Intracutaneous DNA Vaccination with the E8 Gene of Cottontail Rabbit Papillomavirus Induces Protective Immunity against Virus Challenge in Rabbits

Hu, Jiafen; Han, Ruiqin; Cladel, Nancy M.; Pickel, M.; Christensen, Neil D.

doi:10.1128/jvi.76.13.6453-6459.2002

Cited by 40 publications

(72 citation statements)

References 51 publications

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“…Because CRPV DNA can be modified extensively without losing its ability to induce papillomas on animals, we are able to examine efficiency and specificity of different vaccine candidates in this model system [22]. Most of the CRPV early proteins are immunogenic and can provide partial or complete protection against viral infection by stimulating cell-mediated immune responses in rabbits [12,23]. In contrast, late proteins (L1 and L2) predominantly stimulate strong humoral immune responses that result in complete protection against virus infection [24,25].…”

Section: Discussionmentioning

confidence: 99%

Protective immunity with an E1 multivalent epitope DNA vaccine against cottontail rabbit papillomavirus (CRPV) infection in an HLA-A2.1 transgenic rabbit model

Cladel

Peng

et al. 2008

Vaccine

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Cottontail rabbit papillomavirus (CRPV)/rabbit model is widely used to study pathogenesis of papillomavirus infections and malignant tumor progression. Recently, we established HLA-A2.1 transgenic rabbit lines and demonstrated efficacy for the testing of immunogenicity of a well-known A2-resticted epitope (HPV16E7/82-90) [1]. In the present study, we screened five HLA-A2.1 restricted epitopes from CRPV E1 (selected using online MHCI epitope prediction software) and constructed a multivalent epitope DNA vaccine (CRPVE1ep1-5). CRPVE1ep1-5 and a control DNA vaccine (Ub3) were then delivered intracutaneously onto normal and HLA-A2.1 transgenic rabbits respectively by a helium-driven gene-gun delivery system. One, two or three immunizations were given to different groups of animals from both New Zealand White outbred and EIII/JC inbred genetic background. Two and three immunizations with CRPVE1ep1-5 DNA vaccine provided complete protection against viral DNA infection of HLA-A2.1 transgenic rabbits from both genetic backgrounds but not in the control vaccinated groups. One immunization, however, failed to protect HLA-A2.1 transgenic rabbits against viral DNA infection. This study further demonstrated that the HLA-A2.1 transgenic rabbits can be used to test the immunogenicity of HLA-A2.1 restricted epitopes identified by MHCI epitope predication software.

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Section: Discussionmentioning

confidence: 99%

Protective immunity with an E1 multivalent epitope DNA vaccine against cottontail rabbit papillomavirus (CRPV) infection in an HLA-A2.1 transgenic rabbit model

Cladel

Peng

et al. 2008

Vaccine

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“…The virus was found to be reliably infectious at dilutions of 10 −2 in previous studies (Han et al 2000). H.CRPV DNA cloned at SalI was used for this study (Hu et al 2002b). The Hershey strain differs minimally from the reference clone (GenBank accession number is KO2708 for reference clone), primarily in the putative E5 region but also in other regions throughout the genome.…”

Section: Hershey Crpv Virus and Crpv Dnamentioning

confidence: 99%

“…For gene gun delivery, the bullets were prepared as described previously (Hu et al 2002b). In brief, the DNA was concentrated to 1µg/µl and coated onto 1.6 micron gold particles following the protocol supplied by the manufacturer.…”

Section: Dna Infectionmentioning

confidence: 99%

Wounding prior to challenge substantially improves infectivity of cottontail rabbit papillomavirus and allows for standardization of infection

Cladel

Balogh

et al. 2008

Journal of Virological Methods

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The cottontail rabbit papillomavirus (CRPV) / rabbit model has proved useful for the investigation of prophylactic and therapeutic vaccines and for the study of the pathogenesis of papillomavirus infection. It is currently the only animal model in which the entire viral program can be recapitulated, including progression to cancer. CRPV DNA is infectious in domestic rabbits and therefore mutants can be studied without the need to generate corresponding viruses. Although the CRPV animal model is used widely in various laboratories, no optimized or standardized method is used for creating CRPV viral and especially DNA infections. These different methods have made it difficult for investigators to compare results from laboratory to laboratory. A simple and highly efficient method is reported here; it has been refined based on previous methodology for the production of CRPV infections from both virus and plasmid DNA. This method can be adapted easily by other investigators in the field. The resulting standardization will aid in the evaluation of data from different laboratories.

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“…CRPV E8 shows little, if any, transforming activity in vitro (31) but has been reported to induce anchorage-independent growth of rodent cell lines in the presence of platelet-derived growth factor (PDGF) (30). The E8 protein has been shown to induce protective immunity against virus challenge in rabbits and has been reported to play a role in papilloma growth but not to be essential for papilloma formation (34).…”

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confidence: 99%

Cottontail Rabbit Papillomavirus E8 Protein Is Essential for Wart Formation and Provides New Insights into Viral Pathogenesis

Nonnenmacher¹,

Salmon²,

Jacob

et al. 2006

J Virol

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The cottontail rabbit papillomavirus (CRPV) a and b subtypes display a conserved E8 open reading frame encoding a 50-amino-acid hydrophobic protein, with structural similarities to the E5 transmembrane oncoprotein of genital human PVs (HPVs). CRPV E8 has been reported to play a role in papilloma growth but not to be essential in papilloma formation. Here we report that the knockout of E8 start codon almost prevented wart induction upon biobalistic inoculation of viral DNA onto rabbit skin. The scarce warts induced showed very slow growth, despite sustained expression of E6 and E7 oncogenes. This points to an essential role of E8 in disturbing epidermal homeostasis. Using a yeast two-hybrid screen, we found that E8 interacted with the zinc transporter ZnT1, protocadherin 1 (PCDH1), and AHNAK/desmoyokin, three proteins as yet unrelated to viral pathogenesis or cell transformation. HPV16 E5 also interacted with these proteins in two-hybrid assay. CRPV E8 mainly localized to the Golgi apparatus and the early endosomes of transfected keratinocytes and colocalized with ZnT1, PCDH1, and AHNAK. We showed that ZnT1 and PCDH1 formed a complex and that E8 disrupted this complex. CRPV E8, like HPV16 E5, increased epidermal growth factor (EGF)-dependent extracellular signal-regulated kinase 1/2 (ERK1/2) phosphorylation and both the EGF-dependent and the EGF-independent activity of activating protein-1 (AP-1). Competition experiments with a nonfunctional truncated ZnT1 protein showed that E8-ZnT1 interaction was required for AP-1 activation. Our data identify CRPV E8 as a key player in papilloma induction and unravel novel cellular targets for inducing the proliferation of keratinocytes.Papillomaviruses (PVs) are small DNA viruses that induce cutaneous and mucosal epithelial proliferations in animals and humans. These lesions usually regress, but those associated with a subset of PVs may persist and progress into invasive carcinomas. The Shope cottontail rabbit papillomavirus (CRPV) induces skin warts and carcinomas in domestic rabbits (50). Among human PVs (HPVs), HPV5 is associated with flat wartlike lesions and carcinomas of the skin in patients suffering from epidermodysplasia verruciformis (47), and genital highrisk HPVs, mainly HPV16 and -18, cause anogenital intraepithelial lesions and are responsible for the vast majority of carcinomas of the uterine cervix (64). PVs contain two main oncogenes, E6 and E7, that are essential for epithelial proliferation and vegetative viral DNA replication. Both play a central role in the malignant progression of lesions associated with high-risk genotypes (for reviews, see references 10 and 44). High-and low-risk genital HPVs encode also an E5 oncoprotein with weak transforming activity in vitro. HPV E5 are short hydrophobic proteins associated with intracellular membranes that upregulate the mitogen-activated protein kinase (MAPK) signal cascade initiated by the epidermal growth factor (EGF) receptor (reviewed in reference 20) and increase the transcription of jun and fos early respo...

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Intracutaneous DNA Vaccination with the E8 Gene of Cottontail Rabbit Papillomavirus Induces Protective Immunity against Virus Challenge in Rabbits

Cited by 40 publications

References 51 publications

Protective immunity with an E1 multivalent epitope DNA vaccine against cottontail rabbit papillomavirus (CRPV) infection in an HLA-A2.1 transgenic rabbit model

Protective immunity with an E1 multivalent epitope DNA vaccine against cottontail rabbit papillomavirus (CRPV) infection in an HLA-A2.1 transgenic rabbit model

Wounding prior to challenge substantially improves infectivity of cottontail rabbit papillomavirus and allows for standardization of infection

Cottontail Rabbit Papillomavirus E8 Protein Is Essential for Wart Formation and Provides New Insights into Viral Pathogenesis

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