title: Anti-tumor effects of genetic vaccines against HPV major oncogenes.
abstract: Expression of HPV E5, E6 and E7 oncogenes are likely to overcome the regulation of cell proliferation and to escape immunological control, allowing uncontrolled growth and providing the potential for malignant transformation. Thus, their three oncogenic products may represent ideal target antigens for immunotherapeutic strategies. In previous attempts, we demonstrated that genetic vaccines against recombinant HPV16 E7 antigen were able to affect the tumor growth in a pre-clinical mouse model. To improve this anti-HPV strategy we developed a novel approach in which we explored the effects of E5-based genetic immunization. We designed novel HPV16 E5 genetic vaccines based on two different gene versions: whole E5 gene and E5Multi. The last one is a long multi epitope gene designed as a harmless E5 version. Both E5 genes were codon optimized for mammalian expression. In addition, we demonstrated that HPV 16 E5 oncogene is expressed in C3 mouse cell line making it an elective model for the study of E5 based vaccine. In this mouse model the immunological and biological activity of the E5 vaccines were assessed in parallel with the activity of anti-E7 and anti-E6 vaccines already reported to be effective in an immunotherapeutic setting. These E7 and E6 vaccines were made with mutated oncogenes, the E7GGG mutant that does not bind pRb and the E6F47R mutant that is less effective in inhibiting p53, respectively. Results confirmed the immunological activity of genetic formulations based on attenuated HPV16 oncogenes and showed that E5-based genetic immunization provided notable anti-tumor effects.
authors.affiliation: a Federal University of Pernambuco; Department of Genetics; Laboratory of Molecular Studies and Experimental Therapy (LEMTE); Pernambuco, Brazil.
authors.forename: Marcelo Nazário
authors.initials: MN
authors.lastname: Cordeiro
authors.forename: Francesca
authors.initials: F
authors.lastname: Paolini
authors.forename: Silvia
authors.initials: S
authors.lastname: Massa
authors.forename: Gianfranca
authors.initials: G
authors.lastname: Curzio
authors.forename: Elena
authors.initials: E
authors.lastname: Illiano
authors.forename: Anna Jéssica
authors.initials: AJ
authors.lastname: Duarte Silva
authors.forename: Rosella
authors.initials: R
authors.lastname: Franconi
authors.forename: Massimiliano
authors.initials: M
authors.lastname: Bissa
authors.forename: Carlo De Giuli
authors.initials: Cde G
authors.lastname: Morghen
authors.forename: Antonio Carlos
authors.initials: AC
authors.lastname: de Freitas
authors.forename: Aldo
authors.initials: A
authors.lastname: Venuti
mesh_terms: D000818:Animals; D045744:Cell Line, Tumor; D005260:Female; D052162:Human papillomavirus 16 / Q000235:genetics / Q000276:immunology*; D008810:Mice, Inbred C57BL; D009856:Oncogene Proteins, Viral / Q000235:genetics / Q000276:immunology*; D053918:Papillomavirus Vaccines / Q000008:administration & dosage / Q000235:genetics / Q000276:immunology*; D002583:Uterine Cervical Neoplasms / Q000517:prevention & control*; D019444:Vaccines, DNA / Q000008:administration & dosage / Q000235:genetics / Q000276:immunology*; D000086082:Viroporin Proteins
chemical_list: D009856:Oncogene Proteins, Viral; D053918:Papillomavirus Vaccines; D019444:Vaccines, DNA; C054859:oncogene protein E5, Human papillomavirus type 16; D000086082:Viroporin Proteins
keywords: C3 cell line; DNA vaccines; HPV16 E5; Human Papillomavirus; immunologic response