Enhanced Immunogenicity of HPV 16 E7 Fusion Proteins in DNA Vaccination

Michel, Nico; Osen, Wolfram; Gissmann, Lutz; Schumacher, Ton N.; Zentgraf, Hanswalter; Müller, Martin

doi:10.1006/viro.2001.1321

Cited by 70 publications

(48 citation statements)

References 41 publications

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“…Our results proved that VP22 could make the SS more easily recognized and processed by the mouse immunity system, and then enhanced the immunogenicity of antigen. Moreover, it is consistent with the results of Michel and Kim (Michel et al, 2002;Kim et al, 2004). They proved that VP22 may improve immune presentation in different ways, either through enhanced direct priming by transfected antigenpresenting cells (APCs) or by amplified cross-presentation after release from transfected nonprofessional APCs.…”

Section: Discussionsupporting

confidence: 89%

Evaluation of the VP22 gene adjuvant for enhancement of DNA vaccine against somatostatin in mice

Han

Liang

Zhang

et al. 2008

Animal

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Somatostatin (SS) is a hormone that inhibits the secretion of growth hormone. Immunization against SS can promote the growth of animals. A novel SS-VP22 fused vaccine, pEGS2SS-V, was constructed from pEGS2SS plasmid with a VP22 gene fragment. Two times of immunization with pEGS2SS-V-induced anti-SS antibodies in mice. Compared with mice immunized with pEGS2SS and 0.85% saline, the growth performance of mice immunized with pEGS2SS-V was increased by 14.1% (P , 0.05) and 48.4% (P , 0.01) on the 2nd week after the first vaccination, respectively. The results indicated that the effects of the somatostatin DNA vaccine could be improved effectively by VP22 gene adjuvant.Keywords: BHV-1 VP22, somatostatin, DNA vaccine IntroductionThe circadian and pulsatile secretion of growth hormone (GH) from the anterior pituitary gland plays a crucial role in postnatal longitudinal growth and development, tissue growth, lactation, reproduction, as well as protein, lipid and carbohydrate metabolism (Ohlsson et al., 1998;Ayuk and Sheppard, 2006). The secretion of GH is down-regulated by somatostatin (SS), which is secreted by the hypothalamus (Vance et al., 1992). The SS has broad inhibitory effect on animals, especially on animal growth and immune response; thus, exhausting or immuno-neutralizing the SS level could lead to increase in GH and promote animal growth (Ohlsson et al., 1998). Therefore, as an alternative approach to direct GH injection, immunization against SS that inhibits GH secretion has been suggested as a method to promote the growth of animals by inactivating SS in the plasma.SS is a 14-peptide-hormone with a small molecular weight and a very short half-life. Synthetic SS conjugated to a carrier protein promotes the growth rates of immunized animals, including lambs, steers and chickens (Buonomo et al., 1987;Van Kessel et al., 1990). However, native SS preparation is limited in source.Chemical synthesis is inefficient for polypeptides longer than about 300 amino acids, and the synthesized proteins may not readily assume their native tertiary structure. Besides, these programs are time-consuming and relatively expensive, which limit the application of SS immunization to promote animal growth.DNA immunization represents a novel vaccine strategy (Tang et al., 1992). So far, there have been several reports on DNA vaccines encoding the SS gene that can promote the growth of immunized animals in our lab (Liang et al., 2008). However, the potency of naked DNA vaccines is limited by their inability to amplify and spread in vivo; in primates and other large animals the responses are less impressive and the quantities of DNA required may be large (Calarota et al., 1998;Macgregor et al., 1998;Wang et al., 1998). It was reported that the tegument protein VP22 of bovine herpesvirus-1 (BHV-1) could increase the immunogenicity of antigens to which it was fused (Oliveira et al., 2001;Wills et al., 2001;Hung et al., 2002). VP22 of BHV-1 is a 258 amino acid tegument protein (Liang et al., 1995) that can transport proteins to neighbor...

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Section: Discussionsupporting

confidence: 89%

Evaluation of the VP22 gene adjuvant for enhancement of DNA vaccine against somatostatin in mice

Han

Liang

Zhang

et al. 2008

Animal

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“…Although this hypothesis is attractive, several observations indicated that the immune enhancement might be unrelated to the apparent translocatory functions. For example, a VP22 deletion mutant that lacked translocatory activity was, nevertheless, able to increase the immunogenicity of an attached antigen, 28 and VP22 alone appeared to increase tumor immunity, 12 suggesting the possibility that this viral protein might have a nonspecific adjuvant effect.…”

Section: Discussionmentioning

confidence: 99%

The cationic region from HIV tat enhances the cell-surface expression of epitope/MHC class I complexes

et al. 2003

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The potential of genetic immunization has been acknowledged for almost a decade, but disappointing immunogenicity in humans has delayed its introduction into the clinical arena. To try to increase the potency of genetic immunization, we and others have evaluated 'translocatory' proteins, which are thought to exit living cells by an uncharacterized pathway, and enter neighboring cells in an energy-independent manner. Several laboratories, including our own, have begun to question these remarkable properties. Our previous studies showed that the ability of an epitope to induce major histocompatibility complex (MHC) class I restricted CD8 þ T cells was, indeed, enhanced by its being attached to the proposed translocatory sequence of the HIV-1 tat protein. However, we found little evidence that the increased immunogenicity resulted from transfer of the fusion peptide between living cells, and we proposed that it resulted instead from an increased epitope/MHC expression on the surface of transfected cells. Here, we directly test this hypothesis. We show that cells cotransfected with plasmids encoding an epitope, and the relevant MHC class I allele, can stimulate epitope-specific T cells, and that attachment of the epitope to a putative translocatory sequence -which we term herein an 'integral cationic region' (ICR) -leads to a marked increase in stimulatory activity. This elevated stimulatory capacity does not result from a nonspecific increase in MHC class I expression. We use a high-affinity T-cell receptor (TcR) specific for the epitope/MHC combination to quantitate directly the cell-surface expression of the immunogenic complex, and we show that the attachment of the tat ICR to an epitope results in a substantial enhancement of its cellsurface presentation. These data suggest an alternative explanation for the immune enhancement seen with ICRs.

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“…By contrast, the CTL tolerance is extremely strong, since attempts to break it with protein or DNA vaccination have thus far been unsuccessful. 12,13 The inability of K10HPV16-E6/E7 Tg mice to mount an E7-specific CTL response is not due to a general CTL unresponsiveness, because these mice are capable of generating specific CTL activity against, for example, ovalbumin. 12 These results suggest that, similar to the HPV-transgenic murine model in which HPV16-E6/E7 is expressed from the K14 promotor, expression from the K10 promotor results in 'split' tolerance, in which antigen-specific CTL responses are strongly suppressed but the antibody and T helper responses remain unaffected.…”

mentioning

confidence: 99%

“…In contrast, pCTL levels in wild-type mice can be determined directly ex vivo, both by Elispot and tetramer analysis. 8 Michel et al 13 recently demonstrated that immunization of K10HPV16-E6/E7 Tg mice with VP22-E7 1-60 DNA was unable to overcome the E7-specific tolerance. Since the experimental conditions of the CTL assay used by these authors differed from the conditions in our experiments, we directly compared the efficacy of the DNA immunization with SFV-enhE6,7 immunization in our model.…”

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confidence: 99%

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Induction of human papilloma virus E6/E7-specific cytotoxic T-lymphocyte activity in immune-tolerant, E6/E7-transgenic mice

Riezebos‐Brilman

Regts

et al. 2005

Gene Ther

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Despite promising preclinical results of various therapeutic anticancer immunization strategies, these approaches may not be effective enough to eradicate tumors in cancer patients. While most animal models are based on fastgrowing transplantable tumors, malignancies in, for example, cervical cancer patients in general develop much more slowly, which may lead to immune suppression and/or immune tolerance. As a consequence, the immunomodulating signal of any therapeutic immunization regimen should be sufficiently potent to overcome this immunocompromised condition. In previous studies, we demonstrated that an experimental vaccine against human papillomavirus (HPV)-induced cervical cancer, based on Semliki Forest virus (SFV), induces robust HPV-specific cellular immune responses in mice. Now we studied whether this strategy is potent enough to also prime a cellular immune response in immune-tolerant HPV transgenic mice, in which CTL activity cannot be induced using protein or DNA vaccines. We demonstrate that, depending on the route of immunization, SFV-expressing HPV16 E6 and E7 indeed has the capacity to induce HPV16 E7-specific cytotoxic T cells in HPVtransgenic mice. Gene Therapy (2005) Cervical cancer is the third most common cancer among women worldwide. It is caused by infection with highrisk human papillomavirus (HPV), in particular types 16, 18, 31, 33 or 45. Indeed, in over 99% of all cervical carcinomas, DNA derived from these HPV types is detectable. 1 High-risk HPVs have the capacity to transform cervical epithelial cells by integrating the open reading frames encoding the viral early proteins E6 and E7 into the host cell genome. This integration may lead to constitutive overexpression of E6 and E7, mediating transformation of the cells to a malignant phenotype. 2 Since the continued production of E6 and E7 is required for the maintenance of the transformed phenotype, E6 and E7 in fact represent tumor-specific antigens in cervical carcinoma and premalignant HPV-transformed cells. As a consequence, E6 and E7 are potential targets for immunotherapeutic intervention strategies involving induction or stimulation of cytotoxic T lymphocyte (CTL) activity against HPV-transformed cells. 3

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Enhanced Immunogenicity of HPV 16 E7 Fusion Proteins in DNA Vaccination

Cited by 70 publications

References 41 publications

Evaluation of the VP22 gene adjuvant for enhancement of DNA vaccine against somatostatin in mice

Evaluation of the VP22 gene adjuvant for enhancement of DNA vaccine against somatostatin in mice

The cationic region from HIV tat enhances the cell-surface expression of epitope/MHC class I complexes

Induction of human papilloma virus E6/E7-specific cytotoxic T-lymphocyte activity in immune-tolerant, E6/E7-transgenic mice

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