146 results on '"Frazer, I. H."'
Search Results
2. A robust experimental and computational analysis framework at multiple resolutions, modalities and coverages.
- Author
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Tran, M., Yoon, S., Teoh, M., Andersen, S., Lam, P. Y., Purdue, B. W., Raghubar, A., Hanson, S. J., Devitt, K., Jones, K., Walters, S., Monkman, J., Kulasinghe, A., Tuong, Z. K., Soyer, H. P., Frazer, I. H., and Nguyen, Q.
- Subjects
CELL communication ,NUCLEIC acid hybridization ,SQUAMOUS cell carcinoma ,BASAL cell carcinoma ,RNA sequencing ,PROTEIN-ligand interactions - Abstract
The ability to study cancer-immune cell communication across the whole tumor section without tissue dissociation is needed, especially for cancer immunotherapy development, which requires understanding of molecular mechanisms and discovery of more druggable targets. In this work, we assembled and evaluated an integrated experimental framework and analytical process to enable genome-wide scale discovery of ligand-receptors potentially used for cellular crosstalks, followed by targeted validation. We assessed the complementarity of four different technologies: single-cell RNA sequencing and Spatial transcriptomic (measuring over >20,000 genes), RNA In Situ Hybridization (RNAscope, measuring 4-12 genes) and Opal Polaris multiplex protein staining (4-9 proteins). To utilize the multimodal data, we implemented existing methods and also developed STRISH (Spatial TRanscriptomic In Situ Hybridization), a computational method that can automatically scan across the whole tissue section for local expression of gene (e.g. RNAscope data) and/or protein markers (e.g. Polaris data) to recapitulate an interaction landscape across the whole tissue. We evaluated the approach to discover and validate cell-cell interaction in situ through in-depth analysis of two types of cancer, basal cell carcinoma and squamous cell carcinoma, which account for over 70% of cancer cases. We showed that inference of cell-cell interactions using scRNA-seq data can misdetect or detect false positive interactions. Spatial transcriptomics still suffers from misdetecting lowly expressed ligand-receptor interactions, but reduces false discovery. RNAscope and Polaris are sensitive methods for defining the location of potential ligand receptor interactions, and the STRISH program can determine the probability that local gene co-expression reflects true cell-cell interaction. We expect that the approach described here will be widely applied to discover and validate ligand receptor interaction in different types of solid cancer tumors. [ABSTRACT FROM AUTHOR]
- Published
- 2022
- Full Text
- View/download PDF
3. Genomewide scans of red cell indices suggest linkage on chromosome 6q23
- Author
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Iliadou, A, Evans, D M, Zhu, G, Duffy, D L, Frazer, I H, Montgomery, G W, and Martin, N G
- Published
- 2007
4. A major quantitative trait locus for CD4-CD8 ratio is located on chromosome 11
- Author
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Evans, D M, Zhu, G, Duffy, D L, Frazer, I H, Montgomery, G W, and Martin, N G
- Published
- 2004
5. Association of clinical, radiological and synovial immunopathological responses to anti-rheumatic treatment in rheumatoid arthritis
- Author
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Pettit, A. R., Weedon, H., Ahern, M., Zehntner, S., Frazer, I. H., Slavotinek, J., Au, V., Smith, M. D., and Thomas, R.
- Published
- 2001
6. Expression, purification and immunological characterization of the transforming protein E7, from cervical cancer-associated human papillomavirus type 16
- Author
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FERNANDO, G. J. P., MURRAY, B., ZHOU, J., and FRAZER, I. H.
- Published
- 1999
7. Vaccine-Induced Th1-Type Responses are Dominant over Th2-Type Responses in the Short Term whereas Pre-existing Th2 Responses are Dominant in the Longer Term
- Author
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FERNANDO, G. J. P., STEWART, T. J., TINDLE, R. W., and FRAZER, I. H.
- Published
- 1998
8. Hpv Dna In Oropharyngeal Squamous Cell Cancers: Comparison of Results from Four DNA Detection Methods
- Author
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Frazer, I. H., Leonard, J. H., Schonrock, J., Wright, R. G., and Kearsley, J. H.
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- 1993
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9. Is Infusion Phlebitis Preventable?
- Author
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Frazer, I. H., Eke, N., and Laing, M. S.
- Published
- 1977
10. Efficiency of delivery of DNA to cells by bovine papillomavirus type-1 L1/L2 pseudovirions.
- Author
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Liu, Y., Frazer, I. H., Liu, W. J., Liu, X. S., McMillan, N., and Zhao, K.-N.
- Subjects
DNA ,CELLS ,PAPILLOMAVIRUSES ,PLASMIDS ,GREEN fluorescent protein - Abstract
To investigate the efficiency of encapsidation of plasmid by papillomavirus virus-like particles (PV VLPs), and the infectivity of the resultant PV pseudovirions, Cos-1 cells were transfected with an 8-kb plasmid incorporating a green fluorescent protein (GFP) reporter gene (pGSV), and infected with bovine PV (BPV-1) L1/L2 recombinant vaccinia virus to produce BPV1 pseudovirions. Approximately 1 in 1.5×10
4 of dense (1.35 g/ml) PV pseudovirions and 0.3 in 104 of less-dense (1.29 g/ml) pseudovirions packaged an intact pGSV plasmid. The majority (>75%) of packaged plasmids contained deletions, and the deletions affected all tested genes. After exposure of Cos-1 cells to BPV-1 pseudovirions at an MOI of 40,000:1, 6% of cells expressed GFP, giving a calculated efficiency of delivery of the pGSV plasmid, by pseudovirions which had packaged an intact plasmid, of approximately 5%. Plasmid delivery was not effected by purified pGSV plasmid, was blocked by antiserum against BPV-1, and was not blocked by DNase treatment of pseudovirions, confirming that delivery was mediated by DNA within the pseudovirion. We conclude that a major limitation to the use of PV pseudovirions as a gene delivery system is that intact plasmid DNA is not efficiently selected for packaging by VLPs in cell-based pseudovirions production systems. [ABSTRACT FROM AUTHOR]- Published
- 2001
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11. Antibodies to liver membrane antigens in chronic active hepatitis (CAH). II. Specificity for autoimmune CAH.
- Author
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Frazer, I. H., Kronborg, I. J., and Mackay, I. R.
- Subjects
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LIVER diseases , *BLOOD plasma , *ANTIGENS , *IMMUNOGLOBULINS , *LIVER cells , *EPITOPES - Abstract
An immunoradiometric assay for IgG class autoantibody to liver membrane antigens, based on serum binding to glutaraldehyde treated monkey hepatocytes, was used to examine sera from patients with chronic active hepatitis (CAH) and other acute and chronic liver diseases. All sera from normals and patients showed binding, up to a titre of 1/2,048. For comparison of assays, results were normalized by selecting two reference sera, one with a high degree of binding, and one from a healthy subject with a low degree of binding: at a dilution of 1/2,048, these sera were given binding values of 100% and 0%. The values for the binding of unknown sera at the same dilution were calculated from these two reference values. For 26 patients with autoimmune CAH, the mean (±s.d.) percentage binding value (70 ±33%) was significantly higher than the mean value for 26 healthy subjects (10±15%), and high binding values were significantly associated with biochemically active hepatitis. The mean percentage binding value was moderately increased for eight patients with HBsAg associated CAH (42±12%), 13 patients with alcoholic hepatitis with cirrhosis (37±25%) and 45 patients with acute viral hepatitis A (40±27%) or B (52±37%). At a cut-off binding value of 65%, the assay as a single diagnostic procedure was shown to have a 70% sensitivity and a 95% specificity for the diagnosis of autoimmune CAH. Better understanding of the pathogenetic significance of antibodies to liver membrane antigens in CAH and other liver diseases will depend upon biochemical analysis of the presumably multiple antigenic determinants on the hepatocyte membrane. [ABSTRACT FROM AUTHOR]
- Published
- 1983
12. Cell-mediated immunity to hepatitis B virus antigens in mice: correlation of in vivo and in vitro assays.
- Author
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De Moerloose, P. A., Frazer, I. H., Sewell, W. A., Collins, Elizabeth J., and Mackay, I. R.
- Subjects
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CELLULAR immunity , *ANTIGENS , *HEPATITIS B virus , *IMMUNIZATION , *LYMPHOCYTES , *INTERFERONS - Abstract
Cell mediated immunity (CMI) to hepatitis B viral antigens was studied in BALB/mice after immunization with purified hepatitis B surface antigen (HBsAg), or core antigen (HBcAg), with adjuvants. The two in vitro assays for cell-mediated immunity (CMI), utilizing lymph node cells, were release of interferon after exposure to antigen, and blast transformation of lymphocytes, and the in vivo assay was ear swelling at 24 h after local injection of antigen. Immunization with HBsAg or HBcAg with adjuvants induced antigen-specific cutaneous reactivity; if no adjuvants were given, immunization with HBcAg, but not HbsAg, induced cutaneous reactivity. CMI could be adoptively transferred by lymph node cells, but for only a limited period after immunization with HbsAg or MBcAg. The ability of lymph node cells from mice immunized with HBV antigens to transfer adoptively CMI correlated well with their production of interferon after challenge with antigen in vitro, but less well with blastogenesis after challenge with antigen in vitro, or with cutaneous reactivity to antigen in the donor mouse. Reliable antigen-specific lymphokine release assays, rather than blast transformation of lymphocytes or cutaneous reactivity after antigen challenge, arc required to assess CMI to HBV antigens in the mouse and, by inference, in man. [ABSTRACT FROM AUTHOR]
- Published
- 1986
13. Absence of autoimmune serological reaction in chronic non A, non B viral hepatitis.
- Author
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Mackay, I. R., Frazer, I. H., Toh, B.-H., Pedersen, J. S., and Alter, H. J.
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AUTOIMMUNE diseases , *HEPATITIS viruses , *AUTOANTIBODIES , *INJECTIONS , *IMMUNOGLOBULINS , *IMMUNOLOGIC diseases , *LIVER - Abstract
In 18 cases of chronic liver disease due to non-A, non-B hepatitis virus(es) in which the diagnosis was established by transmission, including chimpanzee inoculation in nine, sera were tested for the autoantibodies characteristically associated with autoimmune chronic active hepatitis. The frequency of autoantibodies to nuclear, smooth muscle, cytofilament, mitochondrial and liver membrane antigens was low, being not greater than that recorded for a normal population, and the few positive reactions obtained were at very low titre. These findings suggest that among cases of "HBsAg negative" chronic hepatitis, those due to NANB infection are distinguishable from those due to autoimmune chronic hepatitis by negative serological tests for autoantibodies. [ABSTRACT FROM AUTHOR]
- Published
- 1985
14. The cellular infiltrate in the liver in auto-immune chronic active hepatitis: analysis with monoclonal antibodies.
- Author
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Frazer, I. H., Mackay, I. R., Bell, J., and Becker, G.
- Abstract
ABSTRACT- The mononuclear cell infiltrate in the liver was analyzed, using a panel of monoclonal antibodies (MAbs) of known specificity, in 10 patients with auto-immune chronic active hepatitis and, for contrast, in 14 with other types of chronic parenchymal liver diseases. In all cases, the mononuclear cell (MNC) infiltrate in the liver consisted mostly of T lymphocytes. Helper (Th) cells were more frequent than suppressor/cytotoxic T cells (Tsc) in the portal tracts and cirrhotic scar tissue, while Tsc were more common in the hepatic parenchyma. The number of Tsc cells in the parenchyma was greatest in patients with histologically active CAH and least in patients with quiescent cirrhosis. 'Plasmacytoid' cells with the morphology of plasma cells, a hallmark of the MNC infiltrate in auto-immune CAH, were more frequent in histologically active CAH than in quiescent cirrhosis. These plasmacytoid cells were T200 + ve, and hence of bone marrow origin, but the majority expressed neither membrane nor cytoplasmic immunoglobulin nor any lineage-specific marker antigens, and hence did not fulfil criteria for B lymphocytes; however, these cells were positive for OKT10 and HLA DR. No difference was evident between the MNC infiltrate in the liver in auto-immune CAH and that in the other acute or chronic liver diseases studied, including HBV-associated CAH; hence immunohistological studies do not point to any pathological processes uniquely responsible for the pattern of hepatocyte damage seen in auto-immune CAH. [ABSTRACT FROM AUTHOR]
- Published
- 1985
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15. Lymphocyte ectoenzyme activity compared in healthy persons and patients seropositive to or at high risk of HIV infection.
- Author
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Chalmers, A. H., Hare, C., Woolley, G., and Frazer, I. H.
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EXTRACELLULAR enzymes ,ENZYMES ,LYMPHOCYTES ,LEUCOCYTES ,HIV ,HIV infections ,CYTOLOGY - Abstract
We measured two ectoenzymes, ecto-5 ′-nucleotidase (NT) and dipeptidyl peptidase IV (DP) in the peripheral blood lymphocytes of various groups of HIV-infected patients because of the previous implied relationship of these enzymes to immune function. NT expressed as mean nmol/h per mg protein (±s.d.) was significantly depressed in the HIV-seropositive asymptomatic (42 ± 32; P <0.01) and AIDS groups (14 ± 7; P <0.002) when compared with a healthy HIV-seronegative male population (83 ± 27). The NT activities in asymptomatic HIV-seropositive and HIV-seronegative high risk groups (53 ± 30) were not significantly different from one another but both groups had significantly higher enzyme activities than the AIDS group (P = 0.01 and <0.002, respectively). The seronegative high risk and normal healthy group had similar NT activities. DP activities expressed as mean nmol/h per mg protein (± s.d.) in both seropositive asymptomatic (0.188 ± 0.038) and high risk seronegative (0.180 ± 0.05) groups had higher enzyme activities than the healthy seronegative (0.117 ± 0.015; P = 0.02 and 0.05, respectively) and A1DS group (0.096 ± 0.036; P = 0.002 and 0.02, respectively). The healthy seronegative group had DP activities not significantly different to the AIDS groups. Similarly the high risk seronegative and healthy seropositive group had similar DP activities. These results taken together indicate that measurement of both DP and NT should be evaluated prospectively as a monitor of the clinical progression of HIV infection. [ABSTRACT FROM AUTHOR]
- Published
- 1990
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16. Some adverse reactions to allopurinol may be mediated by lymphocyte reactivity to oxypurinol.
- Author
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Emmerson, B. T., Hazelton, R. A., and Frazer, I. H.
- Published
- 1988
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17. The role of vaccines in the control of STDs: HPV vaccines.
- Author
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Frazer, I H
- Abstract
Prophylactic vaccines for genital human papillomavirus (HPV) infection have been shown to be feasible in animal models, and suitable vaccine material based on virus-like particles can be produced in bulk at reasonable cost. Initiation of phase III clinical trials will follow definition of trial outcome measures through further epidemiological studies, and development of assays of host protective immunity. Vaccines could in principle eliminate HPV-related disease, as the human race is the only natural host for the relevant papillomaviruses (PVs). Therapeutic vaccines for genital HPV infection are also possible, but have not yet been demonstrated as feasible in practice because the choice of vaccine antigens is difficult, the method of their optimal delivery is uncertain, and the nature of the relevant antiviral immunity is unknown. PV species specificity will require trials to be conducted in man, which will slow definition of an ideal vaccine. [ABSTRACT FROM PUBLISHER]
- Published
- 1996
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18. T lymphocyte subpopulations defined by two sets of monoclonal antibodies in chronic active hepatitis and systemic lupus erythematosus
- Author
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Frazer, I H and Mackay, I R
- Subjects
Adult ,Male ,T-Lymphocytes ,Antibodies, Monoclonal ,T-Lymphocytes, Helper-Inducer ,Middle Aged ,T-Lymphocytes, Regulatory ,Leukocyte Count ,Azathioprine ,Humans ,Lupus Erythematosus, Systemic ,Female ,Research Article ,Aged ,Hepatitis, Chronic - Abstract
Lymphocyte subpopulations were enumerated in human peripheral blood using murine monoclonal antibodies with specificity for all peripheral blood T lymphocytes (OKT3, alpha-Leu 1) and for the helper subset (OKT4, alpha Leu 3a) and suppressor/cytotoxic subset (OKT8, alpha Leu 2a). Patients with chronic active hepatitis (CAH) (23) or systemic lupus erythematosus (SLE) (10), compared with healthy subjects (20), had a lower mean T lymphocyte count. Patients with CAH had normal numbers of suppressor/cytotoxic (TSC) cells, but fewer helper (TH) cells than healthy subjects (0 . 96 +/- 0 . 11 X 10(9)/1 versus 1 . 45 +/- 0 . 15 X 10(9)/1), and those with SLE also had fewer TH cells (0 . 93 +/- 0 . 11 X 10(9)/1). Patients with CAH receiving azathioprine (n = 8) had significantly fewer TSC cells, and a higher TH/TSC ratio (2 . 69 +/- 0 . 35) than those (n = 15) not on this therapy (1 . 85 +/- 0 . 15). When patients taking azathioprine were excluded, no correlation was found between disease activity and the TH/TSC ratio for either disease.
- Published
- 1982
19. Transmission of Human Papillomaviruses from Mother to Child.
- Author
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Fredericks;, B. D., Balkin, A., Daniel, H. W., Schonrock:., J., Ward, B., and Frazer, I. H.
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- 1993
- Full Text
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20. Re: Cervical carcinoma and human papillomavirus: on the road to preventing a major human cancer.
- Author
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Bosch, F X, Muñoz, N, de Sanjosé, S, Franco, E L, Lowy, D R, Schiffman, M, Franceschi, S, Kjaer, S K, Meijer, C J, Frazer, I H, and Cuzick, J
- Subjects
PAPILLOMAVIRUS disease prevention ,TUMOR prevention ,VIRAL vaccines ,DNA ,PAPILLOMAVIRUS diseases ,PAPILLOMAVIRUSES ,TUMORS ,CERVIX uteri tumors ,DISEASE complications ,VACCINES - Published
- 2001
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21. Murine HPV16 E7-expressing transgenic skin effectively emulates the cellular and molecular features of human high-grade squamous intraepithelial lesions.
- Author
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Tuong ZK, Noske K, Kuo P, Bashaw AA, Teoh SM, and Frazer IH
- Subjects
- Animals, Disease Models, Animal, Female, Gene Expression Profiling, Human papillomavirus 16 immunology, Humans, Hyperplasia immunology, Hyperplasia pathology, Immunosuppression Therapy, Keratin-14 immunology, Mice, Mice, Transgenic, Papillomavirus E7 Proteins immunology, Papillomavirus Infections immunology, Papillomavirus Infections pathology, Papillomavirus Infections virology, Skin immunology, Skin virology, Skin Transplantation, Squamous Intraepithelial Lesions of the Cervix genetics, Human papillomavirus 16 genetics, Keratin-14 genetics, Papillomavirus E7 Proteins genetics, Skin pathology, Squamous Intraepithelial Lesions of the Cervix immunology, Squamous Intraepithelial Lesions of the Cervix virology
- Abstract
Currently available vaccines prevent HPV infection and development of HPV-associated malignancies, but do not cure existing HPV infections and dysplastic lesions. Persistence of infection(s) in immunocompetent patients may reflect induction of local immunosuppressive mechanisms by HPV, providing a target for therapeutic intervention. We have proposed that a mouse, expressing HPV16 E7 oncoprotein under a Keratin 14 promoter (K14E7 mice), and which develops epithelial hyperplasia, may assist with understanding local immune suppression mechanisms that support persistence of HPV oncogene-induced epithelial hyperplasia. K14E7 skin grafts recruit immune cells from immunocompetent hosts, but consistently fail to be rejected. Here, we review the literature on HPV-associated local immunoregulation, and compare the findings with published observations on the K14E7 transgenic murine model, including comparison of the transcriptome of human HPV-infected pre-malignancies with that of murine K14E7 transgenic skin. We argue from the similarity of i) the literature findings and ii) the transcriptome profiles that murine K14E7 transgenic skin recapitulates the cellular and secreted protein profiles of high-grade HPV-associated lesions in human subjects. We propose that the K14E7 mouse may be an appropriate model to further study the immunoregulatory effects of HPV E7 expression, and can facilitate development and testing of therapeutic vaccines., (Copyright © 2017 The Authors. Published by Elsevier B.V. All rights reserved.)
- Published
- 2018
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22. Human papillomavirus e7 oncoprotein transgenic skin develops an enhanced inflammatory response to 2,4-dinitrochlorobenzene by an arginase-1-dependent mechanism.
- Author
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Tran LS, Bergot AS, Mattarollo SR, Mittal D, and Frazer IH
- Subjects
- Animals, Drug Eruptions pathology, Ear, External immunology, Ear, External pathology, Female, Human papillomavirus 16 immunology, Immunity, Innate drug effects, Male, Mice, Inbred C57BL, Mice, Knockout, Myeloid Cells drug effects, Myeloid Cells immunology, Papillomavirus E7 Proteins metabolism, Papillomavirus Infections immunology, Skin drug effects, Skin pathology, Th2 Cells drug effects, Th2 Cells immunology, Arginase metabolism, Dinitrofluorobenzene toxicity, Drug Eruptions immunology, Papillomavirus E7 Proteins immunology, Skin immunology
- Abstract
We have shown that the expression of human papillomavirus type 16 E7 (HPV16.E7) protein within epithelial cells results in local immune suppression and a weak and ineffective immune response to E7 similar to that occuring in HPV-associated premalignancy and cancers. However, a robust acute inflammatory stimulus can overcome this to enable immune elimination of HPV16.E7-transformed epithelial cells. 2,4-Dinitrochlorobenzene (DNCB) can elicit acute inflammation and it has been shown to initiate the regression of HPV-associated genital warts. Although the clinical use of DNCB is discouraged owing to its mutagenic potential, understanding how DNCB-induced acute inflammation alters local HPV16.E7-mediated immune suppression might lead to better treatments. Here, we show that topical DNCB application to skin expressing HPV16.E7 as a transgene induces a hyperinflammatory response, which is not seen in nontransgenic control animals. The E7-associated inflammatory response is characterized by enhanced expression of Th2 cytokines and increased infiltration of CD11b(+)Gr1(int)F4/80(+)Ly6C(hi)Ly6G(low) myeloid cells, producing arginase-1. Inhibition of arginase with an arginase-specific inhibitor, N(omega)-hydroxy-nor-L-arginine, ameliorates the DNCB-induced inflammatory response. Our results demonstrate that HPV16.E7 protein enhances DNCB-associated production of arginase-1 by myeloid cells and consequent inflammatory cellular infiltration of skin.
- Published
- 2014
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23. Serologic response to human papillomavirus 16 among Australian women with high-grade cervical intraepithelial neoplasia.
- Author
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Tabrizi SN, Frazer IH, and Garland SM
- Subjects
- Antigens, Viral immunology, Australia, Cross-Sectional Studies, DNA Probes, HPV analysis, DNA, Viral analysis, Female, Human papillomavirus 16 isolation & purification, Human papillomavirus 18 immunology, Humans, Uterine Cervical Dysplasia immunology, Antibodies, Viral blood, Human papillomavirus 16 immunology, Uterine Cervical Dysplasia virology
- Abstract
This study evaluated the detection of human papillomavirus (HPV) 16 antibody in HPV 16-associated cervical intraepithelial neoplasia (CIN) in Australian women. Seroreactivity to HPV 16 L1 virus-like particles was assessed in patients with CIN 2 (n= 169) and CIN 3 (n= 229) lesions previously tested for the presence of HPV DNA. Seropositivity was significantly commoner in women with HPV 16 DNA-positive lesions (98/184) than in women with no HPV DNA in the lesion (15/47) or with HPV of types other than 16 in the lesion (43/167) (P= 0.0004). In addition, seropositivity was observed in 33% (55/169) of women with CIN 2 and 46% (106/229) of women with CIN 3, in keeping with the lower fraction of CIN 2 (57/169) than CIN 3 (127/229) biopsies positive for HPV 16 DNA. HPV 16 seropositivity is most common in women with HPV 16-associated CIN, but many patients with HPV-associated CIN 3 are seronegative, and HPV 16 seropositivity is common in women with CIN associated with other HPV types. Overall, HPV 16 serology is a poor predictor of presence of HPV 16-associated CIN 3 in patient population studied.
- Published
- 2006
- Full Text
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24. Expression of the HPV16E7 oncoprotein by thymic epithelium is accompanied by disrupted T cell maturation and a failure of the thymus to involute with age.
- Author
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Malcolm KM, Gill J, Leggatt GR, Boyd R, Lambert P, and Frazer IH
- Subjects
- Animals, Apoptosis, CD4 Antigens metabolism, CD8 Antigens metabolism, Cell Movement, Down-Regulation, Fibroblasts, Gene Expression Regulation, Mice, Oncogene Proteins, Viral genetics, Papillomavirus E7 Proteins, Sexual Maturation physiology, Thymus Gland anatomy & histology, Thymus Gland cytology, Thymus Gland growth & development, Time Factors, Aging physiology, Cell Differentiation, Epithelium metabolism, Oncogene Proteins, Viral metabolism, T-Lymphocytes cytology, T-Lymphocytes immunology, Thymus Gland metabolism
- Abstract
Transgenic mice expressing the E7 protein of HPV16 from the keratin 14 promoter demonstrate increasing thymic hypertrophy with age. This hypertrophy is associated with increased absolute numbers of all thymocyte types, and with increased cortical and medullary cellularity. In the thymic medulla, increased compartmentalization of the major thymic stromal cell types and expansion of thymic epithelial cell population is observed. Neither an increased rate of immature thymocyte division nor a decreased rate of immature thymocyte death was able to account for the observed hypertrophy. Thymocytes with reduced levels of expression of CD4 and/or CD8 were more abundant in transgenic (tg) mice and became increasingly more so with age. These thymic SP and DP populations with reduced levels of CD4 and/or CD8 markers had a lower rate of apoptosis in the tg than in the non-tg mice. The rate of export of mature thymocytes to peripheral lymphoid organs was less in tg animals relative to the pool of available mature cells, particularly for the increasingly abundant CD4lo population. We therefore suggest that mature thymocytes that would normally die in the thymus gradually accumulated in E7 transgenic animals, perhaps as a consequence of exposure to a hypertrophied E7-expressing thymic epithelium or to factors secreted by this expanded thymic stromal cell population. The K14E7 transgenic mouse thus provides a unique model to study effects of the thymic epithelial cell compartment on thymus development and involution.
- Published
- 2003
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25. Polynucleotide viral vaccines: codon optimisation and ubiquitin conjugation enhances prophylactic and therapeutic efficacy.
- Author
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Liu WJ, Zhao KN, Gao FG, Leggatt GR, Fernando GJ, and Frazer IH
- Subjects
- Animals, Antibodies, Viral blood, Codon genetics, Female, Genes, Viral, Humans, Hypersensitivity, Delayed, Immunity, Cellular, Mice, Mice, Inbred BALB C, Mice, Inbred C57BL, Neutralization Tests, Papillomaviridae pathogenicity, Papillomavirus Infections immunology, Papillomavirus Infections prevention & control, Papillomavirus Infections therapy, T-Lymphocytes, Cytotoxic immunology, Tumor Virus Infections immunology, Tumor Virus Infections prevention & control, Tumor Virus Infections therapy, Ubiquitin immunology, Vaccines, Conjugate genetics, Vaccines, Conjugate pharmacology, Vaccines, Conjugate therapeutic use, Vaccines, DNA genetics, Vaccines, DNA pharmacology, Vaccines, DNA therapeutic use, Viral Vaccines genetics, Viral Vaccines therapeutic use, Papillomaviridae genetics, Papillomaviridae immunology, Viral Vaccines pharmacology
- Abstract
Papillomavirus infection is a major antecedent of anogenital malignancy. We have previously established that the L1 and L2 capsid genes of papillomavirus have suboptimal codon usage for expression in mammalian cells. We now show that the lack of immunogenicity of polynucleotide vaccines based on the L1 gene can be overcome with codon modified L1, which induces strong immune responses, including conformational virus neutralising antibody and delayed type hypersensitivity. Conjugation of a ubiquitin gene to a hybrid gene incorporating L1 and the E7 non-structural papillomavirus protein improved E7 specific CTL responses, and induced protection against an E7 expressing tumour, but induced little neutralising antibody. However, a mixture of ubiquitin conjugated and non-ubiquitin conjugated polynucleotides induced virus neutralising antibody and E7 specific CD8 T cells. An optimal combined prophylactic/therapeutic viral vaccine might therefore comprise ubiquitin conjugated and non-ubiquitinated genes, to induce prophylactic neutralising antibody and therapeutic cell mediated immune responses.
- Published
- 2001
- Full Text
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26. Tolerance or immunity to a tumor antigen expressed in somatic cells can be determined by systemic proinflammatory signals at the time of first antigen exposure.
- Author
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Frazer IH, De Kluyver R, Leggatt GR, Guo HY, Dunn L, White O, Harris C, Liem A, and Lambert P
- Subjects
- Animals, Antigens, Bacterial administration & dosage, Antigens, Bacterial immunology, Antigens, Neoplasm biosynthesis, Antigens, Neoplasm genetics, Antigens, Neoplasm metabolism, Cells, Cultured, Female, Graft Rejection genetics, Graft Rejection immunology, Inflammation genetics, Inflammation immunology, Injections, Intravenous, Keratinocytes immunology, Keratinocytes metabolism, Listeriosis genetics, Listeriosis immunology, Mice, Mice, Inbred C57BL, Mice, Transgenic, Oncogene Proteins, Viral biosynthesis, Oncogene Proteins, Viral genetics, Oncogene Proteins, Viral immunology, Papillomaviridae genetics, Papillomaviridae immunology, Papillomavirus E7 Proteins, Signal Transduction genetics, Skin Transplantation immunology, Skin Transplantation methods, Time Factors, Tumor Cells, Cultured, Antigen Presentation genetics, Antigens, Neoplasm immunology, Immune Tolerance genetics, Signal Transduction immunology
- Abstract
Mice transgenic for the E7 tumor Ag of human papillomavirus type 16, driven from a keratin 14 promoter, express E7 in keratinocytes but not dendritic cells. Grafted E7-transgenic skin is not rejected by E7-immunized mice that reject E7-transduced transplantable tumors. Rejection of recently transplanted E7-transgenic skin grafts, but not of control nontransgenic grafts or of established E7-transgenic grafts, is induced by systemic administration of live or killed Listeria monocytogenes or of endotoxin. Graft recipients that reject an E7 graft reject a subsequent E7 graft more rapidly and without further L. monocytogenes exposure, whereas recipients of an E7 graft given without L. monocytogenes do not reject a second graft, even if given with L. monocytogenes. Thus, cross-presentation of E7 from keratinocytes to the adaptive immune system occurs with or without a proinflammatory stimulus, but proinflammatory stimuli at the time of first cross-presentation of Ag can determine the nature of the immune response to the Ag. Furthermore, immune effector mechanisms responsible for rejection of epithelium expressing a tumor Ag in keratinocytes are different from those that reject an E7-expressing transplantable tumor. These observations have implications for immunotherapy for epithelial cancers.
- Published
- 2001
- Full Text
- View/download PDF
27. Re: Cervical carcinoma and human papillomavirus: on the road to preventing a major human cancer.
- Author
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Bosch FX, Muñoz N, de Sanjosé S, Franco EL, Lowy DR, Schiffman M, Franceschi S, Kjaer SK, Meijer CJ, Frazer IH, and Cuzick J
- Subjects
- DNA, Viral isolation & purification, Female, Humans, Papillomaviridae genetics, Papillomavirus Infections complications, Tumor Virus Infections complications, Uterine Cervical Neoplasms virology, Papillomaviridae immunology, Papillomaviridae isolation & purification, Papillomavirus Infections prevention & control, Tumor Virus Infections prevention & control, Uterine Cervical Neoplasms prevention & control, Viral Vaccines therapeutic use
- Published
- 2001
- Full Text
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28. Nonspecific down-regulation of CD8+ T-cell responses in mice expressing human papillomavirus type 16 E7 oncoprotein from the keratin-14 promoter.
- Author
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Tindle RW, Herd K, Doan T, Bryson G, Leggatt GR, Lambert P, Frazer IH, and Street M
- Subjects
- Animals, Down-Regulation, Female, Humans, Immunization, Immunologic Memory, Keratin-14, Mice, Papillomavirus E7 Proteins, Receptors, Antigen, T-Cell physiology, Receptors, Antigen, T-Cell, alpha-beta physiology, T-Lymphocytes, Cytotoxic immunology, Uterine Cervical Neoplasms virology, CD8-Positive T-Lymphocytes immunology, Keratins genetics, Oncogene Proteins, Viral physiology, Promoter Regions, Genetic
- Abstract
The E7 oncoprotein of human papillomavirus 16 (HPV16) transforms basal and suprabasal cervical epithelial cells and is a tumor-specific antigen in cervical carcinoma, to which immunotherapeutic strategies aimed at cytotoxic T-lymphocyte (CTL) induction are currently directed. By quantifying major histocompatibility complex class I tetramer-binding T cells and CTL in mice expressing an HPV16 E7 transgene from the keratin-14 (K14) promoter in basal and suprabasal keratinocytes and in thymic cortical epithelium, we show that antigen responsiveness of both E7- and non-E7-specific CD8+ cells is down-regulated compared to non-E7 transgenic control mice. We show that the effect is specific for E7, and not another transgene, expressed from the K14 promoter. Down-regulation did not involve deletion of CD8+ T cells of high affinity or high avidity, and T-cell receptor (TCR) Vbeta-chain usage and TCR receptor density were similar in antigen-responsive cells from E7 transgenic and non-E7 transgenic mice. These data indicate that E7 expressed chronically from the K14 promoter nonspecifically down-regulates CD8+ T-cell responses. The in vitro data correlated with the failure of immunized E7 transgenic mice to control the growth of an E7-expressing tumor challenge. We have previously shown that E7-directed CTL down-regulation correlates with E7 expression in peripheral but not thymic epithelium (T. Doan et al., J. Virol. 73:6166-6170, 1999). The findings have implications for the immunological consequences of E7-expressing tumor development and E7-directed immunization strategies. Generically, the findings illustrate a T-cell immunomodulatory function for a virally encoded human oncoprotein.
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- 2001
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29. Association of bovine papillomavirus type 1 with microtubules.
- Author
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Liu WJ, Qi YM, Zhao KN, Liu YH, Liu XS, and Frazer IH
- Subjects
- Active Transport, Cell Nucleus drug effects, Animals, Blotting, Western, Bovine papillomavirus 1 drug effects, Bovine papillomavirus 1 physiology, Bovine papillomavirus 1 ultrastructure, Capsid metabolism, Cattle, Cell Line, Cell Membrane drug effects, Cell Membrane metabolism, Cell Membrane virology, Cell Nucleus drug effects, Cell Nucleus metabolism, Cell Nucleus virology, Cytoplasmic Vesicles drug effects, Cytoplasmic Vesicles metabolism, Cytoplasmic Vesicles virology, Fluorescent Antibody Technique, Indirect, Microscopy, Electron, Microtubules chemistry, Microtubules drug effects, Microtubules ultrastructure, Nocodazole pharmacology, Paclitaxel pharmacology, Protein Binding, Temperature, Tubulin metabolism, Virion drug effects, Virion metabolism, Virion physiology, Virion ultrastructure, Warts virology, Bovine papillomavirus 1 metabolism, Microtubules metabolism
- Abstract
Transport of BPV-1 virus from the cell membrane to the nucleus was studied in vitro in CV-1 cells. At reduced temperature (4 degrees C), BPV-1 binding to CV-1 cells was unaffected but there was no transport of virions across the cytosol. Electron microscopy showed BPV-1 virions in association with microtubules in the cytoplasm, a finding confirmed by co-immunoprecipitation of L1 protein and tubulin. Internalization of virus was unimpaired in cells treated with the microtubule-depolymerizing drug nocodazole but virions were retained in cytoplasmic vesicles and not transported to the nucleus. We conclude that a microtubule transport mechanism in CV-1 cells moves intact BPV-1 virions from the cell surface to the nuclear membrane., (Copyright 2001 Academic Press.)
- Published
- 2001
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30. Low level expression of human papillomavirus type 16 (HPV16) E6 in squamous epithelium does not elicit E6 specific B- or T-helper immunological responses, or influence the outcome of immunisation with E6 protein.
- Author
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Azoury-Ziadeh R, Herd K, Fernando GJ, Lambert P, Frazer IH, and Tindle RW
- Subjects
- Amino Acid Sequence, Animals, Antibodies, Viral immunology, Epithelium pathology, Epithelium virology, Epitopes, T-Lymphocyte immunology, Humans, Immunization, Lymphocyte Activation, Mice, Mice, Transgenic, Molecular Sequence Data, Oncogene Proteins, Viral genetics, Papillomaviridae metabolism, Papillomavirus Infections immunology, Papillomavirus Infections pathology, Papillomavirus Infections virology, Peptides chemical synthesis, Peptides chemistry, Peptides immunology, Skin pathology, Tumor Virus Infections immunology, Tumor Virus Infections pathology, Tumor Virus Infections virology, B-Lymphocytes immunology, Epithelium metabolism, Oncogene Proteins, Viral immunology, Oncogene Proteins, Viral metabolism, Papillomaviridae immunology, Repressor Proteins, T-Lymphocytes, Helper-Inducer immunology
- Abstract
Mice transgenic for E6/E7 oncogenes of Human Papillomavirus type 16 display life-long expression of E6 in lens and skin epithelium, and develop inflammatory skin disease late in life, which progresses to papillomata and squamous carcinoma in some mice. We asked whether endogenous expression of E6 induced a specific immunological outcome, i.e. immunity or tolerance, or whether the mice remained immunologically naïve to E6. We show that prior to the onset of skin disease, E6 transgenic mice did not develop a spontaneous E6-directed antibody response, nor did they display T-cell proliferative responses to dominant T-helper epitope peptides within E6. In contrast, old mice in which skin disease had arisen, developed antibodies to E6. We also show that following immunisation with E6, specific antibody responses did not differ significantly among groups of E6-transgenic mice of different ages (and therefore of different durations and amounts of exposure to endogenous E6), and non-transgenic controls. Additionally, E6 immunisation-induced T-cell proliferative responses were similar in E6-transgenic and non-transgenic mice. These data are consistent with the interpretation that unimmunised E6-transgenic mice that have not developed inflammatory skin disease remain immunologically naïve to E6 at the B- and Th levels. There are implications for E6-mediated tumorigenesis in humans, and for the development of putative E6 therapeutic vaccines.
- Published
- 2001
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31. Papillomavirus virus-like particles for the delivery of multiple cytotoxic T cell epitopes.
- Author
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Liu WJ, Liu XS, Zhao KN, Leggatt GR, and Frazer IH
- Subjects
- Amino Acid Sequence, Animals, Cells, Cultured, Chimera, Enzyme-Linked Immunosorbent Assay, Epitopes, T-Lymphocyte immunology, Female, Genetic Vectors, Mice, Mice, Inbred BALB C, Mice, Inbred C57BL, Mice, Transgenic, Molecular Sequence Data, Spodoptera, Virion genetics, Bovine papillomavirus 1 genetics, Epitopes, T-Lymphocyte administration & dosage, T-Lymphocytes, Cytotoxic immunology
- Abstract
Chimeric papillomavirus (PV) virus-like particles (VLPs) based on the bovine papillomavirus type 1 (BPV-1) L1 protein were constructed by replacing the 23-carboxyl-terminal amino acids of the BPV1 major protein L1 with an artificial "polytope" minigene, containing known CTL epitopes of human PV16 E7 protein, HIV IIIB gp120 P18, Nef, and reverse transcriptase (RT) proteins, and an HPV16 E7 linear B epitope. The CTL epitopes were restricted by three different MHC class I alleles (H-2(b), H-2(d), HLA-A*0201). The chimeric L1 protein assembled into VLPs when expressed in SF-9 cells by recombinant baculovirus. After immunization of mice with polytope VLPs in the absence of adjuvant, serum antibodies were detected which reacted with both polytope VLPs and wild-type BPV1L1 VLPs, in addition to the HPV16E7 linear B cell epitope. CTL precursors specific for the HPV16 E7, HIV P18, and RT CTL epitopes were also detected in the spleen of immunized mice. Polytope VLPs can thus deliver multiple B and T epitopes as immunogens to the MHC class I and class II pathways, extending the utility of VLPs as self-adjuvanting immunogen delivery systems., (Copyright 2000 Academic Press.)
- Published
- 2000
- Full Text
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32. Differences in the post-translational modifications of human papillomavirus type 6b major capsid protein expressed from a baculovirus system compared with a vaccinia virus system.
- Author
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Fang NX, Frazer IH, and Fernando GJ
- Subjects
- Animals, Capsid genetics, Electrophoresis, Gel, Two-Dimensional, Fatty Acids metabolism, Glycosylation, Phosphorylation, Protein Engineering methods, Recombinant Proteins genetics, Recombinant Proteins metabolism, Serine, Threonine, Baculoviridae genetics, Capsid metabolism, Papillomaviridae chemistry, Protein Processing, Post-Translational, Vaccinia virus genetics
- Abstract
Virus-like particles (VLPs) are being currently investigated in vaccines against viral infections in humans. There are different recombinant-protein-expression systems available for obtaining the necessary VLP preparation for vaccination. However, the differences in post-translational modifications of the recombinant proteins obtained and their differences in efficacy in eliciting an anti-viral response in vaccines are not well established. In this study we have compared the post-translational modifications of human papillomavirus type-6b major capsid protein L1 (HPV 6bL1) expressed using recombinant baculovirus (rBV) in Sf9 (Spodoptera frugiperda) insect cells, with the protein expressed using recombinant vaccinia virus (rVV) in CV-1 kidney epithelial cells. Two-dimensional gel electrophoresis of biosynthetically labelled rBV-expressed HPV 6bL1 showed several post-translationally modified variants of the protein, whereas rVV-expressed HPV 6bL1 showed only a few variants. Phosphorylations were detected at threonine and serine residues for the L1 expressed from rBV compared with phosphorylation at serine residues only for the L1 expressed from rVV. HPV 6bL1 expressed using rBV incorporated [(3)H]mannose and [(3)H]galactose, whereas HPV 6bL1 expressed using rVV incorporated only [(3)H]galactose. We conclude that post-translational modification of recombinant HPV 6bL1 can differ according to the system used for its expression. Since recombinant L1 protein is a potential human-vaccine candidate, the implication of the observed differences in post-translational modifications on immunogenicity of L1 VLPs warrants investigation.
- Published
- 2000
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33. BPV1 E2 protein enhances packaging of full-length plasmid DNA in BPV1 pseudovirions.
- Author
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Zhao KN, Hengst K, Liu WJ, Liu YH, Liu XS, McMillan NA, and Frazer IH
- Subjects
- Animals, Bovine papillomavirus 1 genetics, COS Cells, Capsid metabolism, Cell Line, DNA, Circular metabolism, Neutralization Tests, Sequence Deletion, Virion genetics, Bovine papillomavirus 1 physiology, Capsid Proteins, DNA, Viral metabolism, DNA-Binding Proteins physiology, Enhancer Elements, Genetic, Plasmids metabolism, Viral Proteins physiology, Virion metabolism, Virus Assembly genetics
- Abstract
We studied determinants of efficient encapsidation of circular DNA, incorporating a PV early region DNA sequence (nt 584-1978) previously shown to enhance packaging of DNA within papillomavirus (PV)-like particles (VLPs). Insect coelomic cells (Sf-9) and cultured monkey kidney cells (Cos-1) were transfected with an 8-kb reporter plasmid incorporating the putative BPV packaging sequence and infected with BPV1 L1 and L2 recombinant baculovirus or vaccinia virus. Heavy (1.34 g/ml) and light (1.30 g/ml) VLPs were produced, and each packaged some of the input plasmid. In light VLPs, truncated plasmids, which nevertheless incorporated the PV-derived DNA packaging sequence, were more common than full-length plasmids. Packaging efficiency of the plasmid was estimated at 1 plasmid per 10(4) VLPs in both Cos-1 and Sf-9 cells. In each cell type, expression of the BPV1 early region protein E2 in trans doubled the quantity of heavy but not light VLPs and also increased the packaging efficiency of full-length circular plasmids by threefold in heavy VLPs. The resultant pseudovirions incorporated significant amounts of E2 protein. Pseudovirions, comprising plasmids packaged within heavy VLPs, mediated the delivery of packaged plasmid into Cos-1 cells, whereby "infectivity" was blocked by antisera to BPV1 L1, but not antisera to BPV1 E4. We conclude that (a) packaging of DNA within PV L1+L2 pseudovirions is enhanced by BPV1 E2 acting in trans, (b) E2 may be packaged with the pseudovirion, and (c) E2-mediated enhancement of packaging favors 8-kb plasmid incorporation over incorporation of shorter DNA sequences., (Copyright 2000 Academic Press.)
- Published
- 2000
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34. E2F-1 induces proliferation-specific genes and suppresses squamous differentiation-specific genes in human epidermal keratinocytes.
- Author
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Dicker AJ, Popa C, Dahler AL, Serewko MM, Hilditch-Maguire PA, Frazer IH, and Saunders NA
- Subjects
- Base Sequence, Biomarkers, Cells, Cultured, DNA Primers, DNA-Binding Proteins genetics, E2F Transcription Factors, E2F1 Transcription Factor, Epidermal Cells, Humans, Retinoblastoma-Binding Protein 1, Transcription Factor DP1, Transcription Factors genetics, Carrier Proteins, Cell Cycle Proteins, Cell Differentiation genetics, Cell Division genetics, DNA-Binding Proteins physiology, Epidermis metabolism, Keratinocytes metabolism, Transcription Factors physiology
- Abstract
Squamous differentiation of keratinocytes is associated with decreases in E2F-1 mRNA expression and E2F activity, and these processes are disrupted in squamous cell carcinoma cell lines. We now show that E2F-1 mRNA expression is increased in primary squamous cell carcinomas of the skin relative to normal epidermis. To explore the relationship between E2F-1 and squamous differentiation further, we examined the effect of altering E2F activity in primary human keratinocytes induced to differentiate. Promoter activity for the proliferation-associated genes, cdc2 and keratin 14, are inhibited during squamous differentiation. This inhibition can be inhibited by overexpression of E2F-1 in keratinocytes. Overexpression of E2F-1 also suppressed the expression of differentiation markers (transglutaminase type 1 and keratin 10) in differentiated keratinocytes. Blocking E2F activity by transfecting proliferating keratinocytes with dominant negative E2F-1 constructs inhibited the expression of cdc2 and E2F-1, but did not induce differentiation. Furthermore, expression of the dominant negative construct in epithelial carcinoma cell lines and normal keratinocytes decreased expression from the cdc2 promoter. These data indicate that E2F-1 promotes keratinocyte proliferation-specific marker genes and suppresses squamous differentiation-specific marker genes. Moreover, these data indicate that targeted disruption of E2F-1 activity may have therapeutic potential for the treatment of squamous carcinomas. Oncogene (2000).
- Published
- 2000
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35. Immune responses induced by BCG recombinant for human papillomavirus L1 and E7 proteins.
- Author
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Jabbar IA, Fernando GJ, Saunders N, Aldovini A, Young R, Malcolm K, and Frazer IH
- Subjects
- Adjuvants, Immunologic administration & dosage, Animals, Antibodies, Viral biosynthesis, BCG Vaccine administration & dosage, BCG Vaccine genetics, Base Sequence, Cloning, Molecular, DNA Primers genetics, Humans, Hypersensitivity, Delayed, Lymphocyte Activation, Mice, Mice, Inbred BALB C, Mice, Inbred C57BL, Oncogene Proteins, Viral genetics, Papillomaviridae genetics, Papillomavirus E7 Proteins, Plasmids genetics, T-Lymphocytes immunology, T-Lymphocytes, Cytotoxic immunology, Vaccines, Synthetic administration & dosage, Vaccines, Synthetic genetics, Viral Proteins, BCG Vaccine immunology, Capsid Proteins, Oncogene Proteins, Viral immunology, Papillomaviridae immunology, Vaccines, Synthetic immunology
- Abstract
Recombinant bacille Calmette-Guerin (BCG) based vaccine delivery systems could potentially share the safety and effectiveness of BCG. We therefore prepared recombinant BCG vaccines which expressed the L1 late protein of the human papillomavirus (HPV) 6b or the E7 early protein of the HPV 16. The two recombinants were evaluated as immunogens in C57BL/6J and BALB/c mice, and compared with a conventional protein/adjuvant system using E7 or L1 mixed with Quil-A adjuvant. rBCG6bL1 and rBCG16E7 primed specific immune responses, represented by DTH, T-proliferation and antibody, and rBCG16E7 induced cytotoxic immune response to E7 protein. The magnitude of the observed responses were less than those elicited by protein/adjuvant vaccine. As recombinant BCG vaccines expressing HPV6bL1 or HPV16E7 persist at low levels in the immunised host, they may be beneficial to prime or retain memory responses to antigens, but are unlikely to be useful as a single component vaccine strategy.
- Published
- 2000
- Full Text
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36. HPV6b virus like particles are potent immunogens without adjuvant in man.
- Author
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Zhang LF, Zhou J, Chen S, Cai LL, Bao QY, Zheng FY, Lu JQ, Padmanabha J, Hengst K, Malcolm K, and Frazer IH
- Subjects
- Adolescent, Adult, Antibodies, Viral blood, Humans, Hypersensitivity, Delayed etiology, Immunization, Middle Aged, Viral Vaccines adverse effects, Capsid immunology, Condylomata Acuminata therapy, Papillomaviridae immunology, Viral Vaccines immunology
- Abstract
Subjects with genital warts were immunized three times or more with HPV6b VLPs without adjuvant. All immunized subjects had DTH to HPV6b L1 protein. Of 32 subjects, nine had HPV6b specific antibody prior to immunization and 22 acquired antibody with immunization. VLP specific antibody increased following a single immunization in 6 of 8 subjects with low level antibody at recruitment. Complete regression of genital warts was observed in 25 of 33 evaluable subjects over the 20-week observation period. We conclude that immunization with HPV6b L1 VLPs without adjuvant induces immunity to the L1 protein epitopes recognised during natural infection, and may accelerate regression of warts.
- Published
- 2000
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37. Multiple conformational epitopes are recognized by natural and induced immunity to the E7 protein of human papilloma virus type 16 in man.
- Author
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Malcolm K, Meschede W, Pawlita M, Koutsky LA, and Frazer IH
- Subjects
- Adult, Antigens, Viral, Tumor blood, Antigens, Viral, Tumor chemistry, Blotting, Western, Enzyme-Linked Immunosorbent Assay, Female, Humans, Immunity, Innate, Oncogene Proteins, Viral blood, Oncogene Proteins, Viral chemistry, Papillomavirus E7 Proteins, Protein Conformation, Radioimmunoprecipitation Assay, Antigens, Viral, Tumor immunology, Epitopes chemistry, Oncogene Proteins, Viral immunology, Papillomaviridae immunology, Papillomavirus Infections immunology, Tumor Virus Infections immunology, Uterine Cervical Neoplasms immunology
- Abstract
The reactivity of sera from patients with cervical cancer with the E7 protein of human papilloma virus type 16 (HPV16) was estimated using a novel non-radioactive immunoprecipitation assay and four established protein- and peptide-based immunoassays. Six of 14 sera from patients with cervical cancer and 1 of 10 sera from healthy laboratory staff showed repeated reactivity with E7 in at least one assay. Four of the 7 reactive sera were consistently reactive in more than one assay, but only one was reactive in all four assays. Following immunization with E7, 2 of 5 patients with cervical cancer had increased E7-specific reactivity, measurable in one or more assays. No single assay was particularly sensitive for E7 reactivity, or predictive of cervical cancer. Mapping of E7 reactivity to specific E7 peptides was unsuccessful, suggesting that natural or induced E7 reactivity in human serum is commonly directed to conformational epitopes of E7. These results suggest that each assay employed in this study measures a different aspect of E7 reactivity, and that various reactivities to E7 may manifest following HPV infection or immunization. This finding is of significance for monitoring of E7 immunotherapy and for serological screening for cervical cancer., (Copyright 2000 S. Karger AG, Basel)
- Published
- 2000
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38. Genetic and environmental causes of variation in basal levels of blood cells.
- Author
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Evans DM, Frazer IH, and Martin NG
- Subjects
- Antigens, CD genetics, Child, Female, Genetics, Medical, Humans, Lymphocyte Subsets, Male, Twins, Dizygotic, Twins, Monozygotic, Blood Cell Count, Erythrocyte Indices genetics
- Abstract
The genetic and environmental determinants of variation in blood cell size and number were investigated in 392 pairs of 12-year-old twins. The following blood cell indices were measured: haemoglobin, red blood cell count, haematocrit, mean corpuscular volume, platelet number, total white cell count, level of neutrophils, monocytes, eosinophils, total lymphocytes, CD3+ lymphocytes, CD4+ lymphocytes, CD8+ lymphocytes, CD19+ lymphocytes, CD56+ lymphocytes and CD4+/CD8+ ratio. Genetic factors contributed significantly to all blood cell measures accounting for between 61 and 96% of variance. Heritability estimates did not differ significantly between males and females, although the sample size of the present study was not large enough to exclude the possibility of sex-limited gene expression. Common environmental factors were important in determining red blood cell count and haematocrit, but were not important in determining basal levels of any white blood cell type.
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- 1999
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39. Capture ElISA and in vitro cell binding assay for the detection of antibodies to human papillomavirus type 6b virus-like particles in patients with anogenital warts.
- Author
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Peng S, Qi Y, Christensen N, Hengst K, Kennedy L, Frazer IH, and Tindle RW
- Subjects
- Adolescent, Adult, Aged, DNA, Viral analysis, Female, Humans, Immunoglobulin G blood, Male, Middle Aged, Neutralization Tests, Oncogene Proteins, Viral genetics, Papillomaviridae genetics, Papillomaviridae isolation & purification, Polymerase Chain Reaction, Protein Binding, Reproducibility of Results, Sensitivity and Specificity, Antibodies, Viral analysis, Condylomata Acuminata virology, Enzyme-Linked Immunosorbent Assay methods, Oncogene Proteins, Viral immunology, Papillomaviridae immunology, Skin Diseases, Infectious virology, Virion immunology
- Abstract
To investigate human papillomavirus (HPV) virus-like particle (VLP)-specific antibody responses among anogenital warts patients, a VLP-based capture ELISA was established. Twenty-six percent (35/134) of control subjects and 50.0% (39/78) of patients with current anogenital warts showed IgG seropositivity to HPV 6b VLPs. HPV 6b VLP-specific antibody responses recognised native VLPs only, and had no cross-reaction with HPV type 16 VLPs. No differences in reactivity were observed between L1 and L1 + L2 VLPs, suggesting that L2 contributes little to the total immunogenicity of the papillomavirus virion. A VLP-cell binding assay was also established. Some sera from patients with anogenital warts specifically inhibited VLP binding to the surface of epithelial cells, suggesting that these antibodies might be functionally neutralising. These data show that serological responses to HPV 6b VLPs were induced among some but not all patients with anogenital warts, and give a proportional estimate of infection in the community.
- Published
- 1999
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40. Expression of the alpha6 integrin confers papillomavirus binding upon receptor-negative B-cells.
- Author
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McMillan NA, Payne E, Frazer IH, and Evander M
- Subjects
- Animals, B-Lymphocytes metabolism, Binding Sites, COS Cells, Flow Cytometry, Humans, Integrin alpha6, Virus Replication, Antigens, CD physiology, B-Lymphocytes virology, Papillomaviridae physiology, Receptors, Virus physiology
- Abstract
Papillomaviruses (PV) bind to a wide range of cell lines in a specific and saturable manner. We have recently identified a candidate receptor for papillomavirus as the alpha6 integrin (Evander et al., J. Virol. 71, 2449-2456, 1997). We have further investigated the role the alpha6 integrin plays in PV binding. Here we show that the cells expressing the alpha6 integrin, partnered with either the beta4 integrin or the beta1 integrin, are equally able to bind PV HPV6b L1 virus-like particles, indicating that the beta partner does not play a major role in virus binding. In order to provide definitive evidence that the alpha6 integrin is required for PV binding we undertook to genetically complement the receptor-negative B-cell line DG75 by expressing the human alpha6A gene. The transduction of the alpha6 integrin gene into DG75 cells results in the cell surface expression of the alpha6 protein and this expression confers upon DG75 cells the ability to bind laminin, a normal ligand for alpha6 integrin. Furthermore, the alpha6 protein is partnered with the beta1 integrin in DG75 cells. Finally, we show that the DG75-alpha6 cells were able to bind papillomavirus VLPs and this binding was inhibited by a functionally blocking anti-alpha6 antibody. Together these data indicate that the alpha6 integrin is a primary cell receptor for papillomaviruses and is both necessary and sufficient for PV binding., (Copyright 1999 Academic Press.)
- Published
- 1999
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41. Nucleotides 1506-1625 of bovine papillomavirus type 1 genome can enhance DNA packaging by L1/L2 capsids.
- Author
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Zhao KN, Frazer IH, Jun Liu W, Williams M, and Zhou J
- Subjects
- Animals, Cattle, DNA, Viral chemistry, Nucleic Acid Conformation, Sequence Analysis, DNA, Bovine papillomavirus 1 genetics, Capsid genetics, Capsid Proteins, DNA, Viral genetics, Genome, Viral
- Abstract
We have previously described a DNA-packaging assay using bovine papillomavirus type 1 (BPV-1) virus-like particles (VLPs) and have identified a region of the BPV genome that assists in packaging. In this study, we identify a specific BPV sequence involved in DNA packaging by BPV-1 VLPs. In the initial screening of BPV-1 genomic sequences essential for DNA packaging, we observed that a plasmid with deletions between nucleotides (nt) 948 and 2113 failed to be packaged into BPV-1 VLPs. However, plasmids containing nt 948 to 2113 were efficiently packaged, suggesting that this 1.2-kb fragment contains a packaging enhancement sequence (PES). Further mapping of the BPV-1 genome showed that this packaging sequence lies between nt 1506 and 1625. Furthermore, this packaging sequence is also recognized by HPV6b VLPs, suggesting that a common packaging mechanism may be used by the two papillomavirus types. Given the phylogenetic difference between these two viral types, it is likely that other papillomavirus types may also use the same packaging mechanism. Identification of the PES has allowed a minimal viral genome sequence to be used in the packaging assay, improving the usefulness of the assay in studying the process of papillomavirus DNA encapsidation., (Copyright 1999 Academic Press.)
- Published
- 1999
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42. Potential strategies utilised by papillomavirus to evade host immunity.
- Author
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Frazer IH, Thomas R, Zhou J, Leggatt GR, Dunn L, McMillan N, Tindle RW, Filgueira L, Manders P, Barnard P, and Sharkey M
- Subjects
- Animals, Epithelial Cells immunology, Epithelial Cells virology, Hematopoietic Stem Cells immunology, Humans, Interferon-alpha immunology, Keratinocytes immunology, Keratinocytes virology, Oncogene Proteins, Viral immunology, Papillomavirus E7 Proteins, T-Lymphocytes, Cytotoxic immunology, Viral Proteins immunology, Papillomaviridae immunology, Papillomavirus Infections immunology, Tumor Virus Infections immunology
- Abstract
The co-evolution of papillomaviruses (PV) and their mammalian hosts has produced mechanisms by which PV might avoid specific and non-specific host immune responses. Low level expression of PV proteins in infected basal epithelial cells, together with an absence of inflammation and of virus-induced cell lysis, restricts the opportunity for effective PV protein presentation to immunocytes by dendritic cells. Additionally, PV early proteins, by a range of mechanisms, may restrict the efficacy of antigen presentation by these cells. Should an immune response be induced to PV antigens, resting keratinocytes (KC) appear resistant to interferon-gamma-enhanced mechanisms of cytotoxic T-lymphocyte (CTL)-mediated lysis, and expression of PV antigens by resting KC can tolerise PV-specific CTL. Thus, KC, in the absence of inflammation, may represent an immunologically privileged site for PV infection. Together, these mechanisms play a part in allowing persistence of PV-induced proliferative skin lesions for months to years, even in immunocompetent hosts.
- Published
- 1999
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43. Post translational modifications of recombinant human papillomavirus type 6b major capsid protein.
- Author
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Fang NX, Frazer IH, Zhou J, and Fernando GJ
- Subjects
- Animals, Capsid metabolism, Cell Line, Glycosylation, Humans, Myristic Acid metabolism, Palmitic Acid metabolism, Phosphorylation, Protein Processing, Post-Translational, Recombinant Proteins genetics, Recombinant Proteins metabolism, Vaccinia virus genetics, Virion metabolism, Capsid genetics, Papillomaviridae genetics
- Abstract
We have determined the post-translational modifications of the major capsid protein, L1 of human papillomavirus (HPV) type 6b. Since this virus cannot be cultured in the laboratory to obtain sufficient material for a study, a recombinant L1 protein produced in a vaccinia virus expression system was used in this investigation. Our results show that this protein is phosphorylated at serine residues and is also glycosylated. No myristoylation or palmitoylation was detected. The fraction of L1 protein incorporated into virus-like particles was not glycosylated. Since recombinant L1 protein is a potential human vaccine candidate, knowledge of the post-translation modifications of this protein may prove useful for the design of anti-HPV vaccines.
- Published
- 1999
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44. T-helper epitopes identified within the E6 transforming protein of cervical cancer-associated human papillomavirus type 16.
- Author
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Azoury-Ziadeh R, Herd K, Fernando GJ, Frazer IH, and Tindle RW
- Subjects
- Amino Acid Sequence, Animals, B-Lymphocytes immunology, Epitope Mapping, Female, Histocompatibility Antigens Class II immunology, Humans, Immunization, Lymph Nodes cytology, Lymph Nodes immunology, Lymphocyte Activation, Mice, Mice, Inbred C57BL, Molecular Sequence Data, Oncogene Proteins, Viral chemistry, Oncogene Proteins, Viral genetics, Papillomavirus E7 Proteins, Papillomavirus Infections immunology, Papillomavirus Infections virology, Peptides chemical synthesis, Peptides immunology, Tumor Virus Infections immunology, Tumor Virus Infections virology, Uterine Cervical Neoplasms immunology, Viral Vaccines immunology, Epitopes, T-Lymphocyte immunology, Oncogene Proteins, Viral immunology, Papillomaviridae immunology, Repressor Proteins, T-Lymphocytes, Helper-Inducer immunology, Uterine Cervical Neoplasms virology
- Abstract
The E6 oncoprotein of human papillomavirus type 16 (HPV16 E6) produced by tumor cells of HPV16-associated cervical carcinoma is poorly immunogenic in patients, but nonetheless is a tumor-specific antigen to which therapeutic vaccine strategies may be directed. To investigate the subunit immunogenicity of E6 protein at the T-helper cell level, we immunized mice with overlapping peptides spanning the entire 158 amino acid sequence. Two peptides recalled a proliferative response in lymph node cells (LNC) from C57BL/6 (H-2b)-immunized mice. One of these peptides also recalled proliferative responses in the context of 5/5 other major histocompatibility complex (MHC) class II haplotypes, indicating a "promiscuous" T-epitope. Minimal consensus motif analysis identified the epitopes as 60VYRDGNPYA68 and 98GYNKPLCDLL107. LNC from mice immunized with T-epitope proliferated in response to challenge with whole E6 protein. Immunization with E6 T-epitopes linked to B-epitopes of HPV16 E7 protein elicited specific antibody indicating that T-cells recognizing the T-epitopes provided cognate "help" for B-cells. LNC from mice co-immunized with E6 T-epitope and the major T-helper epitope of HPV16 E7 (48DRAHYNI54) proliferated comparably when challenged with the peptides individually indicating co-dominance of the two T-epitopes. The findings have implications for incorporation of E6 into a therapeutic vaccine.
- Published
- 1999
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45. T cell-mediated and non-specific inflammatory mechanisms contribute to the skin pathology of HPV 16 E6E7 transgenic mice.
- Author
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Hilditch-Maguire PA, Lieppe DM, West D, Lambert PF, and Frazer IH
- Subjects
- Age Factors, Animals, Cyclosporine therapeutic use, Dinitrochlorobenzene, Female, Humans, Hyperplasia chemically induced, Hyperplasia immunology, Hyperplasia pathology, Immunity, Cellular, Immunosuppressive Agents therapeutic use, Irritants, Mice, Mice, Inbred BALB C, Mice, Nude, Mice, SCID, Oncogene Proteins, Viral genetics, Papillomaviridae genetics, Papillomavirus E7 Proteins, Skin drug effects, Skin immunology, Skin virology, Skin Diseases chemically induced, Skin Diseases drug therapy, Specific Pathogen-Free Organisms, Mice, Transgenic genetics, Repressor Proteins, Skin pathology, Skin Diseases immunology, T-Lymphocytes immunology
- Abstract
One of three lines of mice transgenic for the E6 and E7 genes of human papillomavirus type 16 (HPV16) expressed from an alphaA-crystallin promoter also expresses the transgene ectopically in the skin. This line, designated alphaACE6E7#19, develops skin disease from 3 months of age, characterised by epidermal hyperplasia and eventual skin loss. Administration of complete Freund's adjuvant (CFA) to alphaACE6E7#19 mice, but not to non-transgenic littermate controls, induced local epidermal hyperplasia which was histologically similar to the spontaneously arising skin pathology. Local application of 2,4-dinitrochlorobenzene (DNCB) to DNCB-sensitised alphaACE6E7#19 mice, but not DNCB-sensitised controls, also induced hyperplasia. Treatment with cyclosporin A (CsA) or systemic depletion of CD4+ cells significantly reduced the incidence of skin disease. These data suggest that local inflammation, and cytokines produced by T helper cells, contribute to the induction of hyperplastic skin disease in alphaACE6E7#19 mice. Spontaneous skin disease with similar histological appearance, frequency, age of onset and severity in alphaACE6E7#19 mice was observed in scid-/- alphaACE6E7#19 mice, despite immune paresis. Antigen-specific immune responses and T-cell cytokines are therefore not necessary for the induction of skin disease. We propose that epidermal hyperplasia associated with HPV16 E6 and E7 expression in skin is accelerated by local secretion of pro-inflammatory cytokines, whose production can be enhanced by activated CD4+ T cells.
- Published
- 1999
- Full Text
- View/download PDF
46. Construction and production of fluorescent papillomavirus-like particles.
- Author
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Peng S, Zhou J, and Frazer IH
- Subjects
- Baculoviridae genetics, Bovine papillomavirus 1 growth & development, Capsid Proteins physiology, Cell Line, Green Fluorescent Proteins, Luminescent Proteins physiology, Recombinant Fusion Proteins biosynthesis, Recombinant Fusion Proteins genetics, Virion genetics, Virus Assembly, Bovine papillomavirus 1 physiology, Luminescent Proteins genetics, Virion physiology
- Abstract
The green fluorescent protein (GFP) from the jellyfish Aequorea victoria has attracted widespread interest since it was demonstrated to be fluorescent in vivo when expressed in other organisms. In order to investigate papillomavirus life cycle which hampered by the unavailability of conventional cell culture system, we constructed a chimeric bovine papillomavirus (BPV) type 1 virus-like particles (VLPs) containing GFP. It was found that fluorescent VLPs could be assembled from L2 protein in which GFP is inserted into the N-terminal region of L2 (aa 88). The fluorescent VLPs could also be assembled from a GFP/L2 fusion protein in which part of the L2 sequence had been deleted. In vitro, fluorescent VLPs could bind to CV-1 cells, and this VLP/cell interaction could be analyzed by FACS assay. These results demonstrated that GFP could incorporate into BPV1 VLPs without disruption of the VLP structure. Fluorescent VLPs might be a useful tool for study of papillomavirus virus/cell interaction.
- Published
- 1999
- Full Text
- View/download PDF
47. Mucosal immunisation with papillomavirus virus-like particles elicits systemic and mucosal immunity in mice.
- Author
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Liu XS, Abdul-Jabbar I, Qi YM, Frazer IH, and Zhou J
- Subjects
- Administration, Intranasal, Animals, Antibodies, Viral biosynthesis, Cattle, Cell Division immunology, Female, HIV Envelope Protein gp120 immunology, Injections, Intramuscular, Mice, Mice, Inbred C57BL, Oncogene Proteins, Viral administration & dosage, Oncogene Proteins, Viral immunology, Papillomavirus E7 Proteins, Protein Conformation, Recombinant Fusion Proteins immunology, T-Lymphocytes, Cytotoxic cytology, T-Lymphocytes, Cytotoxic immunology, Viral Proteins administration & dosage, Viral Proteins immunology, Bovine papillomavirus 1 immunology, Immunity, Mucosal, Virion immunology
- Abstract
It has been shown previously that recombinant virus-like particles (VLPs) of papillomavirus can induce VLP-specific humoral and cellular immune responses following parenteral administration. To test whether mucosal administration of bovine papillomavirus type 1 (BPV1) VLPs could produce mucosal as well as systemic immune responses to VLPs, 50 micrograms chimeric BPV1 VLPs containing an HPV16 E7 CTL epitope (BPVL1/E7 VLP) was administered intranasally to mice. After two immunisations, L1-specific serum IgG and IgA were observed. L1-specific IgG and IgA were also found in respiratory and vaginal secretions. Both serum and mucosal antibody inhibited papillomavirus VLP-induced agglutination of RBC, indicating that the antibody induced by mucosal immunisation may recognize conformational determinants associated with virus neutralisation. For comparison, VLPs were given intramuscularly, and systemic and mucosal immune responses were generally comparable following systemic or mucosal delivery. However, intranasal administration of VLP induced significantly higher local IgA response in lung, suggesting that mucosally delivered HPV VLP may be more effective for mediating local mucosal immune responses. Intranasal immunisation with HPV6b L1 VLP produced VLP-specific T proliferative responses in splenocytes, and immunisation with BPVL1 VLP containing an HPV16 E7 CTL epitope induced E7-specific CTL responses. We conclude that immunisation with papillomavirus VLPs via mucosal and intramuscular routes, without adjuvant, can elicit specific antibody at mucosal surfaces and also systemic VLP epitope specific T cell responses. These findings suggest that mucosally delivered VLPs may offer an alternative HPV VLP vaccine strategy for inducing protective humoral immunity to anogenital HPV infection, together with cell-mediated immune responses to eliminate any cells which become infected.
- Published
- 1998
- Full Text
- View/download PDF
48. Histologic and immunohistochemical responses after aortic valve allografts in the rat.
- Author
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Green MK, Walsh MD, Dare A, Hogan PG, Zhao XM, Frazer IH, Bansal AS, and O'Brien MF
- Subjects
- Animals, Antibody Formation, Aortic Valve chemistry, Aortic Valve pathology, CD4 Lymphocyte Count, CD4-Positive T-Lymphocytes pathology, CD8-Positive T-Lymphocytes pathology, Cell Count, Endothelium, Vascular pathology, Female, Fibroblasts pathology, Fibrosis, Histocompatibility Antigens Class I analysis, Histocompatibility Antigens Class II analysis, Humans, Immunity, Cellular, Immunohistochemistry, Lymphocyte Count, Macrophages pathology, Major Histocompatibility Complex immunology, Rats, Rats, Inbred Lew, Rats, Inbred Strains, Transplantation Immunology, Transplantation, Homologous, Transplantation, Isogeneic, Tunica Media pathology, Aortic Valve transplantation
- Abstract
Background: Human aortic valve allografts elicit a cellular and humoral immune response. It is not clear whether this is important in promoting valve damage. We investigated the changes in morphology, cell populations, and major histocompatibility complex antigen distribution in the rat aortic valve allograft., Methods: Fresh heart valves from Lewis rats were transplanted into the abdominal aorta of DA rats. Valves from allografted, isografted, and presensitized recipient rats were examined serially with standard morphologic and immunohistochemical techniques., Results: In comparison with isografts, the allografts were infiltrated and thickened by increased numbers of CD4+ and CD8+ lymphocytes, macrophages, and fibroblasts. Thickening of the valve wall and leaflet and the density of the cellular infiltrate was particularly evident after presensitization. Endothelial cells were frequently absent in presensitized allografts whereas isografts had intact endothelium. Cellular major histocompatibility complex class I and II antigens in the allograft were substantially increased. A long-term allograft showed dense fibrosis and disruption of the media with scattered persisting donor cells., Conclusions: The changes in these aortic valve allograft experiments are consistent with an allograft immune response and confirm that the response can damage aortic valve allograft tissue.
- Published
- 1998
- Full Text
- View/download PDF
49. The role of the immune system in anogenital human papillomavirus.
- Author
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Frazer IH
- Subjects
- Antibody Formation, Antigen-Presenting Cells immunology, Antigens, Viral immunology, Cell Division, Condylomata Acuminata virology, Cytokines immunology, Humans, Immunity, Cellular, Immunocompetence, Inflammation Mediators immunology, T-Lymphocytes immunology, Viral Proteins immunology, Virus Replication, Condylomata Acuminata immunology, Papillomaviridae immunology, Papillomavirus Infections immunology, Tumor Virus Infections immunology
- Abstract
There is substantial evidence from experiments of nature that immune competence plays a major part in determining the outcome of anogenital human papillomavirus (HPV) infection. Cellular rather than humoral immunity would appear to be the key to the control and eradication of HPV-induced warts. It seems likely that the HPV early proteins, which are responsible for viral replication (E1 and E2) and for promoting tissue proliferation (E6 and E7) will be the target antigens recognized by antigen-specific T cells. Natural infection is slow to produce an appropriate therapeutic immune response to these proteins, probably because HPV has adopted a strategy to prevent the effective presentation of viral antigens to the host immune system. Human papillomavirus infection is non-lytic so there is little release of viral antigen to professional antigen-presenting cells. Additionally no local proinflammatory cytokine production and no local inflammation is induced by HPV infection. An optimal therapeutic strategy for anogenital HPV infection would be, therefore, to accelerate the induction of a strong virus-specific immune response by inducing local inflammation and the cytokines necessary to invoke HPV-specific immunity.
- Published
- 1998
50. Simplifying the molecular mechanisms of human papillomavirus.
- Author
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Saunders NA and Frazer IH
- Subjects
- Antigens, Viral genetics, Capsid genetics, Cell Transformation, Viral genetics, Condylomata Acuminata virology, DNA-Binding Proteins genetics, Female, Genes, Tumor Suppressor genetics, Genes, Viral genetics, Humans, Keratinocytes cytology, Keratinocytes metabolism, Molecular Biology, Nuclear Proteins genetics, Oncogene Proteins, Viral genetics, Papillomaviridae classification, Papillomaviridae physiology, Papillomavirus Infections physiopathology, Transcription, Genetic, Tumor Virus Infections physiopathology, Uterine Cervical Neoplasms virology, Viral Proteins genetics, Virus Replication genetics, Papillomaviridae genetics
- Abstract
Human papillomaviruses are a common human pathogen responsible for diseases varying in severity from warts to cervical cancer. This article examines the functions of the viral gene products and how they interact with cellular factors to replicate themselves and cause disease.
- Published
- 1998
- Full Text
- View/download PDF
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