Human papillomavirus infection (HPV) is the most common viral infection which is causes cancer or genital warts (1). Based on the location of HPV lesions, various types of cancer such as cervix, anal, vagina, throat, vulva, penis, and breast could be developed. More than 200 types of HPV have been identified, of which 40 types are belong to genital areas (2). HPV types are divided into high and low risk groups. Low-risk types such as 6 and 11 lead to 99% of genital warts and laryngeal papillomatosis; while 70% of cancers are related to high-risk types, such as 16, 18 (3).
The HPV virus belongs to papillomaviridae which is encoding two structural (L1, L2) and nonstructural protein (E1, E2, E4, E5, E6, and E7). E6 oncoprotein, is a key factor in tumor progression, act as P53 suppressor through binding to its C-terminal region. This protein is a transcription factor that controls cell proliferation by preventing the G1 to S phase (4). E7 oncoprotein is a small nuclear protein with no enzymatic activity. This protein is bound to the hypophosphorylated retinoblastoma protein (PRb); in this situation, the cell cycle moves to the S phase. Then, DNA synthesis and cell proliferation takes place (5). Regarding the importance of E6 and E7 in induction and maintenance of cellular transformation, these early genes have been reported as suitable targets for designing anti-tumor vaccines and controlling HPV infection (6) (7).
In particular, dendritic cells (DCs) are one of the most important APCs and play an important role in immune response against viral infections (8). DCs function, macrophage-inflammatory protein-1α (MIP)-1α, MIP-1β and RANTES genes activation is associated with the high expression of MHC-I, CD40, CD80, CD86 and production of IL-1β, TNF-α, IL-12, IL-15 cytokines (9).The serious problem associated with protein and peptide vaccines is that the structure of peptide antigen could be altered and do not elicit strong immune response (10). On the other hand, these proteins enter the cells via an endocytic and activate the MHC-II presentation pathway; so they are unable to induce strong cytotoxic CD8 + T cell response (11). Today, there are several ways are used to transfer protein in to the cell. Cell penetrate peptides (CPP) such as Tat, Pep-1, LAL, Cady-2, P28, hpp10 peptide with potential interact to proteins and peptides are able to transfer different types of cargo (protein and peptides) into the cell (12). It is suggested that a novel delivery system, Tat protein (small and soluble protein with 86–101 amino acids), with high efficiency and low cytotoxicity is able to transport peptides and proteins into cytoplasm via the plasma membrane and it is well-suited for the delivery of antigenic peptide to MHC-1 presentation pathway (13). Study shows that vaccination with Tat protein provides protection against viral replication, which can induce Th1 immune response as well as the Cytotoxic T lymphocytes (CTLs) response (14).
Prophylactic and therapeutic vaccination is highly effective in control and prevention of HPV infection. Two prophylactic HPV vaccines (Gardasil, Cervarix) are composed of L1 virus-like particles (VLPs) and they are used for the prevention of HPV infection and cervical cancer (15). In the current study, we designed a novel therapeutic vaccine based on E7 protein of HPV16,18,6,11 and Tat peptide against cervical cancer. HPV16, 18, 6, 11 E7- Tat (47–57) protein was assessed in vitro and examined for induction of E7-specific humoral and cell-mediated immune responses in C57BL/6 mice model. This study shows how a novel fusion protein induce therapeutic efficacy against HPV16-positive tumor cells in mice.