Herpes simplex virus VP22–human papillomavirus E2 fusion proteins produced in mammalian or bacterial cells enter mammalian cells and induce apoptotic cell death

Infection by high-risk HPV (human papillomavirus) is supposed to be the primary cause of cervical cancer. The HPV E2 protein (E2) is a DNA-binding protein that regulates viral gene expression and is required for efficient viral replication. Overexpression of the E2 protein in cervical cancer cells can induce growth arrest and/or apoptotic cell death, suggesting that E2 might be useful in the treatment of this disease. In the present study, we show that VP22 (herpes simplex virus VP22 protein) can be used to deliver E2 to target cells. VP22–E2 fusion proteins induce apoptosis in transiently transfected HPVtransformed cervical carcinoma cell lines. However, VP22–E2 fusion proteins do not kill COS-7 cells, probably because these cells constitutively express the simian-virus-40 T antigen and this protein sequesters the tumour suppressor protein p53. When COS-7 cells producing VP22–E2 are seeded into cultures of HPV-transformed cells, VP22–E2 enters the nonproducing cells and induces apoptosis. VP22–E2 proteins produced in bacterial cells can also enter cervical cancer cells and induce apoptosis in a dose-dependent manner. Our results suggest that local delivery of VP22–E2 fusion proteins could be used to treat cervical cancer and other HPV-associated diseases.