Virus against virus: strategies for using adenovirus vectors in the treatment of HPV-induced cervical cancer

Abstract

Although most human papillomavirus (HPV) infections are harmless, persistent infection with high-risk types of HPV is known to be the leading cause of cervical cancer. Following the infection of the epithelium and integration into the host genome, the oncogenic proteins E6 and E7 disrupt cell cycle control by inducing p53 and retinoblastoma (Rb) degradation. Despite the FDA approval of prophylactic vaccines, there are still issues with cervical cancer treatment; thus, many therapeutic approaches have been developed to date. Due to strong immunogenicity, a high capacity for packaging foreign DNA, safety, and the ability to infect a myriad of cells, adenoviruses have drawn attention of researchers. Adenovirus vectors have been used for different purposes, including as oncolytic agents to kill cancer cells, carrier for RNA interference to block oncoproteins expression, vaccines for eliciting immune responses, especially in cytotoxic T lymphocytes (CTLs), and gene therapy vehicles for restoring p53 and Rb function.

Keywords: HPV Infection; HPV Oncoproteins; adenovirus; cervical Cancer; human Papillomavirus; vaccine.

Fig. 1

Carcinogenesis property of HPV E5 oncoprotein through enhancing proliferation signaling.

Fig. 2

The carcinogenesis properties of HPV oncoproteins through impairing apoptosis and enhancing progression of the cell cycle.

Fig. 3. Genome structure of adenovirus serotype 5 and different generations of adenovirus vectors.

The adenovirus genome encodes early (E) and late (L) genes in which the E1A protein, an immediate early protein, induces the expression of delayed early proteins, including E1B, E2A, E2B, E3, and E4. In first-generation adenovirus vectors, the E1 and E3 regions were deleted, and in the second generation, E1, E2, E3, and/or E4 were deleted. Helper-dependent adenovirus vectors only contain inverted terminal repeats (ITRs) and packaging signals. Oncolytic vectors are another class of adenovirus vectors. For example, Delta-24 vectors with a deletion in the E1A region replicate in and lyse tumor cells with a defect in the pRB pathway.

Fig. 4. Different strategies for using adenovirus vectors in the treatment of HPV-induced cervical cancer.

Oncolytic Ads infect tumor cells and lyse them, leading to cell disruption and the release of molecules that induce immune responses against cancer. Ads have also been used to deliver tumor suppressor genes, such as p53 and Rb, to restore their normal function in cancer cells. E6- and E7-expressing Ads can enhance immune responses, especially CTLs, against these oncoproteins. The incorporation of antisense RNAs and microRNAs (miRNAs) against oncoproteins in Ad vectors and introduction into cervical cancer cells can block the expression of the HPV oncoproteins E6 and E7.