In vivo Antitumor Effect of an HPV-specific Promoter driving IL-12 Expression in an HPV 16-positive Murine Model of Cervical Cancer

Abstract

Human papillomavirus (HPV) is a DNA virus that infects epithelial cells and has been implicated in the development of cervical cancer. Few therapeutic strategies have been designed for the treatment of cervical intraepithelial neoplasia, a precursor of cervical cancer. In these early stages, the HPV E2 protein is the most important viral factor involved in viral gene expression and plays crucial roles during the vegetative viral cycle in epithelial cells. Papillomavirus E2 binds specifically to palindromic ACCN6GGT sequences, referred to as the E2 binding sites (E2BS), which are concentrated within the viral long control region, and which are responsible for regulation of the HPV protein's expression. Here, we consider E2BS as a candidate sequence to induce the expression of antiviral therapeutic genes selectively in HPV-infected cells expressing the E2 protein. This study focuses on the use of an HPV-specific promoter comprised of four E2BS to drive the expression of IL-12, leading to an antitumor effect in an HPV-positive murine tumor model. The therapeutic strategy was implemented via viral gene therapy using adenoviral vectors with recombinant E2 and IL-12 genes and E2BS-IL-12. We demonstrate that the HPV-specific promoter E2BS is functional in vitro and in vivo through transactivation of HPV E2 transcription factor.

Targeted Gene Delivery Therapies for Cervical Cancer

“…Vaccination, by non-infectious, virus-like particles, is a promising primary prevention strategy, but ineffective in pre-existing HPV infections. Currently, there are three HPV vaccines that provide protection against high-risk HPV types 16 and 18: the bivalent vaccine, the quadrivalent vaccine (HPV 6,11,16 and 18) and, finally, the nonavalent vaccine (HPV 6,11,16,18,31,33,45,52 and 58). HPV vaccine is recommended by the Advisory Committee on Immunization Practices at the age of 11 or 12 years, but can be given at up to 26 years of age.…”

“…Therefore, an E2-specific promotor could be used as a sequence to induce the expression of therapeutic genes selectively in HPV-infected cells, since this expression will only be induced in the presence of E2. In fact, Bermúdez-Morales et al used E2BS to construct an HPV-specific promoter to drive the expression of interleukin (IL)-12, using an adenoviral vector, and showed it to be functional in vitro and in vivo [33]. However, disruption of this sequence during the chromosomal integration of HPV occurs frequently, thus limiting the scope of the vector and therefore lowering the effectiveness of the treatment.…”

“…IL-12 is a cytokine with a central role in innate and adaptive immune responses [108], it is one of the most promising cytokines used in work on cervical cancer therapies. Its delivery using an adenoviral vector achieved inhibition of tumor growth and enhanced survival in a murine tumor model [33]. The treatment with the IL-12 gene in an experimental HPV16-positive mouse tumor model showed an antitumor effect promoting the cellular immune response via shift to a Th1-cytokine profile (activation of CD8+ T cells and Natural killer (NK) T cells that can eliminate tumor cells).…”

Effects of topical PaiTeLing in nude mice implanted with human condyloma acuminatum tissue infected with HPV 6, 31, and 81: comparison with imiquimod and interferon-α-2b

“…CA is caused by human papillomavirus (HPV) infection. Infection with high-risk HPV strains is closely associated cervical cancer as well as other type of cancer in the anogenital region [2, 3]. HPV16 is a major risk for the development of oropharyngeal squamous-cell-carcinoma [4, 5].…”