The Not-So-Good, the Bad and the Ugly: HPV E5, E6 and E7 Oncoproteins in the Orchestration of Carcinogenesis

Infection with HPV starts with the access of the viral particles to basal cells in the epidermis, potentially via microtraumas to the skin. The basal cells are able to keep away these pathogens in normal circumstances through a robust immune response from the host, as HPV infections are, in general, cleared within 2 to 3 weeks. However, the rare instances of persistent infection and/or in cases where the host immune system is compromised are major risk factors for the development of lesions potentially leading to malignancy. Evolutionarily, obligatory pathogens such as HPVs would not be expected to risk exposing the host to lethal cancer, as this would entail challenging their own life cycle, but infection with these viruses is highly correlated with cancer and malignancy—as in cancer of the cervix, which is almost always associated with these viruses. Despite this key associative cause and the availability of very effective vaccines against these viruses, therapeutic interventions against HPV-induced cancers are still a challenge, indicating the need for focused translational research. In this review, we will consider the key roles that the viral proteins play in driving the host cells to carcinogenesis, mainly focusing on events orchestrated by early proteins E5, E6 and E7—the not-so-good, the bad and the ugly—and discuss and summarize the major events that lead to these viruses mechanistically corrupting cellular homeostasis, giving rise to cancer and malignancy.