title: HPV 16 E5 oncoprotein is expressed in early stage carcinogenesis and can be a target of immunotherapy.
abstract: HPV16 persistent infection is a well-known condition that precedes human cancer development. High risk HPV E5 proteins cooperate with E6/E7 oncogenes to promote hyper-proliferation of infected cells leading to possible cancer progression. Thus, presence of E5 viral transcripts could be a key marker of active infection and, in turn, a target of immunotherapy. Purpose of the study is to detect E5 transcripts in clinical samples and to explore the activity of novel anti-HPV16 E5 DNA vaccines. HPV transcripts were detected by PCR with specific primers encompassing the splice-donor sites of E5 transcript. For E5-based immunotherapies, 2 E5-based versions of DNA vaccines carrying whole E5 gene or a synthetic multiepitope gene were improved by fusion to sequence of PVX coat protein. These vaccines were challenged with a new luminescent animal model based on C3-Luc cell line. E5 transcripts were detected in clinical samples of women with HPV positive low-grade SIL, demonstrating the validity of our test. In C3 pre-clinical mouse model, vaccine candidates were able to induce a strong cellular immunity as indicated by ELISPOT assays. In addition, E5-CP vaccines elicited strong anti-tumor effects as showed by decreased tumor growth monitored by animal imaging. The tumor growth inhibition was comparable to those obtained with anti-E7 DNA vaccines. In conclusion, detection of E5 transcripts in clinical samples indicates that E5 is a possible target of immunotherapy. Data from pre-clinical model demonstrate that E5 genetic immunization is feasible, efficacious and could be utilized in clinical trials.
authors.affiliation: a Regina Elena National Cancer Institute, HPV Unit , Rome , Italy.
authors.forename: Francesca
authors.initials: F
authors.lastname: Paolini
authors.affiliation: a Regina Elena National Cancer Institute, HPV Unit , Rome , Italy.
authors.forename: Gianfranca
authors.initials: G
authors.lastname: Curzio
authors.affiliation: b Federal University of Pernambuco , Department of Genetics, LEMTE , Pernambuco , Brazil.
authors.forename: Marcelo Nazario
authors.initials: MN
authors.lastname: Cordeiro
authors.affiliation: c ENEA, Italian National Agency for New Technologies, Energy and Sustainable Economic Development, C.R. Casaccia , Rome , Italy.
authors.forename: Silvia
authors.initials: S
authors.lastname: Massa
authors.affiliation: a Regina Elena National Cancer Institute, HPV Unit , Rome , Italy.
authors.forename: Luciano
authors.initials: L
authors.lastname: Mariani
authors.affiliation: d San Gallicano Dermatologic Institute , Rome , Italy.
authors.forename: Fulvia
authors.initials: F
authors.lastname: Pimpinelli
authors.affiliation: b Federal University of Pernambuco , Department of Genetics, LEMTE , Pernambuco , Brazil.
authors.forename: Antonio Carlos
authors.initials: AC
authors.lastname: de Freitas
authors.affiliation: c ENEA, Italian National Agency for New Technologies, Energy and Sustainable Economic Development, C.R. Casaccia , Rome , Italy.
authors.forename: Rosella
authors.initials: R
authors.lastname: Franconi
authors.affiliation: a Regina Elena National Cancer Institute, HPV Unit , Rome , Italy.
authors.forename: Aldo
authors.initials: A
authors.lastname: Venuti
mesh_terms: D000818:Animals; D058501:Enzyme-Linked Immunospot Assay; D005260:Female; D006801:Humans; D007111:Immunity, Cellular; D007167:Immunotherapy / Q000379:methods*; D008810:Mice, Inbred C57BL; D009856:Oncogene Proteins, Viral / Q000032:analysis / Q000096:biosynthesis*; D030361:Papillomavirus Infections / Q000150:complications*; D053918:Papillomavirus Vaccines / Q000008:administration & dosage*; D016896:Treatment Outcome; D002583:Uterine Cervical Neoplasms / Q000473:pathology* / Q000628:therapy*; D019444:Vaccines, DNA / Q000008:administration & dosage*; 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: E5; HPV; HPV transcripts; cancer; immunotherapy; therapeutic vaccine