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    Keywords: PEPTIDE ; CANCER ; CELLS ; EXPRESSION ; GROWTH ; tumor ; TUMOR-CELLS ; carcinoma ; CELL ; Germany ; human ; THERAPY ; GENE ; GENE-EXPRESSION ; GENES ; transcription ; LINES ; INFECTION ; INTERVENTION ; FLOW ; cell cycle ; CELL-CYCLE ; CYCLE ; E7 ; ACID ; ACIDS ; NUCLEIC-ACIDS ; gene expression ; p53 ; HIGH-RISK ; DNA-DAMAGE ; drug delivery ; HPV ; E6 ; EPITHELIAL-CELLS ; Jun ; PHENOTYPE ; CARCINOMAS ; CARRIERS ; HUMAN-PAPILLOMAVIRUS TYPE-16 ; INFECTIONS ; human papilloma virus ; BEHAVIOR ; FLOW-CYTOMETRY ; TUMOR CELLS ; ANTAGONIST ; PNA ; anti-gene ; cell-cycle-drug-effects ; EARLY GENES ; flow cytometry ; HPV type ; HUMAN CANCER ; immortalization ; oncogene-protein-E6 ; oncogeneprotein-E7 ; P53 GENE ; papillomaviruses ; peptide nucleic acid ; PRB ; RNA INTERFERENCE ; THERAPIES
    Abstract: Approximately 100% of cervical carcinomas are causally linked to infections with high-risk human papillomaviruses (HPVs), whose oncogenicity has been assigned to the continued expression of two early viral genes, E6 and E7. Reversal of the transformed phenotype by inhibiting E6/E7 gene expression therefore provides a suitable goal for tumor therapy. We established an application controlling the E6/E7 expression of the HPV type 18, by using viral gene directed peptide nucleic acids (PNAs). One consequence was the complete change in growth to a stagnated behavior of the HPV 18 positive HeLa-S cells. With flow cytometry, we investigated changes in the cell cycle and expression of the pRB (retinoblastoma) and p53 genes acting as antagonists to E6 and E7. We realized that application of PNAs via intracellular cleavable conjugated peptide carriers mediates specific inhibitory effects and we showed that the combined E6/E7-directed PNA-application mediated a clear morphological change from suspension to adherend state and the cells stopped growth. These data could demonstrate a promising approach for development of new 'anti-gene therapeutics' against papillomavirus-induced human cancers. (C) 2004 Elsevier Ireland Ltd. All rights reserved
    Type of Publication: Journal article published
    PubMed ID: 15145519
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  • 4
    Keywords: MODEL ; MODELS ; GENE ; DRUG ; MOLECULES ; GENE-TRANSFER ; DNA ; DENDRITIC CELLS ; T-CELLS ; BIOLOGY ; MOLECULE ; ACID ; ACIDS ; NEUTRALIZING ANTIBODIES ; NUCLEIC-ACIDS ; PARTICLES ; virus ; VIRUS-LIKE PARTICLES ; SURFACE ; DELIVERY ; VACCINE ; VESSELS ; CROSS-PRESENTATION ; review ; OLIGONUCLEOTIDE ; DRUG-DELIVERY ; CELLULAR IMMUNE-RESPONSES ; PAPILLOMAVIRUS-LIKE PARTICLES ; SUCCINIMIDYL ESTER
    Abstract: Virus-like particles (VLPs) structurally mimic the viral capsid and have therefore been extensively, and quite successfully, used as vaccine and viral serology reagents. The ability of VLPs to include nucleic acids and small molecules has also made them novel vessels for gene and drug delivery. The regular, repetitive surface of VLPs has been exploited as a template for nanoscale synthesis. Recent progress has been made in the development of several virus models
    Type of Publication: Journal article published
    PubMed ID: 15560977
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  • 5
    Keywords: APOPTOSIS ; CANCER ; EXPRESSION ; GROWTH ; human ; IN-VIVO ; PATHWAY ; PATHWAYS ; DEATH ; GENE ; GENES ; PROTEIN ; transcription ; MICE ; TIME ; MECHANISM ; CARCINOGENESIS ; SKIN ; E7 ; papillomavirus ; TRANSGENIC MICE ; p53 ; human papillomavirus ; E6 ; HUMAN-PAPILLOMAVIRUS ; RE ; TUMORIGENESIS ; downregulation ; function ; cutaneous HPV38 ; Delta Np73 ; E6 and E7
    Abstract: The E6 and E7 of the cutaneous human papillomavirus (HPV) type 38 immortalize primary human keratinocytes, an event normally associated with the inactivation of pathways controlled by the tumour suppressor p53. Here, we show for the first time that HPV38 alters p53 functions. Expression of HPV38 E6 and E7 in human keratinocytes or in the skin of transgenic mice induces stabilization of wild-type p53. This selectively activates the transcription of Delta Np73, an isoform of the p53-related protein p73, which in turn inhibits the capacity of p53 to induce the transcription of genes involved in growth suppression and apoptosis. Delta Np73 downregulation by an antisense oligonucleotide leads to transcriptional re-activation of p53-regulated genes and apoptosis. Our findings illustrate a novel mechanism of the alteration of p53 function that is mediated by a cutaneous HPV type and support the role of HPV38 and Delta Np73 in human carcinogenesis
    Type of Publication: Journal article published
    PubMed ID: 16397624
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  • 6
    Keywords: CANCER ; human ; CT ; EPIDEMIOLOGY ; INFECTION ; SKIN ; papillomavirus ; VARIANTS ; virus ; carcinogenicity ; PROGRESSION ; WOMEN ; etiology ; smoking ; cervical cancer ; CERVICAL-CANCER ; CERVIX ; PATHOGENESIS ; human papillomavirus ; HPV ; HUMAN-PAPILLOMAVIRUS ; DIETARY ; TOBACCO ; UTERINE CERVIX ; HERPES-SIMPLEX-VIRUS ; TYPE-2 ; INVASIVE CERVICAL-CANCER ; SKIN-CANCER ; INTEGRATION ; WORLDWIDE ; VARIANT ; HUMAN CANCER ; HIV ; COLLABORATIVE REANALYSIS ; CANCERS ; PERSPECTIVE ; HERPES-SIMPLEX ; nonmelanoma skin cancer ; LONG-TERM USE ; CONTRACEPTIVES ; herpes simplex virus ; HUMAN-PAPILLOMAVIRUS TYPES ; INDIVIDUAL DATA
    Abstract: The causal role of human papillomavirus (HPV) in all cancers of the uterine cervix has been firmly established biologically and epidemiologically. Most cancers of the vagina and anus are likewise caused by HPV, as are a fraction of cancers of the vulva, penis, and oropharynx. HPV-16 and -18 account for about 70% of cancers of the cervix, vagina, and anus and for about 30-40% of cancers of the vulva, penis, and oropharynx. Other cancers causally linked to HPV are non-melanoma skin cancer and cancer of the conjunctiva. Although HPV is a necessary cause of cervical cancer, it is not a sufficient cause. Thus, other cofactors are necessary for progression from cervical HPV infection to cancer. Long-term use of hormonal contraceptives, high parity, tobacco smoking, and co-infection with HIV have been identified as established cofactors; co-infection with Chlamydia trachomatis (CT) and herpes simplex virus type-2 (HSV-2), immunosuppression, and certain dietary deficiencies are other probable cofactors. Genetic and immunological host factors and viral factors other than type, such as variants of type, viral load and viral integration, are likely to be important but have not been clearly identified. (c) 2006 Published by Elsevier Ltd
    Type of Publication: Journal article published
    PubMed ID: 16949995
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  • 7
    Keywords: CANCER ; tumor ; Germany ; human ; THERAPY ; GENE ; PROTEIN ; MONOCLONAL-ANTIBODY ; MICE ; GENE-TRANSFER ; INFECTION ; ANTIGEN ; papillomavirus ; IMMUNE-RESPONSES ; NEUTRALIZING ANTIBODIES ; virus ; WOMEN ; CLINICAL-TRIALS ; CERVICAL-CANCER ; CAPSID PROTEIN ; human papillomavirus ; HUMAN-PAPILLOMAVIRUS ; VACCINE ; L1 ; HUMAN-IMMUNODEFICIENCY-VIRUS ; SERUM ; IMMUNIZATION ; RE ; HERPES-SIMPLEX ; MINOR CAPSID PROTEIN ; TOXIN B-SUBUNIT ; TRANSIENT IMMUNOSUPPRESSION ; VAGINAL SECRETIONS
    Abstract: Adeno-associated viruses (AAV) have been developed and evaluated as recombinant vectors for gene therapy in many preclinical studies, as well as in clinical trials. However, only a few approaches have used recombinant AAV (rAAV) to deliver vaccine antigens. We generated an rAAV encoding the major capsid protein L1 (L1h) from the human papillomavirus type 16 (HPV16), aiming to develop a prophylactic vaccine against HPV16 infections, which are the major cause of cervical cancer in women worldwide. A single dose of rAAV5 L1h administered intranasally was sufficient to induce high titers of U-specific serum antibodies, as well as mucosal antibodies in vaginal washes. Seroconversion was maintained for at least I year. In addition, a cellular immune response was still detectable 60 weeks after immunization. Furthermore, lyophilized rAAV5 L1h successfully evoked a systemic and mucosal immune response in mice. These data clearly show the efficacy of a single-dose intranasal immunization against HPV16 based on the recombinant rAAV5L1h vector without the need of an adjuvant
    Type of Publication: Journal article published
    PubMed ID: 16501072
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  • 8
    Keywords: CANCER ; Germany ; human ; GENE ; GENES ; PROTEIN ; EFFICIENCY ; MONOCLONAL-ANTIBODY ; GENE-TRANSFER ; RESPONSES ; DNA ; INFECTION ; INDUCTION ; E7 ; papillomavirus ; SEQUENCE ; ACIDS ; antibodies ; NEUTRALIZING ANTIBODIES ; PARTICLES ; WOMEN ; CAPSID PROTEIN ; VIRUS-LIKE PARTICLES ; LOCALIZATION ; VACCINE ; HUMAN-PAPILLOMAVIRUS TYPE-16 ; L1 ; AMINO-ACIDS ; PLASMID DNA ; CYTOTOXIC T-LYMPHOCYTES ; IMMUNIZATION ; RE ; assembly ; LONG-TERM PERSISTENCE ; CONTROLLED-TRIAL ; DNA immunization ; INTRAMUSCULAR INJECTION
    Abstract: Infections by human papillomaviruses (HPV) are the major cause of uterine cancer in women worldwide. Aiming to develop a combined prophylactic and therapeutic vaccine we have previously demonstrated immunogenicity of chimeric virus-like particles consisting of a C-terminally truncated HPV 16 L1 capsid protein fused to an E7 portion. Here we show that genetic vaccination with a corresponding DNA was inefficient in the induction of a L1-specific prophylactic immune response. DNA immunization with C-terminally truncated HPV 16 L1 genes of different lengths revealed that only short deletions (L1(1-498)) were tolerated for eliciting a humoral immune response against viral capsids. This correlates with the observation that the C-terminal sequences are critical for nuclear localization, capsomere and capsid assembly. However, only the ability of L1 protein to form capsomeres or capsids showed a direct influence on the outcome of the immune response. C-terminal insertion of 60 amino acids of E7 was tolerated in fusion constructs, whereas insertion of full-length E7(1-98) or shuffled E7 (149 aa) completely abolished the humoral immune response. The L1(1-498)/E7(1-60) fusion construct not only induced L1-specific antibodies but also L1- and E7-specific CTL responses after DNA vaccination. (c) 2005 Elsevier Ltd. All rights reserved
    Type of Publication: Journal article published
    PubMed ID: 16414157
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    Keywords: PEPTIDE ; CANCER ; CANCER CELLS ; CELLS ; EXPRESSION ; tumor ; CELL ; Germany ; human ; INHIBITION ; MODEL ; GENE ; PROTEIN ; PROTEINS ; MONOCLONAL-ANTIBODY ; LINES ; MICE ; DNA ; INDUCTION ; ANTIGEN ; CELL-LINES ; E7 ; papillomavirus ; treatment ; SUSCEPTIBILITY ; antibodies ; antibody ; MOUSE ; DESIGN ; CERVICAL-CANCER ; CELL-LINE ; LINE ; CODON USAGE ; human papillomavirus ; TYPE-16 ; CANCER-CELLS ; HPV ; antigen presentation ; PEPTIDES ; E6 ; MONOCLONAL-ANTIBODIES ; HUMAN-PAPILLOMAVIRUS ; DEGRADATION ; VACCINE ; EPITOPE ; IMMUNE-RESPONSE ; RECOMBINANT VACCINIA ; HUMAN-PAPILLOMAVIRUS TYPE-16 ; MOUSE MODEL ; TARGETS ; cell lines ; CLASS-I MOLECULES ; IMMUNIZATION ; TRANSFECTION ; LEVEL ; PROTEIN-A ; tumor-antigen ; monoclonal antibodies ; function ; cytotoxic T lymphocyte ; E6 and E7 ; RELEVANCE ; PLASMID ; PRECURSOR ; E6 PROTEIN ; DNA immunization ; E7 PROTEIN ; CTL epitope ; CYTOTOXIC T-CELLS ; HPV 16 E6 ; RNA splicing ; THERAPEUTIC VACCINATION
    Abstract: The early proteins E6 and E7 of the cancer-related human papillomavirus type 16 (HPV 16) are constitutively expressed in cancer cells thus are targets for immune therapeutic approaches. Whereas previous studies have mainly focussed on the immunogenicity of E7 protein little is known about E6. In order to evaluate E6-specific DNA immunization strategies in a preclinical mouse model C57BL/6 mice were injected with plasmid pTHampE6 and analyzed for E6-specific CTL induction. CTL specific for the H2-K-b-restricted E6-derived epitope E6 48-57, were readily detectable among splenocytes of immunized animals, however, these CTL showed a differential recognition pattern on various E6-expressing target cells. Using a newly generated E6-specific monoclonal antibody we found that most cell lines expressing E6 encoded by the natural gene showed undetectable protein amounts and were ignored by E6-specific CTL. However, transfection of a codon optimized version of the E6 gene (E6opt) strongly enhanced protein expression levels within these cells turning them into susceptible target cells. Surprisingly, we found that E6-positive TC-1 cells, although recognized by E6-specific CTL, were totally devoid of any detectable E6 protein. Inhibition of proteasomal function by lactacystin treatment diminished E6-specific CTL recognition of TC-1 cells and RMA/E6opt transfectants accompanied by intracellular accumulation of E6 protein as observed in RMA/E6opt transfectants, but not in TC-1 cells. These data suggest that in TC-1 cells rapid degradation processes might prevent stable expression of E6 protein yet generate precursor peptides in amounts sufficient for MHC class I restricted antigen presentation. Thus, the results presented in this paper show that: (i) use of optimized codons in transfection experiments can improve susceptibility of target cells to E6-specific CTL recognition and (ii) lack of detectable protein within a cell does not necessarily indicate the absence of epitope presentation. Both findings are of potential relevance for the design of tumor vaccines. (c) 2006 Elsevier B.V. All rights reserved
    Type of Publication: Journal article published
    PubMed ID: 16949679
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    Keywords: RECEPTOR ; CELLS ; CELL ; Germany ; human ; FOLLOW-UP ; SUPPORT ; DISEASE ; MOLECULES ; ACTIVATION ; RESPONSES ; INFECTION ; ANTIGEN ; DENDRITIC CELLS ; T-CELLS ; BINDING ; treatment ; MOLECULE ; cytokines ; IMMUNE-RESPONSES ; PARTICLES ; virus ; HEALTH ; UP-REGULATION ; MODULATION ; PATHOGENESIS ; TYPE-16 ; VIRUS-LIKE PARTICLES ; SURVEILLANCE ; HPV ; VACCINE ; INVOLVEMENT ; NETHERLANDS ; LECTIN ; immune response ; IMMUNE-RESPONSE ; vaccination ; L1 ; human papilloma virus ; RECEPTORS ; LANGERHANS CELLS ; SUBSETS ; BINDS ; IMPLEMENTATION ; IMMUNIZATION ; CYTOKINE ; PROGRAM ; SUBSET ; interaction ; development ; ESCAPE ; LEVEL ; dendritic cell ; SULFATE ; immunology ; SET ; immune responses ; IL-6 ; LECTINS ; DC-SIGN ; MUCOSAL ; heparan sulfate proteoglycan ; IMMUNE ACTIVATION ; immune surveillance ; papilloma virus ; SQUAMOUS INTRAEPITHELIAL LESIONS ; SUSTAINED EFFICACY ; syndecan ; VLPs
    Abstract: Immunization using human papilloma virus (HPV)-L1 virus-like particles (VLPs) induces a robust and effective immune response, which has recently resulted in the implementation of the HPV-L1 VLP vaccination in health programs. However, during infection, HPV can escape immune surveillance leading to latency and disease. Dendritic cells (DCs) induce effective immune responses after vaccination, but might also induce immune modulation during infection. The interaction of HPV-L1 VLPs with mucosal DCs determines the immune response. However, little is known about the receptors on mucosal DC subsets involved in HPV-L1 VLP binding. Therefore, we set out to investigate the interaction of HPV-L1 VLPs with the different mucosal DC subsets; the subepithelial DCs and Langerhans cells (LCs). We observed strong binding of HPV-L1 VLPs to both DCs and LCs. We did not observe an involvement for C-type lectins such as dendritic cell-specific ICAM-3 grabbing non-integrin (DC-SIGN) and langerin. The HPV-L1 VLP binding to DCs was mediated through heparan sulfates, since it was abrogated by heparinase-II treatment. The heparan sulfate proteoglycan syndecan-3 binds VLPs and is expressed on both DCs and LCs. Binding of VLPs to DCs, but not to LCs, strongly correlated with the levels of heparan sulfates and syndecan-3, suggesting that syndecan-3 is the main receptor for HPV-L1 VLPs on DCs. VLP interaction with DCs resulted in the up-regulation of co-stimulatory molecules and the production of the cytokines IL-6, IL-8, IL-10 and IL-12p40. Our results support an important role for syndecan-3 as a HPV receptor on DCs, which could be important for both vaccine development and understanding HPV pathogenesis. (c) 2007 Elsevier GmbH. All rights reserved
    Type of Publication: Journal article published
    PubMed ID: 18086370
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