carcinoma during an equal length of follow-up had been matched to each of the case women and tested for HPV antibodies. Presence of Human Papillomavirus DNA in the tumours was analysed by general primer and type specific PCR. HPV16-seropositive women had a relative risk of 4.4 (95% CI: 2.2-8.8) to develop cervical carcinoma carrying HPV16 DNA. By contrast, there was no excess risk for Human Papillomavirus 16-seropositive women to develop cervical carcinoma devoid of HPV16 DNA. Prediagnostic HPV16 seropositivity was strongly correlated with later HPV16 DNA positivity of the tumour (P<0.001) and prediagnostic HPV18 seropositivity correlated with HPV18 DNA in the tumour (P<0.03). The link between prediagnostic seropositivity and type of viral DNA in the cancer implies that the carcinogenic effect of infection with these viruses is dependent on persistent presence of type-specific viral DNA. PMID:12107839

  7. AKT-independent signaling downstream of oncogenic PIK3CA mutations in human cancer.

    PubMed

    Vasudevan, Krishna M; Barbie, David A; Davies, Michael A; Rabinovsky, Rosalia; McNear, Chontelle J; Kim, Jessica J; Hennessy, Bryan T; Tseng, Hsiuyi; Pochanard, Panisa; Kim, So Young; Dunn, Ian F; Schinzel, Anna C; Sandy, Peter; Hoersch, Sebastian; Sheng, Qing; Gupta, Piyush B; Boehm, Jesse S; Reiling, Jan H; Silver, Serena; Lu, Yiling; Stemke-Hale, Katherine; Dutta, Bhaskar; Joy, Corwin; Sahin, Aysegul A; Gonzalez-Angulo, Ana Maria; Lluch, Ana; Rameh, Lucia E; Jacks, Tyler; Root, David E; Lander, Eric S; Mills, Gordon B; Hahn, William C; Sellers, William R; Garraway, Levi A

    2009-07-01

    Dysregulation of the phosphatidylinositol 3-kinase (PI3K) signaling pathway occurs frequently in human cancer. PTEN tumor suppressor or PIK3CA oncogene mutations both direct PI3K-dependent tumorigenesis largely through activation of the AKT/PKB kinase. However, here we show through phosphoprotein profiling and functional genomic studies that many PIK3CA mutant cancer cell lines and human breast tumors exhibit only minimal AKT activation and a diminished reliance on AKT for anchorage-independent growth. Instead, these cells retain robust PDK1 activation and membrane localization and exhibit dependency on the PDK1 substrate SGK3. SGK3 undergoes PI3K- and PDK1-dependent activation in PIK3CA mutant cancer cells. Thus, PI3K may promote cancer through both AKT-dependent and AKT-independent mechanisms. Knowledge of differential PI3K/PDK1 signaling could inform rational therapeutics in cancers harboring PIK3CA mutations. PMID:19573809

  8. Transfection of normal human bronchial epithelial cells with the bcl-2 oncogene

    SciTech Connect

    Kennedy, C.H.; Kenyon, K.D.; Tesfaigzi, J.

    1995-12-01

    In vitro, studies examining the transformation of virus-immortalized human bronchial epithelial (HBE) cells after exposure to chemical and physical carcinogens have contributed to our understanding of the mechanisms that underlie the development of lung cancer. Virus-immortalized HBE cells have been used because of both the limited life span of normal human bronchial epithelial (NHBE) cells in culture (approximately 30-35 population doublins) and their resistance to in vitro malignant transformation. For example, human papillomavirus (HPV)-immortalized HBE cells have been used to study the genetic changes that occur after exposure to {alpha}-particles in vitro. Although this model may prove to be useful for studying the 18% or less of bronchogenic carcinomas found to contain HPV sequences, it is not an appropriate model for studying the majority of lung epithelial malignancies in which HPV DNA is not detected. This view is supported by the fact that HPV-immortalized cell lines commonly exhibit aneuploidy. This results of this study suggest that: (1) NHBE cells can be transiently transfected with the pCMV{Beta} vector; and (2) the antibiotic hygromycin-resistant transfected cells.

  9. Tumorigenicity by human papillomavirus type 16 E6 and E7 in transgenic mice correlates with alterations in epithelial cell growth and differentiation.

    PubMed Central

    Griep, A E; Herber, R; Jeon, S; Lohse, J K; Dubielzig, R R; Lambert, P F

    1993-01-01

    The human papillomavirus type 16 (HPV-16) E6 and E7 oncogenes are thought to play a role in the development of most human cervical cancers. These E6 and E7 oncoproteins affect cell growth control at least in part through their association with and inactivation of the cellular tumor suppressor gene products, p53 and Rb. To study the biological activities of the HPV-16 E6 and E7 genes in epithelial cells in vivo, transgenic mice were generated in which expression of E6 and E7 was targeted to the ocular lens. Expression of the transgenes correlated with bilateral microphthalmia and cataracts (100% penetrance) resulting from an efficient impairment of lens fiber cell differentiation and coincident induction of cell proliferation. Lens tumors formed in 40% of adult mice from the mouse lineage with the highest level of E6 and E7 expression. Additionally, when lens cells from neonatal transgenic animals were placed in tissue culture, immortalized cell populations grew out and acquired a tumorigenic phenotype with continuous passage. These observations indicate that genetic changes in addition to the transgenes are likely necessary for tumor formation. These transgenic mice and cell lines provide the basis for further studies into the mechanism of action of E6 and E7 in eliciting the observed pathology and into the genetic alterations required for HPV-16-associated tumor progression. Images PMID:8382301

  10. Recombinant vaccines for the prevention of human papillomavirus infection and cervical cancer.

    PubMed

    Palmer, Kenneth E; Jenson, A Bennett; Kouokam, J Calvin; Lasnik, Amanda B; Ghim, Shin-je

    2009-06-01

    Carcinogenic human papillomaviruses (HPVs) that cause cervical cancer preferentially infect basal, metaplastic squamous cells of the transformation zone. If infection persists, and a vegetative infection ensues, a premalignant lesion may develop with the potential to progress into an invasive squamous cell carcinoma. Papillomavirus prophylactic vaccines target the systemic immune system for induction of neutralizing antibodies that protect the basal cells against infection. Because the carcinogenic HPVs are susceptible to neutralization by antibodies for 9-48 h after reaching the basal cells, both low and high titered HPV type-specific antibodies induced by HPV L1 and L2-based vaccines are highly efficacious. The greatest burden of HPV-associated cancers occurs in poor areas of the world where women do not have access to routine gynecological care. The burden of HIV/AIDS in these same regions of the world has added to the burden of HPV-associated disease. There is an urgent need for a cost-effective, broad-spectrum HPV prophylactic vaccine in developing countries, which necessitates substantial cost subsidization of the virus-like particle (VLP) based vaccines licensed in industrialized countries or an alternative approach with second-generation vaccines that are specifically designed for delivery to women in resource-poor communities. PMID:19454268

  11. Characterisation of human papillomavirus (HPV) genotypes in the Azorean population, Terceira island

    PubMed Central

    Dutra, Isa; Santos, Margarida R; Soares, Marta; Couto, Ana R; Bruges-Armas, Maria; Teixeira, Fernando; Monjardino, Luísa; Hodgson, Shirley; Bruges-Armas, Jácome

    2008-01-01

    Background Human papillomavirus detection is very important for the evaluation of prevention strategies in cervical cancer. In the Azorean population, the virus prevalence has never been studied, and there is no data available to preview a successful outcome with HPV vaccination. In this article, our objective is to characterise the HPV genotypes in Terceira Island, contributing for the epidemiological knowledge on the virus infection. Results Cervical samples were collected from 289 women aged 16–81 in the Gynaecological Outpatient Clinic of the Hospital de Santo Espírito de Angra do Heroísmo (HSEAH). HPV DNA was amplified by Polymerase Chain Reaction using the general consensus primers PGMYO9/PGMY11. Commercially available Papillomavirus Clinical Arrays® kits (Genomica) were used to perform HPV genotyping. 30 women were HPV positive, with a median age of 41 years old. Our results show that the overall HPV prevalence was 10.49%. Seventeen genotypes were identified, including 58.82% high risk, 17.65% low risk and 23.53% undetermined risk. Conclusion Unlike other epidemiological studies, HPV31 was the most frequent type (26.67%) in Terceira Island, followed by HPV16 (10.00%), HPV51, HPV53, HPV70 and HPV82 (6.67%). Further studies are needed to investigate if the HPV types found in our population are associated with the risk of progression to high-grade squamous intraepithelial lesions or cervical cancer. PMID:18426589

  12. Seroprevalence of 34 Human Papillomavirus Types in the German General Population

    PubMed Central

    Michael, Kristina M.; Waterboer, Tim; Sehr, Peter; Rother, Annette; Reidel, Ulrich; Boeing, Heiner; Bravo, Ignacio G.; Schlehofer, Jörg; Gärtner, Barbara C.; Pawlita, Michael

    2008-01-01

    The natural history of infections with many human papillomavirus (HPV) types is poorly understood. Here, we describe for the first time the age- and sex-dependent antibody prevalence for 29 cutaneous and five mucosal HPV types from 15 species within five phylogenetic genera (alpha, beta, gamma, mu, nu) in a general population. Sera from 1,797 German adults and children (758 males and 1,039 females) between 1 and 82 years (median 37 years) were analysed for antibodies to the major capsid protein L1 by Luminex-based multiplex serology. The first substantial HPV antibody reactions observed already in children and young adults are those to cutaneous types of the genera nu (HPV 41) and mu (HPV 1, 63). The antibody prevalence to mucosal high-risk types, most prominently HPV 16, was elevated after puberty in women but not in men and peaked between 25 and 34 years. Antibodies to beta and gamma papillomaviruses (PV) were rare in children and increased homogeneously with age, with prevalence peaks at 40 and 60 years in women and 50 and 70 years in men. Antibodies to cutaneous alpha PV showed a heterogeneous age distribution. In summary, these data suggest three major seroprevalence patterns for HPV of phylogenetically distinct genera: antibodies to mu and nu skin PV appear early in life, those to mucosal alpha PV in women after puberty, and antibodies to beta as well as to gamma skin PV accumulate later in life. PMID:18566657

  13. Characterization of Human Papillomavirus Type 154 and Tissue Tropism of Gammapapillomaviruses

    PubMed Central

    Ure, Agustín Enrique; Forslund, Ola

    2014-01-01

    The novel human papillomavirus type 154 (HPV154) was characterized from a wart on the crena ani of a three-year-old boy. It was previously designated as the putative HPV type FADI3 by sequencing of a subgenomic FAP amplicon. We obtained the complete genome by combined methods including rolling circle amplification (RCA), genome walking through an adapted method for detection of integrated papillomavirus sequences by ligation-mediated PCR (DIPS-PCR), long-range PCR, and finally by cloning of four overlapping amplicons. Phylogenetically, the HPV154 genome clustered together with members of the proposed species Gammapapillomavirus 11, and demonstrated the highest identity in L1 to HPV136 (68.6%). The HPV154 was detected in 3% (2/62) of forehead skin swabs from healthy children. In addition, the different detection sites of 62 gammapapillomaviruses were summarized in order to analyze their tissue tropism. Several of these HPV types have been detected from multiple sources such as skin, oral, nasal, and genital sites, suggesting that the gammapapillomaviruses are generalists with a broader tissue tropism than previously appreciated. The study expands current knowledge concerning genetic diversity and tropism among HPV types in the rapidly growing gammapapillomavirus genus. PMID:24551244

  14. Atypical Protein Kinase Cι as a human oncogene and therapeutic target

    PubMed Central

    Parker, Peter J.; Justilien, Verline; Riou, Philippe; Linch, Mark; Fields, Alan P.

    2014-01-01

    Protein kinase inhibitors represent a major class of targeted therapeutics that has made a positive impact on treatment of cancer and other disease indications. Among the promising kinase targets for further therapeutic development are members of the Protein Kinase C (PKC) family.The PKCs are central components of many signaling pathways that regulate diverse cellular functions including proliferation, cell cycle, differentiation, survival, cell migration, and polarity. Genetic manipulation of individual PKC isozymes has demonstrated that they often fulfill distinct, nonredundant cellular functions.11 Participation of PKC members in different intracellular signaling pathways reflects responses to varying extracellular stimuli, intracellular localization, tissue distribution, phosphorylation status, and intermolecular interactions. PKC activity, localization, phosphorylation, and/or expression are often altered in human tumors, and PKC isozymes have been implicated in various aspects of transformation, including uncontrolled proliferation, migration, invasion, metastasis, angiogenesis, and resistance to apoptosis. Despite the strong relationship between PKC isozymes and cancer, to date only atypical PKCiota has been shown to function as a bona fide oncogene, and as such is a particularly attractive therapeutic target for cancer treatment. In this review, we discuss the role of PKCiota in transformation and describe mechanism-based approaches to therapeutically target oncogenic PKCiota signaling in cancer. PMID:24231509

  15. CCAT1: a pivotal oncogenic long non-coding RNA in human cancers.

    PubMed

    Xin, Yu; Li, Zheng; Shen, Jianxiong; Chan, Matthew T V; Wu, William Ka Kei

    2016-06-01

    Long non-coding RNAs (lncRNAs) compose a group of non-protein-coding RNAs - more than 200 nucleotides in length. Recent studies have shown that lncRNAs play important roles in different cellular processes, including proliferation, differentiation, migration and invasion. Deregulation of lncRNAs has been widely reported in human tumours, in which they are able to function as either oncogenes (on the one hand) or tumour suppressor genes (on the other). Deregulation of CCAT1 (colon cancer-associated transcript-1), an oncogenic lncRNA, has been documented in different types of malignancy, such as gastric cancer, colorectal cancer and hepatocellular carcinoma. In this regard, enforced expression of CCAT1 exerts potent tumorigenic effects by promoting cell proliferation, invasion and migration. Recent evidence has also shown that CCAT1 may serve as a prognostic cancer biomarker. In this review, we provide an overview of current evidence relating to the role and biological function of CCAT1 in tumour development. PMID:27134049

  16. Human Papillomavirus (HPV) Genotyping: Automation and Application in Routine Laboratory Testing

    PubMed Central

    Torres, M; Fraile, L; Echevarria, JM; Hernandez Novoa, B; Ortiz, M

    2012-01-01

    A large number of assays designed for genotyping human papillomaviruses (HPV) have been developed in the last years. They perform within a wide range of analytical sensitivity and specificity values for the different viral types, and are used either for diagnosis, epidemiological studies, evaluation of vaccines and implementing and monitoring of vaccination programs. Methods for specific genotyping of HPV-16 and HPV-18 are also useful for the prevention of cervical cancer in screening programs. Some commercial tests are, in addition, fully or partially automated. Automation of HPV genotyping presents advantages such as the simplicity of the testing procedure for the operator, the ability to process a large number of samples in a short time, and the reduction of human errors from manual operations, allowing a better quality assurance and a reduction of cost. The present review collects information about the current HPV genotyping tests, with special attention to practical aspects influencing their use in clinical laboratories. PMID:23248734

  17. Human Papillomavirus (HPV) Genotyping: Automation and Application in Routine Laboratory Testing.

    PubMed

    Torres, M; Fraile, L; Echevarria, Jm; Hernandez Novoa, B; Ortiz, M

    2012-01-01

    A large number of assays designed for genotyping human papillomaviruses (HPV) have been developed in the last years. They perform within a wide range of analytical sensitivity and specificity values for the different viral types, and are used either for diagnosis, epidemiological studies, evaluation of vaccines and implementing and monitoring of vaccination programs. Methods for specific genotyping of HPV-16 and HPV-18 are also useful for the prevention of cervical cancer in screening programs. Some commercial tests are, in addition, fully or partially automated. Automation of HPV genotyping presents advantages such as the simplicity of the testing procedure for the operator, the ability to process a large number of samples in a short time, and the reduction of human errors from manual operations, allowing a better quality assurance and a reduction of cost. The present review collects information about the current HPV genotyping tests, with special attention to practical aspects influencing their use in clinical laboratories. PMID:23248734

  18. DNA Copy Number Aberrations, and Human Papillomavirus Status in Penile Carcinoma. Clinico-Pathological Correlations and Potential Driver Genes

    PubMed Central

    Lambros, Maryou; Stankiewicz, Elzbieta; Ng, Charlotte K. Y.; Weigelt, Britta; Rajab, Ramzi; Tinwell, Brendan; Corbishley, Cathy; Watkin, Nick; Berney, Dan; Reis-Filho, Jorge S.

    2016-01-01

    Penile squamous cell carcinoma is a rare disease, in which somatic genetic aberrations have yet to be characterized. We hypothesized that gene copy aberrations might correlate with human papillomavirus status and clinico-pathological features. We sought to determine the spectrum of gene copy number aberrations in a large series of PSCCs and to define their correlations with human papillomavirus, histopathological subtype, and tumor grade, stage and lymph node status. Seventy formalin-fixed, paraffin embedded penile squamous cell carcinomas were centrally reviewed by expert uropathologists. DNA was extracted from micro-dissected samples, subjected to PCR-based human papillomavirus assessment and genotyping (INNO-LiPA human papillomavirus Genotyping Extra Assay) and microarray-based comparative genomic hybridization using a 32K Bacterial Artificial Chromosome array platform. Sixty-four samples yielded interpretable results. Recurrent gains were observed in chromosomes 1p13.3-q44 (88%), 3p12.3-q29 (86%), 5p15.33-p11 (67%) and 8p12-q24.3 (84%). Amplifications of 5p15.33-p11 and 11p14.1-p12 were found in seven (11%) and four (6%) cases, respectively. Losses were observed in chromosomes 2q33-q37.3 (86%), 3p26.3-q11.1 (83%) and 11q12.2-q25 (81%). Although many losses and gains were similar throughout the cohort, there were small significant differences observed at specific loci, between human papillomavirus positive and negative tumors, between tumor types, and tumor grade and nodal status. These results demonstrate that despite the diversity of genetic aberrations in penile squamous cell carcinomas, there are significant correlations between the clinico-pathological data and the genetic changes that may play a role in disease natural history and progression and highlight potential driver genes, which may feature in molecular pathways for existing therapeutic agents. PMID:26901676

  19. Economic Burden of Human Papillomavirus-Related Diseases in Italy

    PubMed Central

    Baio, Gianluca; Capone, Alessandro; Marcellusi, Andrea; Mennini, Francesco Saverio; Favato, Giampiero

    2012-01-01

    Introduction Human papilloma virus (HPV) genotypes 6, 11, 16, and 18 impose a substantial burden of direct costs on the Italian National Health Service that has never been quantified fully. The main objective of the present study was to address this gap: (1) by estimating the total direct medical costs associated with nine major HPV-related diseases, namely invasive cervical cancer, cervical dysplasia, cancer of the vulva, vagina, anus, penis, and head and neck, anogenital warts, and recurrent respiratory papillomatosis, and (2) by providing an aggregate measure of the total economic burden attributable to HPV 6, 11, 16, and 18 infection. Methods For each of the nine conditions, we used available Italian secondary data to estimate the lifetime cost per case, the number of incident cases of each disease, the total economic burden, and the relative prevalence of HPV types 6, 11, 16, and 18, in order to estimate the aggregate fraction of the total economic burden attributable to HPV infection. Results The total direct costs (expressed in 2011 Euro) associated with the annual incident cases of the nine HPV-related conditions included in the analysis were estimated to be €528.6 million, with a plausible range of €480.1–686.2 million. The fraction attributable to HPV 6, 11, 16, and 18 was €291.0 (range €274.5–315.7 million), accounting for approximately 55% of the total annual burden of HPV-related disease in Italy. Conclusions The results provided a plausible estimate of the significant economic burden imposed by the most prevalent HPV-related diseases on the Italian welfare system. The fraction of the total direct lifetime costs attributable to HPV 6, 11, 16, and 18 infections, and the economic burden of noncervical HPV-related diseases carried by men, were found to be cost drivers relevant to the making of informed decisions about future investments in programmes of HPV prevention. PMID:23185412

  20. Comprehensive analysis of HPV16 integration in OSCC reveals no significant impact of physical status on viral oncogene and virally disrupted human gene expression.

    PubMed

    Olthof, Nadine C; Speel, Ernst-Jan M; Kolligs, Jutta; Haesevoets, Annick; Henfling, Mieke; Ramaekers, Frans C S; Preuss, Simon F; Drebber, Uta; Wieland, Ulrike; Silling, Steffi; Lam, Wan L; Vucic, Emily A; Kremer, Bernd; Klussmann, Jens-P; Huebbers, Christian U

    2014-01-01

    Infection with high-risk human papillomavirus (HPV) type 16 is an independent risk factor for the development of oropharyngeal squamous cell carcinomas (OSCC). However, it is unclear whether viral integration is an essential hallmark in the carcinogenic process of OSCC and whether HPV integration correlates with the level of viral gene transcription and influences the expression of disrupted host genes. We analyzed 75 patients with OSCC. HPV16-positivity was proven by p16(INK4A) immunohistochemistry, PCR and FISH. Viral integration was examined using DIPS- as well as APOT-PCR. Viral E2, E6 and E7 gene expression levels were quantified by quantitative reverse transcriptase (RT-q)PCR. Expression levels of 7 human genes disrupted by the virus were extracted from mRNA expression profiling data of 32 OSCCs. Viral copy numbers were assessed by qPCR in 73 tumors. We identified 37 HPV16-human fusion products indicating viral integration in 29 (39%) OSCC. In the remaining tumors (61%) only episome-derived PCR products were detected. When comparing OSCC with or without an integration-derived fusion product, we did not find significant differences in the mean RNA expression of viral genes E2, E6 and E7 or the viral copy numbers per cell, nor did the RNA expression of the HPV-disrupted genes differ from either group of OSCC. In conclusion, our data do not support the hypothesis that integration affects the levels of viral and/or HPV-disrupted human gene transcripts. Thus constitutive, rather than a high level, of expression of oncogene transcripts appears to be required in HPV-related OSCC. PMID:24586376

  1. Differential Regulation of Human Papillomavirus Type 8 by Interferon Regulatory Factors 3 and 7▿

    PubMed Central

    Oldak, Monika; Tolzmann, Liv; Wnorowski, Artur; Podgórska, Marta Justyna; Silling, Steffi; Lin, Rongtuan; Hiscott, John; Müller, Cornelia Sigrid Lissi; Vogt, Thomas; Smola, Hans; Smola, Sigrun

    2011-01-01

    The genus β human papillomavirus (HPV) type 8 is associated with nonmelanoma skin cancer in patients with epidermodysplasia verruciformis, and evidence for its protumorigenic potential in the general population increases. To date, strategies to suppress genus β HPV infections are limited. Interferon regulatory factors IRF-3 and IRF-7 play key roles in the activation of the innate immune response to viral infections. In this study, we show for the first time that both IRF-3 and IRF-7 regulate transcription of a papillomavirus, but with opposing effects. IRF-7, expressed in the suprabasal layers of human epidermis, increased HPV8 late promoter activity via direct binding to viral DNA. UV-B light-induced activation of the HPV8 promoter involved IRF-7 as a downstream effector. In contrast, IRF-3, expressed in all layers of human epidermis, induced strong HPV8 suppression in primary keratinocytes. IRF-3-mediated suppression prevailed over IRF-7-induced HPV8 transcription. Unlike the E6 oncoprotein of the mucosal high-risk HPV16, the HPV8 E6 protein did not bind to IRF-3 and only weakly antagonized its activity. Strong antiviral activity was also observed, when keratinocytes were treated with potent IRF-3 activators, poly(I:C) or RNA bearing 5′ phosphates. In conclusion, we show that IRF-3 activation induces a state of cell-autonomous immunity against HPV in primary human keratinocytes. Our study suggests that local application of IRF-3-activating compounds might constitute an attractive novel therapeutic strategy against HPV8-associated diseases, particularly in epidermodysplasia verruciformis patients. PMID:20980500

  2. EUROGIN 2014 roadmap: differences in human papillomavirus infection natural history, transmission and human papillomavirus-related cancer incidence by gender and anatomic site of infection.

    PubMed

    Giuliano, Anna R; Nyitray, Alan G; Kreimer, Aimée R; Pierce Campbell, Christine M; Goodman, Marc T; Sudenga, Staci L; Monsonego, Joseph; Franceschi, Silvia

    2015-06-15

    Human papillomaviruses (HPVs) cause cancer at multiple anatomic sites in men and women, including cervical, oropharyngeal, anal, vulvar and vaginal cancers in women and oropharyngeal, anal and penile cancers in men. In this EUROGIN 2014 roadmap, differences in HPV-related cancer and infection burden by gender and anatomic site are reviewed. The proportion of cancers attributable to HPV varies by anatomic site, with nearly 100% of cervical, 88% of anal and <50% of lower genital tract and oropharyngeal cancers attributable to HPV, depending on world region and prevalence of tobacco use. Often, mirroring cancer incidence rates, HPV prevalence and infection natural history varies by gender and anatomic site of infection. Oral HPV infection is rare and significantly differs by gender; yet, HPV-related cancer incidence at this site is several-fold higher than at either the anal canal or the penile epithelium. HPV seroprevalence is significantly higher among women compared to men, likely explaining the differences in age-specific HPV prevalence and incidence patterns observed by gender. Correspondingly, among heterosexual partners, HPV transmission appears higher from women to men. More research is needed to characterize HPV natural history at each anatomic site where HPV causes cancer in men and women, information that is critical to inform the basic science of HPV natural history and the development of future infection and cancer prevention efforts. PMID:25043222

  3. Prevalence of genital Mycoplasma, Ureaplasma, Gardnerella, and human papillomavirus in Japanese men with urethritis, and risk factors for detection of urethral human papillomavirus infection.

    PubMed

    Shigehara, Kazuyoshi; Kawaguchi, Shohei; Sasagawa, Toshiyuki; Furubayashi, Keiichi; Shimamura, Masayoshi; Maeda, Yuji; Konaka, Hiroyuki; Mizokami, Atsushi; Koh, Eitetsu; Namiki, Mikio

    2011-08-01

    To analyze the risk factors for HPV infection in the urethra, we examined the prevalence of various microorganisms, for example Neisseria gonorrhoeae, Chlamydia trachomatis, Mycoplasma genitalium, Mycoplasma hominis, Ureaplasma urealyticum, Ureaplasma parvum, Gardnerella vaginalis, and human papillomavirus (HPV) in Japanese male patients with urethritis, and investigated their sexual backgrounds. Rubbed samples obtained from the distal urethra and questionnaires regarding sexual activity and demographic information were collected from 176 participants. N. gonorrhoeae, C. trachomatis, M. genitalium, M. hominis, U. urealyticum, U. parvum, G. vaginalis, and HPV were detected in 19, 26, 18, 12, 12, 8.5, 14, and 20%, respectively, of all cases in this study. Multivariate logistic regression analysis indicated that more than 4 sexual partners within the last year and presence of N. gonorrhoeae and/or C. trachomatis and/or M. genitalium infections were independent risk factors for urethral HPV infection, with odds ratios of 3.85 (95% CI 1.49-9.94) and 2.41 (95% CI 1.03-5.61), respectively. It is likely that urethral HPV detection is associated with current sexual activity and the presence of N. gonorrhoeae, C. trachomatis, and/or M. genitalium infections. PMID:21213011

  4. Variant-specific persistence of infections with human papillomavirus Types 31, 33, 45, 56 and 58 and risk of cervical intraepithelial neoplasia.

    PubMed

    Xi, Long Fu; Schiffman, Mark; Koutsky, Laura A; Hughes, James P; Hulbert, Ayaka; Shen, Zhenping; Galloway, Denise A; Kiviat, Nancy B

    2016-09-01

    In our previous study of the etiologic role of oncogenic human papillomavirus (HPV) types other than HPV16 and 18, we observed a significantly higher risk of cervical intraepithelial neoplasia Grades 2-3 (CIN2/3) associated with certain lineages of HPV types 31/33/45/56/58 [called high-risk (HR) variants] compared with non-HR variants. This study was to examine whether these intra-type variants differ in persistence of the infection and persistence-associated risk of CIN2/3. Study subjects were women who had any of HPV types 31/33/45/56/58 newly detected during a 2-year follow-up with 6-month intervals. For each type, the first positive sample was used for variant characterization. The association of reverting-to-negativity with group of the variants and CIN2/3 with length of positivity was assessed using discrete Cox regression and logistic regression, respectively. Of the 598 newly detected, type-specific HPV infections, 312 became undetectable during follow-up. Infections with HR, compared with non-HR, variants were marginally more likely to become negative [adjusted hazard ratio = 1.3; 95% confidence interval (CI), 0.9-1.8]. The adjusted odds ratio associating with the development of CIN2/3 was 3.0 (95% CI, 1.2-7.4) for persistent infections with HR variants for 6 months and 10.0 (95% CI, 3.8-38.0) for persistent infections with HR variants for 12-18 months as compared with the first positive detection of HR variants. Among women with non-HR variants, there were no appreciable differences in risk of CIN2/3 by length of positivity. Findings suggest that the lineage-associated risk of CIN2/3 was not mediated through a prolonged persistent infection, but oncogenic heterogeneity of the variants. PMID:27121353

  5. His499 Regulates Dimerization and Prevents Oncogenic Activation by Asparagine Mutations of the Human Thrombopoietin Receptor.

    PubMed

    Leroy, Emilie; Defour, Jean-Philippe; Sato, Takeshi; Dass, Sharmila; Gryshkova, Vitalina; Shwe, Myat M; Staerk, Judith; Constantinescu, Stefan N; Smith, Steven O

    2016-02-01

    Ligand binding to the extracellular domain of the thrombopoietin receptor (TpoR) imparts a specific orientation on the transmembrane (TM) and intracellular domains of the receptors that is required for physiologic activation via receptor dimerization. To map the inactive and active dimeric orientations of the TM helices, we performed asparagine (Asn)-scanning mutagenesis of the TM domains of the murine and human TpoR. Substitution of Asn at only one position (S505N) activated the human receptor, whereas Asn substitutions at several positions activated the murine receptor. Second site mutational studies indicate that His(499) near the N terminus of the TM domain is responsible for protecting the human receptor from activation by Asn mutations. Structural studies reveal that the sequence preceding His(499) is helical in the murine receptor but non-helical in peptides corresponding to the TM domain of the inactive human receptor. The activating S505N mutation and the small molecule agonist eltrombopag both induce helix in this region of the TM domain and are associated with dimerization and activation of the human receptor. Thus, His(499) regulates the activation of human TpoR and provides additional protection against activating mutations, such as oncogenic Asn mutations in the TM domain. PMID:26627830

  6. Detection of Human Papillomavirus-16 E6-Oncoprotein in Epithelial Ovarian Tumors Samples of Iraqi Patients

    PubMed Central

    Mahmood, Fahem Mohsin; Kadhim, Haider Sabah; Mousa Al Khuzaee, Liqaa Riadh

    2014-01-01

    Background: Human papillomavirus (HPV) is the causal factor for cervical cancer. However, the role of HPV infection in ovarian cancer is unclear. Objectives: This study aimed to determine the presence of human papillomavirus-16 (HPV-16) in ovarian tumor tissues. Patients and Methods: This was a retrospective study, which included 61 Archived human ovarian tumor tissues embedded in paraffin blocks. The ovarian tumor tissues were divided into four groups. The first group was the malignant ovarian epithelial tumor group; it included 31 cases with invasive surface epithelial ovarian tumors. The second group was the borderline epithelial ovarian tumor group: it included four cases with borderline intermediate malignancy. The third group was the benign epithelial ovarian tumors group: it included 18 cases with benign epithelial ovarian tumors. The fourth group had functional ovarian cystic lesions: it included eight cases with non-neoplastic functional ovarian cysts. Sections were made from each of the paraffin embedded blocks and examined using immunohistochemistry to detect HPV 16-E6-oncoprotein in ovarian tumor tissues. Results: Out of the eight cases with functional cysts only one case (12.5%) expressed HPV. No HPV expression was seen in cases with benign and borderline tumors. Out of the 31 cases with one malignant surface epithelial ovarian tumor only three (9.67%) cases expressed HPV. There was no significant statistical difference in HPV expression among neoplastic and non-neoplastic ovarian tumors included in the present study (P= 0.476). Conclusions: HPV type 16 was detected in only 9.67% of malignant epithelial tumors. It appears that HPV infection plays a relatively minor role in the pathogenesis of ovarian carcinomas. PMID:25485061

  7. Comprehensive analysis of the ubiquitinome during oncogene-induced senescence in human fibroblasts

    PubMed Central

    Bengsch, Fee; Tu, Zhigang; Tang, Hsin-Yao; Zhu, Hengrui; Speicher, David W; Zhang, Rugang

    2015-01-01

    Oncogene-induced senescence (OIS) is an important tumor suppression mechanism preventing uncontrolled proliferation in response to aberrant oncogenic signaling. The profound functional and morphological remodelling of the senescent cell involves extensive changes. In particular, alterations in protein ubiquitination during senescence have not been systematically analyzed previously. Here, we report the first global ubiquitination profile of primary human cells undergoing senescence. We employed a well-characterized in vitro model of OIS, primary human fibroblasts expressing oncogenic RAS. To compare the ubiquitinome of RAS-induced OIS and controls, ubiquitinated peptides were enriched by immune affinity purification and subjected to liquid chromatography tandem mass spectrometry (LC-MS/MS). We identified 4,472 ubiquitination sites, with 397 sites significantly changed (>3 standard deviations) in senescent cells. In addition, we performed mass spectrometry analysis of total proteins in OIS and control cells to account for parallel changes in both protein abundance and ubiquitin levels that did not affect the percentage of ubiquitination of a given protein. Pathway analysis revealed that the OIS-induced ubiquitinome alterations mainly affected 3 signaling networks: eIF2 signaling, eIF4/p70S6K signaling, and mTOR signaling. Interestingly, the majority of the changed ubiquitinated proteins in these pathways belong to the translation machinery. This includes several translation initiation factors (eIF2C2, eIF2B4, eIF3I, eIF3L, eIF4A1) and elongation factors (eEF1G, eEF1A) as well as 40S (RPS4X, RPS7, RPS11 and RPS20) and 60S ribosomal subunits (RPL10, RPL11, RPL18 and RPL35a). In addition, we observed enriched ubiquitination of aminoacyl-tRNA ligases (isoleucyl-, glutamine-, and tyrosine-tRNA ligase), which provide the amino acid-loaded tRNAs for protein synthesis. These results suggest that ubiquitination affects key components of the translation machinery to regulate

  8. Kallikrein-8 Proteolytically Processes Human Papillomaviruses in the Extracellular Space To Facilitate Entry into Host Cells

    PubMed Central

    Cerqueira, Carla; Samperio Ventayol, Pilar; Vogeley, Christian

    2015-01-01

    ABSTRACT The entry of human papillomaviruses into host cells is a complex process. It involves conformational changes at the cell surface, receptor switching, internalization by a novel endocytic mechanism, uncoating in endosomes, trafficking of a subviral complex to the Golgi complex, and nuclear entry during mitosis. Here, we addressed how the stabilizing contacts in the capsid of human papillomavirus 16 (HPV16) may be reversed to allow uncoating of the viral genome. Using biochemical and cell-biological analyses, we determined that the major capsid protein L1 underwent proteolytic cleavage during entry. In addition to a dispensable cathepsin-mediated proteolysis that occurred likely after removal of capsomers from the subviral complex in endosomes, at least two further proteolytic cleavages of L1 were observed, one of which was independent of the low-pH environment of endosomes. This cleavage occurred extracellularly. Further analysis showed that the responsible protease was the secreted trypsin-like serine protease kallikrein-8 (KLK8) involved in epidermal homeostasis and wound healing. Required for infection, the cleavage was facilitated by prior interaction of viral particles with heparan sulfate proteoglycans. KLK8-mediated cleavage was crucial for further conformational changes exposing an important epitope of the minor capsid protein L2. Occurring independently of cyclophilins and of furin that mediate L2 exposure, KLK8-mediated cleavage of L1 likely facilitated access to L2, located in the capsid lumen, and potentially uncoating. Since HPV6 and HPV18 also required KLK8 for entry, we propose that the KLK8-dependent entry step is conserved. IMPORTANCE Our analysis of the proteolytic processing of incoming HPV16, an etiological agent of cervical cancer, demonstrated that the capsid is cleaved extracellularly by a serine protease active during wound healing and that this cleavage was crucial for infection. The cleavage of L1 is one of at least four structural

  9. Prevalence of and Risk Factors for Anal Human Papillomavirus Infection Among Young Healthy Women in Costa Rica

    PubMed Central

    Castro, Felipe A.; Quint, Wim; Gonzalez, Paula; Katki, Hormuzd A.; Herrero, Rolando; van Doorn, Leen-Jan; Schiffman, Mark; Struijk, Linda; Rodriguez, Ana Cecilia; DelVecchio, Corey; Lowy, Douglas R.; Porras, Carolina; Jimenez, Silvia; Schiller, John; Solomon, Diane; Wacholder, Sholom; Hildesheim, Allan; Kreimer, Aimée R.

    2012-01-01

    Background. Anal cancer is caused by human papillomavirus (HPV), yet little is known about anal HPV infection among healthy young women. Methods. A total of 2017 sexually active women in the control arm of an HPV-16/18 vaccine trial had a single anal specimen collected by a clinician at the 4-year study visit. Samples were tested for HPV by SPF10 PCR/DEIA/LiPA25, version 1. Results. A total of 4% of women had HPV-16, 22% had oncogenic HPV, and 31% had any HPV detected in an anal specimen. The prevalence of anal HPV was higher among women who reported anal intercourse, compared with those who did not (43.4% vs 28.4%; P < .001). Among women who reported anal intercourse, cervical HPV (adjusted odds ratio [aOR], 5.3 [95% confidence interval {CI}, 3.4–8.2]), number of sex partners (aOR, 2.2 [95% CI, 1.1–4.6] for ≥4 partners), and number of anal intercourse partners (aOR, 1.9 [95% CI, 1.1–3.3] for ≥2 partners) were independent risk factors for anal HPV detection. Among women who reported no anal intercourse, cervical HPV (aOR, 4.7 [95% CI, 3.7–5.9]), number of sex partners (aOR, 2.4 [95% CI, 1.7–3.4] for ≥4 partners), and report of anal fissures (aOR, 2.3 [95% CI, 1.1–4.8]) were associated with an increased odds of anal HPV detection. Conclusion. Anal HPV is common among young women, even those who report no anal sex, and was associated with cervical HPV infection. Anal fissures in women who report never having had anal intercourse may facilitate HPV exposure. Clinical Trials Registration. NCT00128661. PMID:22850119

  10. Human papillomavirus detection in women with and without human immunodeficiency virus infection in Colombia

    PubMed Central

    2014-01-01

    Background HIV infection leads to a decreasing immune response, thereby facilitating the appearance of other infections, one of the most important ones being HPV. However, studies are needed for determining associations between immunodeficiency caused by HIV and/or the presence of HPV during the course of cervical lesions and their degree of malignancy. This study describes the cytological findings revealed by the Papanicolaou test, laboratory characteristics and HPV molecular profile in women with and without HIV infection. Methods A total of 216 HIV-positive and 1,159 HIV-negative women were invited to participate in the study; PCR was used for the molecular detection of HPV in cervical samples. Statistical analysis (such as percentages, Chi-square test and Fisher’s exact test when applicable) determined human papillomavirus (HPV) infection frequency (single and multiple) and the distribution of six types of high-risk-HPV in women with and without HIV infection. Likewise, a logistic regression model was run to evaluate the relationship between HIV-HPV infection and different risk factors. Results An association was found between the frequency of HPV infection and infection involving 2 or more HPV types (also known as multiple HPV infection) in HIV-positive women (69.0% and 54.2%, respectively); such frequency was greater than that found in HIV-negative women (44.3% and 22.7%, respectively). Statistically significant differences were observed between both groups (p = 0.001) regarding HPV presence (both in infection and multiple HPV infection). HPV-16 was the most prevalent type in the population being studied (p = 0.001); other viral types had variable distribution in both groups (HIV-positive and HIV-negative). HPV detection was associated with <500 cell/mm3 CD4-count (p = 0.004) and higher HIV-viral-load (p = 0.001). HPV-DNA detection, <200 cell/mm3 CD4-count (p = 0.001), and higher HIV-viral-load (p = 0.001) were associated with

  11. Human papillomavirus and oropharyngeal squamous cell carcinoma: what the clinician should know.

    PubMed

    Genden, Eric M; Sambur, Ian M; de Almeida, John R; Posner, Marshall; Rinaldo, Alessandra; Rodrigo, Juan P; Strojan, Primož; Takes, Robert P; Ferlito, Alfio

    2013-02-01

    The incidence of oropharyngeal squamous cell carcinoma (OPSCC) is rising in contrast to the decreasing incidence of carcinomas arising in other subsites of the head and neck. The human papillomavirus (HPV) infection has played an increasing role in these epidemiological changes and as the etiology for a significant fraction of head and neck squamous cell carcinomas, OPSCC in particular. Most importantly, many retrospective studies have shown that the prognosis differs significantly between patients with HPV-associated tumors and non-HPV associated tumors. Thus, questions arise on the choices of treatment for patients based on HPV status and the consequences of therapy. Given the recognized relevance of HPV status in OPSCC, many new questions concerning the biology, treatment, and prevention of HPV infection arise. This review is intended to highlight some of the major issues and frequently asked questions relevant for the clinician dealing with patients with OPSCC. PMID:22752642

  12. The Combined Influence of Oral Contraceptives and Human Papillomavirus Virus on Cutaneous Squamous Cell Carcinoma

    PubMed Central

    Efird, Jimmy T.; Toland, Amanda E.; Lea, C. Suzanne; Phillips, Christopher J.

    2011-01-01

    The vast majority of cutaneous squamous cell carcinoma (CSCC) will occur in those with fair complexion, tendency to burn, and high ultraviolet radiation (UVR) exposure. Organ transplant recipients also are an important population at great risk for CSCC. An association has been reported between oral contraceptive (OC) use, human papillomavirus virus (HPV) and cervical cancer, and there could be a similar association for CSCC. The cutaneous HPV β-E6 protein, a close cousin of the transformative E6 protein underlying anogenital cancers, has been shown to inhibit apoptosis in response to UVR damage and stimulate morphologic transformation in rodent fibroblast cell lines. Furthermore, OC use has been shown to enhance HPV transcription and may contribute to CSCC risk through this pathway. PMID:21499554

  13. Delay and refusal of human papillomavirus vaccine for girls, national immunization survey-teen, 2010.

    PubMed

    Dorell, Christina; Yankey, David; Jeyarajah, Jenny; Stokley, Shannon; Fisher, Allison; Markowitz, Lauri; Smith, Philip J

    2014-03-01

    Human papillomavirus (HPV) vaccine coverage among girls is low. We used data reported by parents of 4103 girls, 13 to 17 years old, to assess associations with, and reasons for, delaying or refusing HPV vaccination. Sixty-nine percent of parents neither delayed nor refused vaccination, 11% delayed only, 17% refused only, and 3% both delayed and refused. Eighty-three percent of girls who delayed only, 19% who refused only, and 46% who both delayed and refused went on to initiate the vaccine series or intended to initiate it within the next 12 months. A significantly higher proportion of parents of girls who were non-Hispanic white, lived in households with higher incomes, and had mothers with higher education levels, delayed and/or refused vaccination. The most common reasons for nonvaccination were concerns about lasting health problems from the vaccine, wondering about the vaccine's effectiveness, and believing the vaccine is not needed. PMID:24463951

  14. Environmental Scanning as a Public Health Tool: Kentucky's Human Papillomavirus Vaccination Project.

    PubMed

    Wilburn, Amanda; Vanderpool, Robin C; Knight, Jennifer R

    2016-01-01

    Borrowing from business, quality improvement programs, and strategic planning principles, environmental scanning is gaining popularity in public health practice and research and is advocated as an assessment and data collection tool by federal funding agencies and other health-related organizations. Applicable to a range of current and emerging health topics, environmental scans - through various methods - assess multiple facets of an issue by engaging stakeholders who can ask or answer research questions, exploring related policy, critiquing published and gray literature, collecting and analyzing qualitative and quantitative data in both primary and secondary forms, disseminating findings to internal and external stakeholders, and informing subsequent planning and decision making. To illustrate the environmental scanning process in a public health setting and showcase its value to practitioners in the field, we describe a federally funded environmental scan for a human papillomavirus vaccination project in Kentucky. PMID:27536901

  15. American Society of Clinical Oncology Statement: Human Papillomavirus Vaccination for Cancer Prevention.

    PubMed

    Bailey, Howard H; Chuang, Linus T; duPont, Nefertiti C; Eng, Cathy; Foxhall, Lewis E; Merrill, Janette K; Wollins, Dana S; Blanke, Charles D

    2016-05-20

    American Society of Clinical Oncology (ASCO), the leading medical professional oncology society, is committed to lessening the burden of cancer and as such will promote underused interventions that have the potential to save millions of lives through cancer prevention. As the main providers of cancer care worldwide, our patients, their families, and our communities look to us for guidance regarding all things cancer related, including cancer prevention. Through this statement and accompanying recommendations, ASCO hopes to increase awareness of the tremendous global impact of human papillomavirus (HPV) -caused cancers, refocus the discussion of HPV vaccination on its likely ability to prevent millions of cancer deaths, and increase HPV vaccination uptake via greater involvement of oncology professionals in ensuring accurate public discourse about HPV vaccination and calling for the implementation of concrete strategies to address barriers to vaccine access and acceptance. PMID:27069078

  16. Recombination-Dependent Oligomerization of Human Papillomavirus Genomes upon Transient DNA Replication

    PubMed Central

    Orav, Marit; Henno, Liisi; Isok-Paas, Helen; Geimanen, Jelizaveta; Ustav, Mart

    2013-01-01

    We describe the extensive and progressive oligomerization of human papillomavirus (HPV) genomes after transfection into the U2OS cell line. The HPV genomic oligomers are extrachromosomal concatemeric molecules containing the viral genome in a head-to-tail orientation. The process of oligomerization does not depend on the topology of the input DNA, and it does not require any other viral factors besides replication proteins E1 and E2. We provide evidence that oligomerization of the HPV18 and HPV11 genomes involves homologous recombination. We also demonstrate oligomerization of the HPV18 and HPV11 genomes in SiHa, HeLa, and C-33 A cell lines and provide examples of oligomeric HPV genomes in clinical samples obtained from HPV-infected patients. PMID:23986589

  17. A human papillomavirus public vaccination program in Taiwan: the Kinmen County experience.

    PubMed

    Lee, Chin-Chih; Chen, Tien-Shun; Wu, Tsung-Zu; Huang, Li-Min

    2012-12-01

    In Taiwan, cervical cancer is ranked sixth among all causes of death in women. With the goal of reducing the incidence of cervical cancer, the Kinmen County Health Bureau planned to implement a pilot human papillomavirus (HPV) vaccination program in 2007. The Bureau established a committee to promote public awareness, coordinate with the schools, arrange for the administration of the vaccine, establish a vaccination registry, and develop a plan for follow-up and assessment. Vaccination for female residents aged 16-18 began through a school-based program in 2008. A total of 1633 girls completed the vaccination protocol within 3 years, and vaccine uptake rates of over 90% were achieved by 2010. No serious adverse events were reported among those who were vaccinated. The experience gained from the Kinmen County HPV vaccination program has helped and will continue to help establish an operational model for similar programs throughout the country. PMID:23265746

  18. Scaling up human papillomavirus vaccination: a conceptual framework of vaccine adherence

    PubMed Central

    Katz, Ingrid T.; Ware, Norma C.; Gray, Glenda; Haberer, Jessica E.; Mellins, Claude A.; Bangsberg, David R.

    2011-01-01

    This review article provides a conceptual framework for human papillomavirus (HPV) vaccine acceptance and adherence, with a focus on improving understanding of the sociocultural factors impacting vaccine adherence behaviour. We include a systematic review of the slowly expanding literature on HPV vaccine acceptability and uptake in developed nations, as well as the relatively few publications from poorer nations, where more than 80% of global cervical cancer related deaths occur and where the vaccine will probably have the largest impact. We suggest that this conceptual framework will not only improve our understanding of HPV vaccine uptake and adherence, but it may also guide future sociobehavioural research geared towards improving adherence to the HPV vaccine and other multi-step vaccines in a young population at risk for sexually transmissible infections. PMID:20719215

  19. Immunological studies of cerebrospinal fluid from patients with CNS symptoms after human papillomavirus vaccination.

    PubMed

    Takahashi, Yukitoshi; Matsudaira, Takashi; Nakano, Hitoshi; Nasu, Hirosato; Ikeda, Hitoshi; Nakaoka, Kentaro; Takayama, Rumiko; Oota, Masayasu

    2016-09-15

    In 32 patients with prolonged central nervous system symptoms after human papillomavirus (HPV) vaccination, we measured conventional and immunological markers in cerebrospinal fluid (CSF) and compared with the levels in disease controls. Our studies revealed significantly decreased chloride and neuron-specific enolase (NSE) levels in CSF of patients with CNS symptoms after HPV vaccination compared to disease controls. IL-4, IL-13, and CD4(+) T cells increased significantly in patients, and IL-17 increased significantly from 12 to 24months after symptom onset. Chemokines (IL-8 and MCP-1) were also elevated, but CD8(+) T cells, PDGF-bb and IL-12 were reduced. Antibodies to GluN2B-NT2, GluN2B-CT and GluN1-NT increased significantly. These results suggest biological, mainly immunological, changes in the CSF of patients after HPV vaccination. PMID:27609278

  20. Papanicolaou test screening and prevalence of genital human papillomavirus among women who have sex with women.

    PubMed Central

    Marrazzo, J M; Koutsky, L A; Kiviat, N B; Kuypers, J M; Stine, K

    2001-01-01

    OBJECTIVES: The purpose of this study was to examine frequency of and attitudes toward Papanicolaou (Pap) test screening in women who have sex with women (WSW) and to determine prevalence of genital human papillomavirus (HPV). METHODS: Women were eligible if they reported having engaged in sex with another woman in the preceding year Medical and sexual histories were obtained. Cervical specimens for Pap tests and cervical and vaginal specimens for HPV DNA testing were collected. RESULTS: HPV DNA was detected in 31 of 248 WSW (13%). Women who had never had sex with men were less likely to have undergone pelvic examinations and had fewer recent Pap tests. Reasons for not undergoing Pap tests included lack of insurance, previous adverse experiences, and belief that Pap tests were unnecessary. CONCLUSIONS: Despite the occurrence of genital HPV, WSW do not receive adequate Pap test screening. Pap test screening recommendations should not differ for WSW, regardless of sexual history with men. PMID:11392939

  1. Cumulative Impact of HIV and Multiple Concurrent Human Papillomavirus Infections on the Risk of Cervical Dysplasia

    PubMed Central

    Adler, David H.; Wallace, Melissa; Bennie, Thola; Abar, Beau; Meiring, Tracy L.; Williamson, Anna-Lise; Bekker, Linda-Gail

    2016-01-01

    Infection with HIV is known to increase the risk of cervical cancer. In addition, evidence suggests that concurrent infection with multiple human papillomavirus (HPV) genotypes increases the risk of cervical dysplasia more than infection with a single HPV genotype. However, the impact of the combination of HIV coinfection and presence of multiple concurrent HPV infections on the risk of cervical dysplasia is uncertain. We compared the results of HPV testing and Pap smears between HIV-infected and HIV-uninfected young women to assess the cumulative impact of these two conditions. We found that both HIV and the presence of multiple concurrent HPV infections are associated with increased risk of associated Pap smear abnormality and that the impact of these two risk factors may be additive. PMID:26997954

  2. The new human papillomavirus (HPV) vaccine: pros and cons for pediatric and adolescent health.

    PubMed

    Thomas, Tami L

    2008-01-01

    The new human papillomavirus (HPV) vaccine is a research breakthrough for pediatric/adolescent health to prevent cervical cancer and related morbidity. The annual heath care cost for the treatment of cervical cancer and genital warts is estimated to be more than three billion dollars a year. The new HPV vaccine has incredible potential to improve reproductive health promotion, reduce health care costs, and close health care disparity gaps. However, issues both for and against the new HPV vaccine, including mandating vaccination, high cost of the vaccine, the short duration of protection offered, and the perceived promotion of sexual activity, cause confusion. Pediatric nurses, including those in advanced practice, benefit by understanding the pros and cons of these issues in advocating for their patients. PMID:19051848

  3. Environmental Scanning as a Public Health Tool: Kentucky’s Human Papillomavirus Vaccination Project

    PubMed Central

    Wilburn, Amanda; Knight, Jennifer R.

    2016-01-01

    Borrowing from business, quality improvement programs, and strategic planning principles, environmental scanning is gaining popularity in public health practice and research and is advocated as an assessment and data collection tool by federal funding agencies and other health-related organizations. Applicable to a range of current and emerging health topics, environmental scans — through various methods — assess multiple facets of an issue by engaging stakeholders who can ask or answer research questions, exploring related policy, critiquing published and gray literature, collecting and analyzing qualitative and quantitative data in both primary and secondary forms, disseminating findings to internal and external stakeholders, and informing subsequent planning and decision making. To illustrate the environmental scanning process in a public health setting and showcase its value to practitioners in the field, we describe a federally funded environmental scan for a human papillomavirus vaccination project in Kentucky. PMID:27536901

  4. A PCR-RFLP method for typing human papillomavirus type 16 variants.

    PubMed

    Lugo-Trampe, Ángel; Trujillo-Murillo, Karina del C; Rodriguez-Sanchez, Iram P; Barboza-Cerda, Maria del C; Lugo-Trampe, José de J; Hernández-Ramirez, Laura C; Canseco-Avila, Luis M; Espinoza-Ruiz, Marisol; Domínguez-Arrevillaga, Sergio; Delgado-Enciso, Iván

    2013-02-01

    Infection with some types of human papillomavirus (HPV) is required for cervical cancer development, being HPV type 16 (HPV 16) the most common type in premalignant and malignant cervical lesions. DNA sequencing has revealed the existence of intratypic variants of HPV 16 whose genotyping is clinically useful for distinguishing between persistent and recurrent infections. From the epidemiological perspective, the frequency of diverse HPV 16 variants in several populations could correlate with the presence of precursor high-risk lesions in different anatomical locations. Currently, the "gold standard" method for identifying HPV 16 variants involves the sequencing of genomic regions to identify characteristic polymorphic sites. Although some other methods have been described, they require specialized or high-cost equipment. In this study, a robust and low cost procedure is described for HPV 16 variant typing, based on the long control region of the virus. PMID:23124001

  5. [News items on human papillomavirus and its vaccine in the Valencian press (2006-2011)].

    PubMed

    Tuells, José; Duro Torrijos, José Luis; Chilet Rosell, Elisa; Pastor Villalba, Eliseo; Portero Alonso, Antonio; Navarro Ortiz, Carmen; Galiana de la Villa, Eva María

    2013-01-01

    The process of introducing the human papillomavirus (HPV) vaccine aimed at teenage girls has not been entirely without controversy in Spain. This vaccine was originally hyped as a preventive measure in the fight against cervical cancer but the resulting euphoria was tempered by a message calling for evidence. During administration of the second dose of the vaccine in February 2009, an unexpected turn of events attracted vast media coverage when two teenagers experienced adverse effects after immunization in Valencia (Spain). This study analyzes the scope and content of news items on HPV, immunization and cervical cancer published between 2006 and 2011 in two widely disseminated regional newspapers in Valencia. We also discuss the extent to which the messages transmitted may have influenced acceptability of the vaccine. PMID:23416026

  6. Human papillomavirus-related cancers among people living with AIDS in Puerto Rico.

    PubMed

    Ortiz, Ana Patricia; Pérez-Irizarry, Javier; Soto-Salgado, Marievelisse; Suárez, Erick; Pérez, Naydi; Cruz, Maritza; Palefsky, Joel; Tortolero-Luna, Guillermo; Miranda, Sandra; Colón-López, Vivian

    2014-01-01

    The objective of this study was to estimate the incidence of cancer and human papillomavirus (HPV)-related cancers and the risk of death (by cancer status) among people living with AIDS (PLWA) in Puerto Rico. We used data from the Puerto Rico AIDS Surveillance Program and Central Cancer Registry (1985-2005). Cancers with highest incidence were cervix (299.6/100,000) for women and oral cavity/oropharynx for men (150.0/100,000); the greatest excess of cancer incidence for men (standardized incidence ratio, 86.8) and women (standardized incidence ratio, 52.8) was for anal cancer. PLWA who developed a cancer had decreased survival and increased risk of death compared with those who did not have cancer. Cancer control strategies for PLWA will be essential for improving their disease survival. PMID:24831284

  7. Acceptability of the human papillomavirus vaccine among diverse Hispanic mothers and grandmothers.

    PubMed

    Ramírez, Michelle; Jessop, Amy B; Leader, Amy; Crespo, Carlos Juan

    2014-01-01

    The human papillomavirus (HPV) vaccine has the potential to reduce rates of cervical cancer and other HPV-related morbidity among Hispanic women who are disproportionately affected by this disease. Understanding the barriers faced by this population is an important public health goal. In this qualitative pilot study, 17 mothers and grandmothers of adolescent girls from diverse Hispanic backgrounds in a large northeastern city in the United States were interviewed to examine attitudes regarding vaccine acceptability. The findings reveal that negative media, concerns about sexuality, side effects, and efficacy may impact vaccine uptake and completion. Of the 4 participants whose daughters had received the vaccine, only 1 had completed the full series, which may speak to the trend of lower series completion among Hispanics. This pilot data could inform important considerations when designing longitudinal research that may provide some necessary insights into the factors that facilitate or impede HPV vaccine completion among U.S. Hispanics. PMID:24865437

  8. Human papillomavirus infection in couples with female low-grade intraepithelial cervical lesion.

    PubMed

    Simon, Philippe; Roumeguere, Thierry; Christophe Noël, Jean

    2010-11-01

    Low-grade squamous intraepithelial lesions (LSIL) are frequently found during cervical cancer screening. Usually they are associated with a human papillomavirus (HPV) infection. Does the high-transmission rate of HPV infection to the male partner represent a clinical risk for him? Are preventive measures to be taken to prevent the occurrence of male diseases? More than 80% of all LSIL are associated with HPV infections. The prevalence of HPV infection in males can range up to 40%, with 60% of the male partners of LSIL female patients presenting with penile flat lesions. The spontaneous cure rate for male infections is very high (90% at 5 years) but negative consequences in females (cervical high-grade lesion and cervical cancer) are frequent. Their male counterparts are far rarer but in some patients can require deleterious treatment. Transmission prevention by the use of condoms and circumcision is discussed. The effectiveness of HPV vaccination in this situation has not been validated. PMID:20646823

  9. Telogen effluvium following bivalent human papillomavirus vaccine administration: a report of two cases.

    PubMed

    Tuccori, Marco; Pisani, Chiara; Bachini, Laura; Pardini, Milena; Mantarro, Stefania; Antonioli, Luca; Fornai, Matteo; Rubinelli, Marinella; Cirinei, Carlo; Blandizzi, Corrado

    2012-01-01

    We describe two cases of telogen effluvium occurring in two 11-year-old children following bivalent human papillomavirus (HPV) vaccine administration. The two children began to lose their hair following the second HPV vaccine dose. Alopecia worsened following the third vaccine dose and then resolved spontaneously within a few months. In both cases, laboratory analysis and psychiatric evaluation excluded causes other than anti-HPV vaccine. Social discomfort and isolation were associated with alopecia in the two children. The clinical presentation was consistent with a pattern of telogen effluvium. The identification of specific vaccine components responsible for triggering the adverse event remains difficult. In similar cases, suspension of immunization is not recommended, as it provides health benefits that overcome the possible adverse effect of transient telogen effluvium. Caregivers should ensure psychiatric support to their patients to manage the social and emotional distress that might be associated with hair loss. PMID:22584489

  10. Human Papillomavirus and Vaccination Of Males: Knowledge and Attitudes Of Registered Nurses.

    PubMed

    White, Leah; Waldrop, Julee; Waldrop, Cabe

    2016-01-01

    The American Academy of Pediatrics recommends the human papillomavirus (HPV) vaccine for all 11 to 12-year olds as part of the adolescent immunization platform. However, this vaccine has not been universally accepted by health care providers, parents, or the public, and has lower vaccination coverage rates than other recommended vaccines for the same age group. The purpose of this study was to determine registered nurses' knowledge and attitudes about HPV and associated HPV vaccine for males. One hundred eleven (111) RNs participated in a descriptive exploratory study using a survey method. Nurses were knowledgeable about specific HPV information but were less knowledgeable about the extent of HPV infection seen in males or the availability or indications of HPV vaccine for males. This study demonstrates that nurses need more education about HPV and HPV vaccine. PMID:27019938

  11. Optimized Formulation of a Thermostable Spray-Dried Virus-Like Particle Vaccine against Human Papillomavirus.

    PubMed

    Saboo, Sugandha; Tumban, Ebenezer; Peabody, Julianne; Wafula, Denis; Peabody, David S; Chackerian, Bryce; Muttil, Pavan

    2016-05-01

    Existing vaccines against human papillomavirus (HPV) require continuous cold-chain storage. Previously, we developed a bacteriophage virus-like particle (VLP)-based vaccine for HPV infection, which elicits broadly neutralizing antibodies against diverse HPV types. Here, we formulated these VLPs into a thermostable dry powder using a multicomponent excipient system and by optimizing the spray-drying parameters using a half-factorial design approach. Dry-powder VLPs were stable after spray drying and after long-term storage at elevated temperatures. Immunization of mice with a single dose of reconstituted dry-powder VLPs that were stored at 37 °C for more than a year elicited high anti-L2 IgG antibody titers. Spray-dried thermostable, broadly protective L2 bacteriophage VLPs vaccine could be accessible to remote regions of the world (where ∼84% of cervical cancer patients reside) by eliminating the cold-chain requirement during transportation and storage. PMID:27019231

  12. Journey of the Human Papillomavirus (HPV) in a Developing Country over 5 Years (2010 - 2015).

    PubMed

    Danial, M; Sivasangari, S; Arulappen, Al; Ong, Lm

    2016-01-01

    Human papillomavirus (HPV) is a prevalent sexually transmitted infection with serious medical, sexual, and relationship consequences. HPV vaccine protection is available globally but unfortunately vaccine uptake is inconsistent everywhere. From this study, it was observed that the awareness of cervical cancer, HPV virus and HPV vaccination in Malaysia is high, at 83.1%, 73.9% and 73.3% of respondents, respectively. However, a considerably low percentage had undergone HPV vaccination (8.6%) compared to those who had experienced a Pap smear (32.9%). Awareness between cervical cancer and HPV virus and vaccination was low. Health care providers and the governing bodies have to play a vital role in disseminating holistic information on the vaccine and the importance of getting vaccinated to the public more vigorously in Malaysia. PMID:27039773

  13. RECENT ADVANCES IN STRATEGIES FOR IMMUNOTHERAPY OF HUMAN PAPILLOMAVIRUS-INDUCED LESIONS

    PubMed Central

    Kanodia, Shreya; Da Silva, Diane M.; Kast, W. Martin

    2016-01-01

    Human papillomavirus (HPV)-induced lesions are distinct in that they have targetable foreign antigens, the expression of which is necessary to maintain the cancerous phenotype. Hence, they pose as a very attractive target for “proof of concept” studies in the development of therapeutic vaccines. This review will focus on the most recent clinical trials for the immunotherapy of mucosal and cutaneous HPV-induced lesions as well as emerging therapeutic strategies that have been tested in pre-clinical models for HPV-induced lesions. Progress in peptide-based vaccines, DNA-based vaccines, viral/bacterial vector-based vaccines, immune response modifiers, photodynamic therapy and T cell receptor based therapy for HPV will be discussed. PMID:17973257

  14. Concurrent Human Papillomavirus-Positive Squamous Cell Carcinoma of the Oropharynx in a Married Couple

    PubMed Central

    García, Joaquín J.; Price, Katharine A.; Gao, Ge; Smith, David I.

    2016-01-01

    Background. Although alcohol and tobacco use are known risk factors for development of squamous cell carcinoma in the head and neck, human papillomavirus (HPV) has been increasingly associated with this group of cancers. We describe the case of a married couple who presented with HPV-positive oropharynx squamous cell carcinoma within two months of each other. Methods. Tumor biopsies were positive for p16 and high-risk HPV in both patients. Sanger sequencing showed a nearly identical HPV16 strain in both patients. Both patients received chemoradiation, and one patient also underwent transoral robotic tongue base resection with bilateral neck dissection. Results. Both patients showed no evidence of recurrent disease on follow-up PET imaging. Conclusions. New head and neck symptoms should be promptly evaluated in the partner of a patient with known HPV-positive oropharynx cancer. This case expands the limited current literature on concurrent presentation of HPV-positive oropharynx squamous cell carcinoma in couples. PMID:27418994

  15. Association of Genital Infections Other Than Human Papillomavirus with Pre-Invasive and Invasive Cervical Neoplasia

    PubMed Central

    Mandal, Ranajit; Kundu, Pratip; Biswas, Jaydip

    2016-01-01

    Human papillomavirus (HPV) is a well-established causative agent of malignancy of the female genital tract and a common Sexually Transmitted Infection. The probable co-factors that prevent spontaneous clearance of HPV and progression to neoplasia are genital tract infections from organisms like Chlamydia, Trichomonas vaginalis etc, smoking, nutritional deficiencies and multiparity. Inflammatory conditions can lead to pre-neoplastic manifestations in the cervical epithelium; however their specific role in cervical carcinogenesis is not yet established. Therefore it is imperative to study the likely association between HPV and co-infection with various common pathogens in the genital tract of women having cervical precancer or cancer. A “Pubmed” search was made for articles in Literature on this topic using the words: Cervical neoplasia, HPV, co-infections, Cervical Intraepithelial Neoplasia (CIN), Trichomonas vaginalis, Candida, Chlamydia and the relevant information obtained was used to draft the review. PMID:27042571

  16. Human papillomavirus-related squamous cell carcinoma of the anal canal with papillary features

    PubMed Central

    Leon, Marino E; Shamekh, Rania; Coppola, Domenico

    2015-01-01

    Human papillomavirus (HPV) related squamous cell carcinoma (SCC) involving the anal canal is a well-known carcinoma associated with high-risk types of HPV. HPV-related SCC with papillary morphology (papillary SCC) has been described in the oropharynx. We describe, for the first time, a case of anal HPV-related squamous carcinoma with papillary morphology. The tumor arose from the anal mucosa. The biopsies revealed a superficially invasive SCC with prominent papillary features and associated in situ carcinoma. The tumor cells were positive for p16 and were also positive for high-risk types of HPV using chromogenic in situ hybridization. The findings are consistent with a HPV-related SCC of the anal canal with papillary features. This tumor shows histologic features similar to a papillary HPV-related SCC of the oropharynx. Additional studies are needed to characterize these lesions. PMID:25717259

  17. Social Cognitive Theory Predictors of Human Papillomavirus Vaccination Intentions of College Men at a Southeastern University.

    PubMed

    Priest, Hannah M; Knowlden, Adam P; Sharma, Manoj

    2015-01-01

    The purpose of this study was to use social cognitive theory to predict human papillomavirus (HPV) vaccination intentions of college men attending a large, southeastern university. Data collection comprised two phases. Phase I established face and content validity of the instrument by a panel of six experts. Phase II assessed internal consistency reliability using Cronbach's alpha and predicted behavioral intentions applying multiple linear regression. HPV knowledge, expectations, self-efficacy to get HPV vaccine, situational perception, self-efficacy in overcoming barriers to get HPV vaccine, and self-control to get HPV vaccine were regressed on behavioral intentions. Situational perception and self-control to get HPV vaccine were significant predictors, accounting for 22% of variance in behavioral intentions to get vaccinated within the next 6 months. Overall, college men reported low behavioral intentions to getting vaccinated. Future interventions should target situational perception and self-control to increase HPV vaccination intentions. PMID:26470399

  18. [Research progress in roles of high-risk human papillomavirus E2 protein].

    PubMed

    Wu, En-Qi; Tang, Yuan-Yu

    2014-03-01

    High-risk human papillomavirus (HPV) is the principal cause of various cancers including cervical cancer, anal cancer, vulvar cancer, and some head and neck cancers. In the viral life cycle, by interacting with both viral and host DNA and proteins, the HPV E2 protein plays a pivotal role in viral transcriptional regulation and DNA replication, and it is also associated with modification of various cellular processes, including host gene transcription, RNA processing, apoptosis, ubiquitination, and intracellular trafficking, to create a convenient environment for a replicative cycle of the virus and contribute to the HPV pathogenesis. Elucidating the roles of E2 protein throughout the viral life cycle will improve our understanding of the viral life cycle and pathogenesis and help us identify novel antiviral agents with therapeutic potential. This article reviews the research progress in the structure, roles, and activity of high-risk HPV E2 protein, particularly that of HPV-16. PMID:24923176

  19. Anal human papillomavirus infection: prevalence, diagnosis and treatment of related lesions.

    PubMed

    Benevolo, Maria; Donà, Maria Gabriella; Ravenda, Paola Simona; Chiocca, Susanna

    2016-05-01

    Human papillomavirus (HPV) infection is mostly asymptomatic, but may also have many diverse clinical signs encompassing benign ano-genital lesions, and carcinomas. Recently, interest has also particularly focused on anal cancer since, over the last decades, its incidence has been greatly increasing in developed countries, both in women and men and is drastically higher in specific risk groups, such as men who have sex with men (MSM) and HIV-1 infected individuals. Approximately 88% of anal cancer cases worldwide are associated with HPV infection. This review summarizes our current understanding of anal HPV infection, discussing its epidemiology and risk factors in various populations, and the state of the art in the detection of anal HPV infection and its related lesions through both cytology and histology. Finally, we discuss the clinical management and therapy for these lesions. PMID:27050294

  20. The potential health and economic benefits of preventing recurrent respiratory papillomatosis through quadrivalent human papillomavirus vaccination.

    PubMed

    Chesson, Harrell W; Forhan, Sara E; Gottlieb, Sami L; Markowitz, Lauri E

    2008-08-18

    We estimated the health and economic benefits of preventing recurrent respiratory papillomatosis (RRP) through quadrivalent human papillomavirus (HPV) vaccination. We applied a simple mathematical model to estimate the averted costs and quality-adjusted life years (QALYs) saved by preventing RRP in children whose mothers had been vaccinated at age 12 years. Under base case assumptions, the prevention of RRP would avert an estimated USD 31 (range: USD 2-178) in medical costs (2006 US dollars) and save 0.00016 QALYs (range: 0.00001-0.00152) per 12-year-old girl vaccinated. Including the benefits of RRP reduced the estimated cost per QALY gained by HPV vaccination by roughly 14-21% in the base case and by <2% to >100% in the sensitivity analyses. More precise estimates of the incidence of RRP are needed, however, to quantify this impact more reliably. PMID:18598734

  1. Human papillomavirus: prevalence and factors associated in women prisoners population from the Eastern Brazilian Amazon.

    PubMed

    de Aguiar, Sylvia Regina Vasconcellos; Villanova, Fabiola Elizabeth; Martins, Luisa Carício; dos Santos, Milena Silva; Maciel, Juliana de Paula; Falcão, Luiz Fábio Magno; Fuzii, Hellen Thais; Quaresma, Juarez Antônio Simões

    2014-09-01

    This study aimed to examine the prevalence of human papillomavirus (HPV) and the associated factors among female prisoners in Ananindeua City, State of Pará, Brazil. In 2010, 190 cervical samples were obtained, and Pap smear and polymerase chain reaction (GE Health Care™, Uppsala, Sweden) were performed. Additionally, a questionnaire was used. The prevalence of HPV was 10.5%, and the presence of cervical intraepithelial neoplasia grade I (n = 33, 17.5%; P < 0.1) was associated with HPV infection. The presence of low-grade squamous intraepithelial lesions was greater in women with HPV than in those without HPV infection, indicating that HPV infection is a risk factor for such injuries and that viral screening and prevention are extremely important in public health among female prisoners in Amazon. PMID:24838771

  2. Epidemiology of Human Papillomavirus-Positive Head and Neck Squamous Cell Carcinoma.

    PubMed

    Gillison, Maura L; Chaturvedi, Anil K; Anderson, William F; Fakhry, Carole

    2015-10-10

    Human papillomavirus (HPV) is now established as the principal cause of an increase in incidence of a subset of head and neck squamous cell cancers (HNCs) in numerous geographic regions around the world. Further study of the epidemiology of HPV-positive HNC will be critical to the development and implementation of public health interventions to reverse these global incidence trends. Here, recent data are reviewed to provide insight into several topics, including incidence trends and projections for HPV-positive HNC; the worldwide HPV-attributable fraction; sex disparities in cancer risk; the epidemiology of oral HPV infection; the latency period between infection and cancer; the potential impact of prophylactic HPV vaccination; and prospects for secondary prevention through screening for oral HPV infection or seroreactivity to viral antigens. The identification of a single necessary cause for any cancer provides a rare and perhaps extraordinary opportunity for cancer prevention. PMID:26351338

  3. Recurrent optic neuritis and neuromyelitis optica-IgG following first and second human papillomavirus vaccinations.

    PubMed

    Chang, Hyeyeon; Lee, Hye Lim; Yeo, Minju; Kim, Ji Seon; Shin, Dong-Ick; Lee, Sang-Soo; Lee, Sung-Hyun

    2016-05-01

    Human papillomavirus (HPV) vaccine is widely used to prevent cervical cancer caused by certain types of HPV in girls and young women. Demyelinating disorders within months following HPV innoculation have been reported, but the causal link between HPV vaccination and the onset of demyelinating disorders have not been certain. We report a case of neuromyelitis optica spectrum disorder (NMOSD) that was noteworthy because optic neuritis (ON) occurred in a very close temporal association with both the first and second HPV vaccinations, which might suggest an association between HPV vaccination and the development of NMO-IgG and recurrent ON. This emphasizes the necessity for continuing surveillance for adverse events after HPV vaccination. PMID:27046292

  4. Cumulative Impact of HIV and Multiple Concurrent Human Papillomavirus Infections on the Risk of Cervical Dysplasia.

    PubMed

    Adler, David H; Wallace, Melissa; Bennie, Thola; Abar, Beau; Meiring, Tracy L; Williamson, Anna-Lise; Bekker, Linda-Gail

    2016-01-01

    Infection with HIV is known to increase the risk of cervical cancer. In addition, evidence suggests that concurrent infection with multiple human papillomavirus (HPV) genotypes increases the risk of cervical dysplasia more than infection with a single HPV genotype. However, the impact of the combination of HIV coinfection and presence of multiple concurrent HPV infections on the risk of cervical dysplasia is uncertain. We compared the results of HPV testing and Pap smears between HIV-infected and HIV-uninfected young women to assess the cumulative impact of these two conditions. We found that both HIV and the presence of multiple concurrent HPV infections are associated with increased risk of associated Pap smear abnormality and that the impact of these two risk factors may be additive. PMID:26997954

  5. [Research progress regarding the clinical evaluation on recombinant human papillomavirus vaccines].

    PubMed

    He, W G; Zhao, J; Huang, S J; Wu, T

    2016-06-01

    Human papillomavirus (HPV) is the main cause for cervical cancer, anogenital cancers and genital warts. Three HPV vaccines have been licensed abroad. Data from clinical trials showed high efficacy of the HPV vaccines in young women with 90%-100% vaccine-related HPV diseases prevented. Though efficacy of the vaccine appears lower in older women, this population can still benefit from vaccination. Immunobriging trials show that the two-dose schedule in 9-14 years old girls elicits non-inferior immune response than the three-dose one in young adults. In addition, HPV vaccines can reduce the recurrent rates in CIN2+ patients after therapeutic surgery and the vaccines have cross-protection aganist diseases caused by non-vaccine type HPV. Safety data on HPV vaccines are assuring. Thus HPV vaccine should be widely used in adolescent girls and women of appropriate age groups. PMID:27346126

  6. Comparison of p53 and the PDZ domain containing protein MAGI-3 regulation by the E6 protein from high-risk human papillomaviruses

    PubMed Central

    Ainsworth, Julia; Thomas, Miranda; Banks, Lawrence; Coutlee, Francois; Matlashewski, Greg

    2008-01-01

    Central to cellular transformation caused by human papillomaviruses (HPVs) is the ability of E6 proteins to target cellular p53 and proteins containing PDZ domains, including MAGI-3, for degradation. The aim of this study was to compare E6-mediated degradation of p53 and MAGI-3 under parallel experimental conditions and further with respect to the involvement of proteasomes and ubiquitination. We also compared the degradation of p53 and MAGI-3 by E6 from several HPV types including different variants from HPV-33. All of the E6 genes from different HPV types displayed similar abilities to mediate the degradation of both p53 and MAGI-3 although there may be subtle differences observed with the different 33E6 variants. There were however differences in E6 mediated degradation of p53 and MAGI-3. Proteasome inhibition assays partially protected p53 from E6 mediated degradation, but did not protect MAGI-3. In addition, under conditions where p53 was ubiquitinated by E6 and MDM2 in vivo, ubiquitination of MAGI-3 was not detected. These results imply that although both p53 and MAGI-3 represent effective targets for oncogenic E6, the mechanisms by which E6 mediates p53 and MAGI-3 degradation are distinct with respect to the involvement of ubiquitination prior to proteasomal degradation. PMID:18518978

  7. Prevention of Persistent Human Papillomavirus Infection by an HPV16/18 Vaccine: A Community-Based Randomized Clinical Trial in Guanacaste, Costa Rica

    PubMed Central

    Herrero, Rolando; Wacholder, Sholom; Rodríguez, Ana C.; Solomon, Diane; González, Paula; Kreimer, Aimee R.; Porras, Carolina; Schussler, John; Jiménez, Silvia; Sherman, Mark E.; Quint, Wim; Schiller, John T.; Lowy, Douglas R.; Schiffman, Mark; Hildesheim, Allan

    2011-01-01

    Target groups for human papillomavirus (HPV) vaccination are controversial. We evaluated vaccine efficacy (VE) against 1-year persistent infection, stratified by age and sexual behavior, among young women in Costa Rica. We randomized 7,466 healthy women 18 to 25 years of age to HPV16/18 or hepatitis A vaccine (follow-up, 50.4 months). According-to-protocol (ATP) cohorts included compliant HPV-negative women; intention-to-treat (ITT) included all randomized women. ATP VE was 90.9% (95% CI, 82.0–95.9) against HPV16/18 infections, 44.5% against HPV31/33/45 (95% CI, 17.5–63.1), and 12.4% (95% CI, −3.2 to 25.6) against any oncogenic infection. Overall ITT VE against HPV16/18 infections was 49.0%, but ATP and ITT VE almost reached 100% in year 4 of follow-up. ATP efficacy against HPV16/18 was similar by age, but ITT VE was greatest among youngest women (68.9% among those 18–19 years of age; 21.8% among those 24–25 years of age) and 79.8% among virgins. Among previously unexposed women, vaccination is highly efficacious against HPV16/18 and partially against HPV31/33/45. Vaccination is most effective in women and girls before they initiate sexual activity, with programmatic and individual decision implications. PMID:22586631

  8. Use of quadrivalent human papillomavirus vaccine and the prevalence of antibodies to vaccine-targeted strains among female service members before and after vaccination.

    PubMed

    Hurt, Lee; Nsouli-Maktabi, Hala; Rohrbeck, Patricia; Clark, Leslie L

    2016-02-01

    The quadrivalent human papillomavirus vaccine (HPV4) has been shown to generate a robust immune response among fully vaccinated individuals; however, among U.S. service members, HPV vaccine completion rates are low. This study compared the immunogenicity of HPV4 vaccine among partially and fully vaccinated service members at 4-6 years post-vaccination. A random sample was obtained of 2,091 female service members, aged 17-26 years, who received 1-3 HPV4 doses during 2006-2012, stratified by number of doses (one, two, or three). Pre- and post-immunization sera from these service members were tested for antibodies to the HPV strains covered by the vaccine. Prior to immunization 42% were seropositive for HPV strain 6; 34% for strain 11; 29% for strain 16; and 16% for strain 18. Among those naive to all four strains prior to immunization, there was 100% seroconversion after one, two, or three doses. The results indicate that many service members had already been exposed to strains of HPV prior to receiving the vaccine; however, seropositivity prevalence was lower for the oncogenic HPV strains 16 and 18. The data demonstrate sustained immunogenicity after a single dose of vaccine, with modest improvement with successive doses for all strains except 18. PMID:26930146

  9. Knowledge of human papillomavirus and its association with head and neck benign and malignant lesions in a group of dental patients in pakistan.

    PubMed

    Gichki, Abdul Samad; Buajeeb, Waranun; Doungudomdacha, Sombhun; Khovidhunkit, Siribang-On Pibooniyom

    2015-01-01

    Human papillomaviruses (HPVs) remain a serious world health problem due to their association with cervical and head and neck cancers. While over 100 HPV types have been identified, only a few subtypes are associated with malignancies. HPV 16 and 18 are the most prevalent oncogenic types in head and neck cancers. Although it has been proven that some subsets of benign and malignant head and neck lesions are associated with HPV, the general population have very little awareness and knowledge of their association with HPV. Therefore, the purpose of this study was to determine the knowledge of HPV and its links with head and neck benign and malignant lesions in a group of Pakistani dental patients who attended the Dental Department of the Sandeman provincial hospital in Quetta, Pakistan. One hundred and ninety-two patients were recruited and requested to answer a questionnaire. It was revealed that there was a low level of knowledge about HPV and its association with head and neck benign and malignant lesions among the participants. This result suggested that more education regarding the relationship of HPV in inducing head and neck benign and malignant lesions is required in this group of patients. PMID:25743835

  10. A C-terminal Hydrophobic, Solvent-protected Core and a Flexible N-terminus are Potentially Required for Human Papillomavirus 18 E7 Protein Functionality

    SciTech Connect

    Liu, S.; Tian, Y; Greenaway, F; Sun, M

    2010-01-01

    The oncogenic potential of the high-risk human papillomavirus (HPV) relies on the expression of genes specifying the E7 and E6 proteins. To investigate further the variation in oligomeric structure that has been reported for different E7 proteins, an HPV-18 E7 cloned from a Hispanic woman with cervical intraepithelial neoplasia was purified to homogeneity most probably as a stable monomeric protein in aqueous solution. We determined that one zinc ion is present per HPV-18 E7 monomer by amino acid and inductively coupled plasma-atomic emission spectroscopy analysis. Intrinsic fluorescence and circular dichroism spectroscopic results indicate that the zinc ion is important for the correct folding and thermal stability of HPV-18 E7. Hydroxyl radical mediated protein footprinting coupled to mass spectrometry and other biochemical and biophysical data indicate that near the C-terminus, the four cysteines of the two Cys-X{sub 2}-Cys motifs that are coordinated to the zinc ion form a solvent inaccessible core. The N-terminal LXCXE pRb binding motif region is hydroxyl radical accessible and conformationally flexible. Both factors, the relative flexibility of the pRb binding motif at the N-terminus and the C-terminal metal-binding hydrophobic solvent-protected core, combine together and facilitate the biological functions of HPV-18 E7.

  11. Human papillomavirus (HPV)-16/18 AS04-adjuvanted vaccine for the prevention of cervical cancer and HPV-related diseases.

    PubMed

    Skinner, S Rachel; Apter, Dan; De Carvalho, Newton; Harper, Diane M; Konno, Ryo; Paavonen, Jorma; Romanowski, Barbara; Roteli-Martins, Cecilia; Burlet, Nansa; Mihalyi, Attila; Struyf, Frank

    2016-01-01

    Vaccines are available against human papillomavirus (HPV), the causal agent of cervical and other cancers. Efficacy data from the HPV-16/18 AS04-adjuvanted vaccine clinical trial program were reviewed. Six randomized, controlled phase II/III trials evaluating cervical endpoints enrolled women from diverse populations and geographical locations. The program analyzed extensively the cohorts most relevant from a public health perspective: the total vaccinated cohort (TVC), approximating a general population including those with existing or previous HPV infection, and TVC-naïve, approximating a population of young women before sexual debut. Results show that the vaccine reduces HPV-16/18 infection and associated cervical endpoints in women regardless of age, location, or sexual experience. It provides cross-protection against some non-vaccine oncogenic HPV types and types causing genital warts, and may be effective against vulvar, oral, and anal HPV infection. Early epidemiology data following its introduction suggest a decline in the prevalence of vaccine and some non-vaccine HPV types. PMID:26902666

  12. HLA-DP is the cervical cancer susceptibility loci among women infected by high-risk human papillomavirus: potential implication for triage of human papillomavirus-positive women.

    PubMed

    Jia, Meiqun; Han, Jing; Hang, Dong; Jiang, Jie; Wang, Minjie; Wei, Baojun; Dai, Juncheng; Zhang, Kai; Guo, Lanwei; Qi, Jun; Ma, Hongxia; Shi, Jufang; Ren, Jiansong; Hu, Zhibin; Dai, Min; Li, Ni

    2016-06-01

    Given that only a small proportion of women infected by high-risk human papillomavirus (hrHPV) develop cervical cancer, it's important to identify biomarkers for distinguishing women with hrHPV positivity who might develop cervical cancer from the transient infections. In this study, we hypothesized that human leukocyte antigens (HLA) susceptibility alleles might contribute to cervical cancer risk among females infected by hrHPV, and interact with hrHPV types. A case-control study with 593 cervical cancer cases and 407 controls (all hrHPV positive) was conducted to evaluate the effect of eight HLA-related single-nucleotide polymorphisms (SNPs) and their interactions with hrHPV types on the risk of cervical cancer. Three HLA-DP SNPs (rs4282438, rs3117027, and rs3077) were found to be significantly associated with risk of cervical cancer (rs4282438: odds ratio (OR) = 0.72, 95 % confidence interval (CI) = 0.56-0.93; rs3117027: OR = 1.41, 95 % CI = 1.10-1.83; and rs3077: OR = 1.37, 95 % CI = 1.04-1.80) among women infected with hrHPV. An additive interaction between HPV16 and rs4282438 for cervical cancer risk was also found (P for interaction = 0.002). Compared with subjects carrying variant genotypes (GG/TG) and non-HPV16 infections, those carrying wild-type genotype (TT) of rs4282438 and HPV16 positive had a 5.22-fold increased risk of cervical cancer (95 % CI = 3.39-8.04). Our study supported that certain HLA-DP alleles in concert with HPV16 could have a predisposition for cervical cancer development, which may be translated for triage of hrHPV-positive women. PMID:26711785

  13. Mapping of Betapapillomavirus Human Papillomavirus 5 Transcription and Characterization of Viral-Genome Replication Function

    PubMed Central

    Sankovski, Eve; Männik, Andres; Geimanen, Jelizaveta; Ustav, Ene

    2014-01-01

    Betapapillomavirus replication and transcription have not been studied in detail because of a lack of suitable cellular systems supporting human papillomavirus (HPV) genome replication. We have recently shown that the human osteosarcoma cell line U2OS provides a useful environment for the genome replication of many different HPVs, including the betapapillomaviruses HPV5 and HPV8. Using mutational analysis and complementation assay, we demonstrated herein that the viral early proteins E1 and E2 are viral transfactors that are necessary and sufficient for HPV5 genome replication. We also identified four HPV5 early promoter regions with transcription start sites (TSSs) at nucleotides (nt) 184/191, 460, 840, and 1254, respectively, and the HPV late promoter with a TSS at nt 7640. In addition, we mapped the HPV5 early polyadenylation cleavage sites via 3′ rapid amplification of cDNA ends (3′RACE) to nt 4457 and 4475. In total, 14 different viral mRNA species, originating from the HPV5 genome, were mapped in U2OS cells during transient and stable replication. The main splicing donor and acceptor sites identified herein are consistent with the data previously obtained in HPV5-positive skin lesions. In addition, we identified novel E8 open reading frame (ORF)-containing transcripts (E8^E1C and E8^E2C) expressed from the HPV5 genome. Similar to several other papillomaviruses, the product of the E8^E2C mRNA acts as a repressor of viral genome replication. PMID:24198410

  14. In vivo expression of immunosuppressive cytokines in human papillomavirus-transformed cervical cancer cells.

    PubMed

    Alcocer-González, Juan Manuel; Berumen, Jaime; Taméz-Guerra, Reyes; Bermúdez-Morales, Víctor; Peralta-Zaragoza, Oscar; Hernández-Pando, Rogelio; Moreno, José; Gariglio, Patricio; Madrid-Marina, Vicente

    2006-01-01

    Genital human Papillomavirus infection is common and only a minor fraction of infected subjects develop progressing cervical epithelial lesions or cancer. Bypassing local immune responses is important for the development of cervical cancer. In this work we determined the cytokine pattern in samples from patients with cervical cancer. Thus, we examined the local mRNA expression profile of helper T cell type 1 (Th1), Th2, and Th3 cytokines in HPV-positive cervical cancer biopsies by reverse transcription-polymerase chain reaction. Our data indicate that 80% of the tumors expressed low levels of CD4 mRNA, with all of them expressing higher CD8 mRNA levels. Most tumors expressed interleukin (IL)-4 and IL-10 mRNAs and, most importantly, all of them expressed transforming growth factor (TGF)-beta1 and interferon gamma mRNA. None of the tumors studied expressed IL-12, IL-6, or tumor necrosis factor (TNF) mRNA. Immunohistochemical analysis identified IL-10 only in tumor cells and koilocytic cells, but not in tumor-infiltrating lymphocytes, suggesting that IL-10-producing cells are those transformed by HPV. We found a correlation between immunostaining for IL-10 protein and the level of IL-10 mRNA expression. Moreover, supernatants from HPV-transformed cell cultures contained IL-10 and TGF- beta1. Our findings indicate a predominant expression of immunosuppressive cytokines, which might help downregulate tumor-specific immune responses in the microenvironment of the tumor. This information may be useful for cervical cancer immunotherapies or for therapeutic vaccine design against Human Papillomavirus. PMID:16987066

  15. Characteristics of bacterial vaginosis infection in cervical lesions with high risk human papillomavirus infection

    PubMed Central

    Lu, Huan; Jiang, Peng-Cheng; Zhang, Xiao-Dan; Hou, Wen-Jing; Wei, Zhen-Hong; Lu, Jia-Qi; Zhang, Hao; Xu, Guang-Xu; Chen, Yuan-Ping; Ren, Yuan; Wang, Li; Zhang, Rong; Han, Ying

    2015-01-01

    High risk human papillomavirus (HPV) infection is the major cause of cervical cancer. Bacterial vaginosis (BV) is considered as the most prevalent vaginal imbalance affecting women of reproductive age. However, the relationship between HPV and BV infection is unclear. This study aimed to assess the prevalence of human papillomavirus (HPV) infection combined with bacterial vaginosis (BV) infection in Shanghai suburbs and evaluate associations between bacterial vaginosis with HPV infection, cervical intraepithelial neoplasia (CIN) and cervical cancer. Methods: From October 1, 2009 to October 31, 2013, a total number of 3502 women who visited Fengxian Hospital, Southern Medical University were enrolled in this study. All participants gave informed consent and agreed to HPV, BV, chlamydia, mycoplasma and thinprepcytologic test (TCT). In addition, all women took histopathologic examination under colposcopy. Statistical analyses were done using SPSS 17.0 for windows (IBM). In present study the overall BV-positive rate was 9.25%. The top three high risk HPV types were listed as follows (in descending order): HPV16, 52, 58. Moreover, our data showed BV infection tended to occur in the HPV positive women, HPV infection also tended to occur in the BV positive women. Most of the women who present HPV with BV infection were younger than 30 years old. We also found that CIN and cervical cancer occurred mainly in HPV/BV positive and HPV with BV positive group. BV infection and HPV infection may haveconsistency or synergies. HPV with BV infection may increase the incidence of CIN and cervical cancer. PMID:26885039

  16. BCR first exon sequences specifically activate the BCR/ABL tyrosine kinase oncogene of Philadelphia chromosome-positive human leukemias

    SciTech Connect

    Muller, A.J.; Witte, O.N. ); Young, J.C.; Pendergast, A.; Pondel, M. ); Landau, N.R.; Littman, D.R. )

    1991-04-01

    The c-abl proto-oncogene encodes a cytoplasmic tyrosine kinase which is homologous to the src gene product in its kinase domain and in the upstream kinase regulatory domains SH2 (src homology region 2) and SH3 (src homology region 3). The murine v-abl oncogene product has lost the SH3 domain as a consequence of N-terminal fusion of gag sequences. Deletion of the SH3 domain is sufficient to render the murine c-abl proto-oncogene product transforming when myristylated N-terminal membrane localization sequences are also present. In contrast, the human BCR/ABL oncogene of the Philadelphia chromosome translocation has an intact SH3 domain and its product is not myristylated at the N terminus. To analyze the contribution of BCR-encoded sequences to BCR/ABL-mediated transformation, the effects of a series of deletions and substitutions were assessed in fibroblast and hematopoietic-cell transformation assays. BCR first-exon sequences specifically potentiate transformation and tyrosine kinase activation when they are fused to the second exon of otherwise intact c-ABL. This suggests that BCR-encoded sequences specifically interfere with negative regulation of the ABL-encoded tyrosine kinase, which would represent a novel mechanism for the activation of nonreceptor tyrosine kinase-encoding proto-oncogenes.

  17. Increased Incidence of Squamous Cell Carcinomas in Mastomys natalensis Papillomavirus E6 Transgenic Mice during Two-Stage Skin Carcinogenesis

    PubMed Central

    Helfrich, Iris; Chen, Min; Schmidt, Rainer; Fürstenberger, Gerhard; Kopp-Schneider, Annette; Trick, David; Gröne, Hermann-Josef; zur Hausen, Harald; Rösl, Frank

    2004-01-01

    Papillomaviruses cause certain forms of human cancers, most notably carcinomas of the uterine cervix. In contrast to the well-established involvement of papillomavirus infection in the etiology of cervical carcinomas and in carcinomas of a rare hereditary condition, epidermodysplasia verruciformis, a causative role for cutaneous human papillomavirus types in the development of nonmelanoma skin cancer has not been proven. In order to better understand the functions of individual genes of cutaneous papillomavirus types, we generated transgenic mice carrying oncogene E6 of the Mastomys natalensis papillomavirus (MnPV), which causes keratoacanthomas of the skin in its natural host. In the present study, we demonstrate that under conditions of experimental two-stage skin carcinogenesis, fast-paced squamous cell carcinomas develop in nearly 100% of MnPV E6 transgenic mice in comparison to 10% in their nontransgenic littermates (log rank test; P < 0.0001). Therefore, we conclude that the MnPV E6 transgene favors the malignant progression of chemically induced tumors. Whereas an activating H-ras mutation is a consistent feature in benign and malignant tumors in wild-type mice, the majority of papillomas and keratoacanthomas and all squamous cell carcinomas obtained in MnPV E6 transgenic mice contain nonmutated ras alleles. These results indicate that the development of squamous cell carcinomas in MnPV E6 transgenic mice does not depend on an activated H-ras oncogene. PMID:15078961

  18. Oncogenic KRAS activates an embryonic stem cell-like program in human colon cancer initiation

    PubMed Central

    Le Rolle, Anne-France; Chiu, Thang K.; Zeng, Zhaoshi; Shia, Jinru; Weiser, Martin R.; Paty, Philip B.; Chiu, Vi K.

    2016-01-01

    Colorectal cancer is the third most frequently diagnosed cancer worldwide. Prevention of colorectal cancer initiation represents the most effective overall strategy to reduce its associated morbidity and mortality. Activating KRAS mutation (KRASmut) is the most prevalent oncogenic driver in colorectal cancer development, and KRASmut inhibition represents an unmet clinical need. We apply a systems-level approach to study the impact of KRASmut on stem cell signaling during human colon cancer initiation by performing gene set enrichment analysis on gene expression from human colon tissues. We find that KRASmut imposes the embryonic stem cell-like program during human colon cancer initiation from colon adenoma to stage I carcinoma. Expression of miR145, an embryonic SC program inhibitor, promotes cell lineage differentiation marker expression in KRASmut colon cancer cells and significantly suppresses their tumorigenicity. Our data support an in vivo plasticity model of human colon cancer initiation that merges the intrinsic stem cell properties of aberrant colon stem cells with the embryonic stem cell-like program induced by KRASmut to optimize malignant transformation. Inhibition of the embryonic SC-like program in KRASmut colon cancer cells reveals a novel therapeutic strategy to programmatically inhibit KRASmut tumors and prevent colon cancer. PMID:26744320

  19. Factors predicting the persistence of genital human papillomavirus infections and PAP smear abnormality in HIV-positive and HIV-negative women during prospective follow-up.

    PubMed

    Branca, M; Garbuglia, A R; Benedetto, A; Cappiello, T; Leoncini, L; Migliore, G; Agarossi, A; Syrjänen, K

    2003-06-01

    As part of an extensive multi-institutional DIANAIDS study focused on assessing the risk factors, natural history, diagnosis and follow-up of genital human papillomavirus (HPV) infections in HIV-infected women, the present communication reports a sub-cohort of 142 women (89 HIV+ and 48 HIV-), followed-up for a mean of 14.07 (+/-10.84) months to analyse the factors predicting the persistence and clearance of HPV infections (polymerase chain reaction [PCR] and sequencing) and cervical Papanicolaou (PAP) smear abnormalities, using both univariate (Kaplan-Meier) and multivariate (Cox) survival analysis. The appearance of new HPV infections during the follow-up was significantly more frequent in HIV-positive than in HIV-negative women, odds ratio (OR) 8.800 (95% confidence interval [CI]: 1.199-64.611), and also the clearance rate was significantly less frequent in HIV-positive than in HIV-negative women, 69.2% vs 22.8%, respectively (OR 0.330; 95% CI: 0.163-0.670). These two groups were also markedly different with respect to the clinical course of the cervical lesions, in the frequency of progressive disease (determined by PAP smear) was higher in HIV-positive group (12/89) than in HIV-negative women (2/52) (OR 3.506; 95% CI 0.816-15.055) (P = 0.055), in whom the disease regressed more frequently than in HIV-positive women (13.5% vs 7.9%) (OR 0.584; 95% CI 0.217-1.573). Using (1) HPV-positivity, (2) oncogenic HPV-type and (3) significant PAP smear abnormality at the end of follow-up as outcome measures, (1) was significantly (P < 0.001) predicted by the following variables in univariate analysis: age, mode of contraception, CD4 count, and HIV-positivity. The significant predictors of (2) were age and mode of contraception. The outcome measure (3) was significantly predicted by CD4 count, PAP smear abnormality and PCR status at entry. In the multivariate analysis, the significant independent predictive factors for HPV-positivity proved to be only the HIV status (P < 0

  20. Oncogenic Intra-p53 Family Member Interactions in Human Cancers

    PubMed Central

    Ferraiuolo, Maria; Di Agostino, Silvia; Blandino, Giovanni; Strano, Sabrina

    2016-01-01

    The p53 gene family members p53, p73, and p63 display several isoforms derived from the presence of internal promoters and alternative splicing events. They are structural homologs but hold peculiar functional properties. p53, p73, and p63 are tumor suppressor genes that promote differentiation, senescence, and apoptosis. p53, unlike p73 and p63, is frequently mutated in cancer often displaying oncogenic “gain of function” activities correlated with the induction of proliferation, invasion, chemoresistance, and genomic instability in cancer cells. These oncogenic functions are promoted either by the aberrant transcriptional cooperation of mutant p53 (mutp53) with transcription cofactors (e.g., NF-Y, E2F1, Vitamin D Receptor, Ets-1, NF-kB and YAP) or by the interaction with the p53 family members, p73 and p63, determining their functional inactivation. The instauration of these aberrant transcriptional networks leads to increased cell growth, low activation of DNA damage response pathways (DNA damage response and DNA double-strand breaks response), enhanced invasion, and high chemoresistance to different conventional chemotherapeutic treatments. Several studies have clearly shown that different cancers harboring mutant p53 proteins exhibit a poor prognosis when compared to those carrying wild-type p53 (wt-p53) protein. The interference of mutantp53/p73 and/or mutantp53/p63 interactions, thereby restoring p53, p73, and p63 tumor suppression functions, could be among the potential therapeutic strategies for the treatment of mutant p53 human cancers. PMID:27066457