scholarly journals Preclinical development of highly effective and safe DNA vaccines directed against HPV 16 E6 and E7

2011 ◽  
Vol 129 (2) ◽  
pp. 397-406 ◽  
Author(s):  
Koen Oosterhuis ◽  
Peter Öhlschläger ◽  
Joost H. van den Berg ◽  
Mireille Toebes ◽  
Raquel Gomez ◽  
...  
Keyword(s):  
Dna Vaccines ◽  
Preclinical Development ◽  
Hpv 16 ◽  
Highly Effective ◽  
E6 And E7

scholarly journals Multiple ASF/SF2 Sites in the Human Papillomavirus Type 16 (HPV-16) E4-Coding Region Promote Splicing to the Most Commonly Used 3′-Splice Site on the HPV-16 Genome

2010 ◽  
Vol 84 (16) ◽  
pp. 8219-8230 ◽  
Author(s):  
Monika Somberg ◽  
Stefan Schwartz
Keyword(s):  
Cervical Cancer ◽  
Human Papillomavirus ◽  
Splice Site ◽  
Binding Sites ◽  
Mrna Levels ◽  
Coding Region ◽  
Cervical Lesions ◽  
Hpv 16 ◽  
Human Papillomavirus Type 16 ◽  
E6 And E7

ABSTRACT Our results presented here demonstrate that the most abundant human papillomavirus type 16 (HPV-16) mRNAs expressing the viral oncogenes E6 and E7 are regulated by cellular ASF/SF2, itself defined as a proto-oncogene and overexpressed in cervical cancer cells. We show that the most frequently used 3′-splice site on the HPV-16 genome, site SA3358, which is used to produce primarily E4, E6, and E7 mRNAs, is regulated by ASF/SF2. Splice site SA3358 is immediately followed by 15 potential binding sites for the splicing factor ASF/SF2. Recombinant ASF/SF2 binds to the cluster of ASF/SF2 sites. Mutational inactivation of all 15 sites abolished splicing to SA3358 and redirected splicing to the downstream-located, late 3′-splice site SA5639. Overexpression of a mutant ASF/SF2 protein that lacks the RS domain, also totally inhibited the usage of SA3358 and redirected splicing to the late 3′-splice site SA5639. The 15 ASF/SF2 binding sites could be replaced by an ASF/SF2-dependent, HIV-1-derived splicing enhancer named GAR. This enhancer was also inhibited by the mutant ASF/SF2 protein that lacks the RS domain. Finally, silencer RNA (siRNA)-mediated knockdown of ASF/SF2 caused a reduction in spliced HPV-16 mRNA levels. Taken together, our results demonstrate that the major HPV-16 3′-splice site SA3358 is dependent on ASF/SF2. SA3358 is used by the most abundantly expressed HPV-16 mRNAs, including those encoding E6 and E7. High levels of ASF/SF2 may therefore be a requirement for progression to cervical cancer. This is supported by our earlier findings that ASF/SF2 is overexpressed in high-grade cervical lesions and cervical cancer.

scholarly journals Adeno-Associated Virus Major Rep78 Protein Disrupts Binding of TATA-Binding Protein to the p97 Promoter of Human Papillomavirus Type 16

2000 ◽  
Vol 74 (5) ◽  
pp. 2459-2465 ◽  
Author(s):  
Pei-Fen Su ◽  
Shu-Yuan Chiang ◽  
Cheng-Wen Wu ◽  
Felicia Y.-H. Wu
Keyword(s):  
Human Papillomavirus ◽  
Binding Protein ◽  
Core Promoter ◽  
Tata Binding Protein ◽  
Tata Box ◽  
Dependent Manner ◽  
Hpv 16 ◽  
Adeno Associated Virus ◽  
Human Papillomavirus Type 16 ◽  
E6 And E7

ABSTRACT Adeno-associated virus type 2 (AAV) is known to inhibit the promoter activities of several oncogenes and viral genes, including the human papillomavirus type 16 (HPV-16) E6 and E7 transforming genes. However, the target elements of AAV on the long control region (LCR) upstream of E6 and E7 oncogenes are elusive. A chloramphenicol acetyltransferase assay was performed to study the effect of AAV on the transcription activity of the HPV-16 LCR in SiHa (HPV-positive) and C-33A (HPV-negative) cells. The results reveal that (i) AAV inhibited HPV-16 LCR activity in a dose-dependent manner, (ii) AAV-mediated inhibition did not require the HPV gene products, and (iii) the AAV replication gene product Rep78 was involved in the inhibition. Deletion mutation analyses of the HPV-16 LCR showed that regulatory elements outside the core promoter region of the LCR may not be direct targets of AAV-mediated inhibition. Further study with the electrophoretic mobility shift assay demonstrated that Rep78 interfered with the binding of TATA-binding protein (TBP) to the TATA box of the p97 core promoter more significantly than it disrupted the preformed TBP-TATA complex. These data thus suggest that Rep78 may inhibit transcription initiation of the HPV-16 LCR by disrupting the interaction between TBP and the TATA box of the p97 core promoter.

scholarly journals A combination of DNA vaccines targeting human papillomavirus type 16 E6 and E7 generates potent antitumor effects

Gene Therapy ◽  
2005 ◽  
Vol 13 (3) ◽  
pp. 257-265 ◽  
Author(s):  
S Peng ◽  
T T Tomson ◽  
C Trimble ◽  
L He ◽  
C-F Hung ◽  
...  
Keyword(s):  
Human Papillomavirus ◽  
Dna Vaccines ◽  
Antitumor Effects ◽  
Human Papillomavirus Type 16 ◽  
E6 And E7

Modelling the population-level impact of vaccination on the transmission of human papillomavirus type 16 in Australia

Sexual Health ◽  
2007 ◽  
Vol 4 (3) ◽  
pp. 147 ◽  
Author(s):  
David G. Regan ◽  
David J. Philp ◽  
Jane S. Hocking ◽  
Matthew G. Law
Keyword(s):  
Human Papillomavirus ◽  
Cost Effectiveness ◽  
Hpv Infection ◽  
Conclusive Evidence ◽  
Effective Vaccine ◽  
High Coverage ◽  
Hpv 16 ◽  
Highly Effective ◽  
Catch Up ◽  
The Impact

Background: Vaccines are now available to prevent the development of cervical cancer from genital human papillomavirus (HPV) infection. The decision to vaccinate depends on a vaccine’s cost-effectiveness. A rigorous cost-effectiveness model for vaccinated individuals is presented in a companion paper; this paper investigates the additional benefits the community might receive from herd immunity. Methods: A mathematical model was developed to estimate the impact of a prophylactic vaccine on transmission of HPV type 16 in Australia. The model was used to estimate the expected reduction in HPV incidence and prevalence as a result of vaccination, the time required to achieve these reductions, and the coverage required for elimination. The modelled population was stratified according to age, gender, level of sexual activity and HPV infection status using a differential equation formulation. Clinical trials show that the vaccine is highly effective at preventing persistent infection and pre-cancerous lesions. These trials do not, however, provide conclusive evidence that infection is prevented altogether. The possible modes of vaccine action were investigated to see how vaccination might change the conclusions. Results: The model predicts that vaccination of 80% of 12-year-old girls will eventually reduce HPV 16 prevalence by 60–100% in vaccinated and 7–31% in unvaccinated females. If 80% of boys are also vaccinated, reductions will be 74–100% in vaccinated and 86–96% in unvaccinated females. A campaign covering only 12-year-old girls would require 5–7 years to achieve 50% of the eventual reduction. With a catch-up campaign covering 13–26-year-olds, this delay would be reduced to only 2 years. Unrealistically high coverage in both sexes would be required to eliminate HPV 16 from the population. Under pessimistic assumptions about the duration of vaccine-conferred immunity, HPV 16 incidence is predicted to rise in some older age groups. Conclusions: Mass vaccination with a highly effective vaccine against HPV 16 has the potential to substantially reduce the incidence and prevalence of infection. Catch-up vaccination offers the potential to substantially reduce the delay before the benefits of vaccination are observed. A booster vaccination might be required to prevent an increase in incidence of infection in women over 25 years of age.

Tissue engineered cartilage using human articular chondrocytes immortalized by HPV-16 E6 and E7 genes

2006 ◽  
Vol 76A (3) ◽  
pp. 512-520 ◽  
Author(s):  
Wei-Hung Chen ◽  
Wen-Fu Lai ◽  
Win-Ping Deng ◽  
Wen K. Yang ◽  
Wen-Cheng Lo ◽  
...  
Keyword(s):  
Articular Chondrocytes ◽  
Human Articular Chondrocytes ◽  
Hpv 16 ◽  
E6 And E7 ◽  
Engineered Cartilage

Frequency of HPV-associated tonsillar cancer in Sweden

2009 ◽  
Vol 27 (15_suppl) ◽  
pp. 6030-6030
Author(s):  
P. Attner ◽  
A. Näsman ◽  
L. Marklund ◽  
L. Hammarstedt ◽  
J. Lindholm ◽  
...  
Keyword(s):  
Hpv 16 ◽  
Hpv Dna ◽  
Incidence Data ◽  
Tonsillar Cancer ◽  
Cancer Registry Data ◽  
Comparison Results ◽  
The Usa ◽  
E6 And E7 ◽  
Pre Treatment ◽  
Almost All

6030 Background: Numerous studies has shown an increase of the incidence of tonsillar squamous cell carcinoma (SCC) both in the USA and in Sweden. This increase in incidence is despite a decreasing prevalence in smoking, a well-known risk factor for developing tonsillar cancer. The proportion of human papillomavirus (HPV) positive tonsillar SCC has also been shown to increase. This study aims to examine the incidence of tonsillar SCC and the proportion of HPV positive tonsillar SCC between 2003–2007 in the County of Stockholm, Sweden in correlation to data from 1970–2002. Methods: All patients (n = 120) diagnosed with tonsillar SCC during 2003–2007 in the County of Stockholm were included in this study. Ninety-eight pre-treatment biopsies were available and presence of HPV DNA and HPV-16 E6 and E7 mRNA were tested by PCR and RT-PCR. Incidence data between 2003–2007 for Sweden and in the County of Stockholm was obtained from the Swedish Cancer Registry. Data reported from 1970 to 2002 was also obtained for comparison. Results: HPV DNA was present in 83/98 (85%) of the tonsillar SCC biopsies from 2003–2007. Of the 77 HPV-16 positive tumors, HPV-16 E6 and E7 mRNA were found in 98% of the analyzed cases. The proportion of HPV-positive cancers had significantly increased both from 1970 to 2007 (p < 0.0001) as well from 2000 to 2007 (p < 0.01), with 68% (95% CI, 53–81) 2000–2002; 77% (95% CI, 63–87) 2003–2005; and 93% (95% CI, 82–99) 2006–2007. The incidence rate of HPV-positive tumors almost doubled each decade between 1970–2007, in parallel with a decline of HPV-negative tumors. Conclusions: Today, almost all tonsillar SCC in the County of Stockholm is HPV positive, and the incidence of HPV-positive cancers is still increasing. The data suggest that we are dealing with an epidemic of a virus-induced carcinoma, and that soon practically all tonsillar SCC will be HPV positive; a similar situation observed in cervical cancer. No significant financial relationships to disclose.

Are E6 and E7 Oncoproteins the Key Modulators of Radiosensitivity in HPV 16 and 18 Carcinoma Cell Lines?

2008 ◽  
Vol 72 (1) ◽  
pp. S708-S709
Author(s):  
H.K. Lord ◽  
D. Violot ◽  
D. Biard ◽  
J. Bourhis ◽  
M. Vozenin-Brotons ◽  
...  
Keyword(s):  
Cell Lines ◽  
Carcinoma Cell ◽  
Hpv 16 ◽  
Carcinoma Cell Lines ◽  
E6 And E7 Oncoproteins ◽  
E6 And E7

scholarly journals The Human Papillomavirus 16 E7 Oncoprotein Attenuates AKT Signaling To Promote Internal Ribosome Entry Site-Dependent Translation and Expression of c-MYC

2016 ◽  
Vol 90 (12) ◽  
pp. 5611-5621 ◽  
Author(s):  
Sydney Webb Strickland ◽  
Scott Vande Pol
Keyword(s):  
Human Papillomavirus ◽  
Cancer Progression ◽  
Akt Signaling ◽  
Signaling Cascades ◽  
Cell Cycle Regulators ◽  
Entry Site ◽  
Hpv 16 ◽  
Cervical Cancers ◽  
Phosphorylated Akt ◽  
E6 And E7

ABSTRACTWhile the role of high-risk human papillomavirus (HPV) oncoproteins E6 and E7 in targeting p53 and retinoblastoma (Rb) has been intensively studied, how E6 and E7 manipulate cellular signaling cascades to promote the viral life cycle and cancer development is less understood. Keratinocytes containing the episomal HPV-16 genome had decreased activation of AKT, which was phenocopied by HPV-16 E7 expression alone. Attenuation of phosphorylated AKT (pAKT) by E7 was independent of the Rb degradation function of E7 but could be ablated by a missense mutation in the E7 carboxy terminus, H73E, thereby defining a novel structure-function phenotype for E7. Downstream of AKT, reduced phosphorylation of p70 S6K and 4E-BP1 was also observed in E7-expressing keratinocytes, which coincided with an increase in internal ribosomal entry site (IRES)-dependent translation that enhanced the expression of several cellular proteins, including MYC, Bax, and the insulin receptor. The decrease in pAKT mediated by E7 is in contrast to the widely observed increase of pAKT in invasive cervical cancers, suggesting that the activation of AKT signaling could be acquired during the progression from initial productive infections to invasive carcinomas.IMPORTANCEHPV causes invasive cervical cancers through the dysregulation of the cell cycle regulators p53 and Rb, which are degraded by the viral oncoproteins E6 and E7, respectively. Signaling cascades contribute to cancer progression and cellular differentiation, and how E6 and E7 manipulate those pathways remains unclear. The phosphoinositol 3-kinase (PI3K)/AKT pathway regulates cellular processes, including proliferation, cell survival, and cell differentiation. Surprisingly, we found that HPV-16 decreased the phosphorylation of AKT (pAKT) and that this is a function of E7 that is independent of the Rb degradation function. This is in contrast to the observed increase in AKT signaling in nearly 80% of cervical cancers, which typically show an acquired mutation within the PI3K/AKT cascade leading to constitutive activation of the pathway. Our observations suggest that multiple changes in the activation and effects of AKT signaling occur in the progression from productive HPV infections to invasive cervical cancers.

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